start-ver=1.4
cd-journal=joma
no-vol=44
cd-vols=
no-issue=8-9
article-no=
start-page=695
end-page=707
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2023
dt-pub=20230817
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Dual roles of cellular communication network factor 6 (CCN6) in the invasion and metastasis of oral cancer cells to bone via binding to BMP2 and RANKL
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=The acquisition of motility via epithelial–mesenchymal transition (EMT) and osteoclast induction are essential for the invasion and metastasis of oral squamous cell carcinoma (OSCC) to bone. However, the molecule suppressing both EMT and osteoclastogenesis is still unknown. In this study, we found that cellular communication network factor 6 (CCN6) was less produced in a human OSCC cell line, HSC-3 with mesenchymal phenotype, than in HSC-2 cells without it. Notably, CCN6 interacted with bone morphogenetic protein 2 (BMP2) and suppressed the cell migration of HSC-3 cells stimulated by BMP2. Moreover, knockdown of CCN6 in HSC-2 cells led to the promotion of EMT and enhanced the effect of transforming growth factor-β (TGF-β) on the promotion of EMT. Furthermore, CCN6 combined with BMP2 suppressed EMT. These results suggest that CCN6 strongly suppresses EMT in cooperation with BMP2 and TGF-β. Interestingly, CCN6 combined with BMP2 increased the gene expression of receptor activator of nuclear factor-κB ligand (RANKL) in HSC-2 and HSC-3 cells. Additionally, CCN6 interacted with RANKL, and CCN6 combined with RANKL suppressed RANKL-induced osteoclast formation. In metastatic lesions, increasing BMP2 due to the bone destruction led to interference with binding of CCN6 to RANKL, which results in the promotion of bone metastasis of OSCC cells due to continuous osteoclastogenesis. These findings suggest that CCN6 plays dual roles in the suppression of EMT and in the promotion of bone destruction of OSCC in primary and metastatic lesions, respectively, through cooperation with BMP2 and interference with RANKL.
en-copyright=
kn-copyright=

en-aut-name=HochiHiroaki
en-aut-sei=Hochi
en-aut-mei=Hiroaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=KubotaSatoshi
en-aut-sei=Kubota
en-aut-mei=Satoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=NishidaTakashi
en-aut-sei=Nishida
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

affil-num=1
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=

affil-num=2
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=

affil-num=3
en-affil=Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Faculty of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=

affil-num=4
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
kn-affil=
END

start-ver=1.4
cd-journal=joma
no-vol=24
cd-vols=
no-issue=24
article-no=
start-page=17294
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2023
dt-pub=20231209
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Positive Regulation of S-Adenosylmethionine on Chondrocytic Differentiation via Stimulation of Polyamine Production and the Gene Expression of Chondrogenic Differentiation Factors
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=S-adenosylmethionine (SAM) is considered to be a useful therapeutic agent for degenerative cartilage diseases, although its mechanism is not clear. We previously found that polyamines stimulate the expression of differentiated phenotype of chondrocytes. We also found that the cellular communication network factor 2 (CCN2) played a huge role in the proliferation and differentiation of chondrocytes. Therefore, we hypothesized that polyamines and CCN2 could be involved in the chondroprotective action of SAM. In this study, we initially found that exogenous SAM enhanced proteoglycan production but not cell proliferation in human chondrocyte-like cell line-2/8 (HCS-2/8) cells. Moreover, SAM enhanced gene expression of cartilage-specific matrix (aggrecan and type II collagen), Sry-Box transcription factor 9 (SOX9), CCN2, and chondroitin sulfate biosynthetic enzymes. The blockade of the methionine adenosyltransferase 2A (MAT2A) enzyme catalyzing intracellular SAM biosynthesis restrained the effect of SAM on chondrocytes. The polyamine level in chondrocytes was higher in SAM-treated culture than control culture. Additionally, Alcian blue staining and RT-qPCR indicated that the effects of SAM on the production and gene expression of aggrecan were reduced by the inhibition of polyamine synthesis. These results suggest that the stimulation of polyamine synthesis and gene expression of chondrogenic differentiation factors, such as CCN2, account for the mechanism underlying the action of SAM on chondrocytes.
en-copyright=
kn-copyright=

en-aut-name=HoangLoc Dinh
en-aut-sei=Hoang
en-aut-mei=Loc Dinh
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=AoyamaEriko
en-aut-sei=Aoyama
en-aut-mei=Eriko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=HiasaMiki
en-aut-sei=Hiasa
en-aut-mei=Miki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=OmoteHiroshi
en-aut-sei=Omote
en-aut-mei=Hiroshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=KubotaSatoshi
en-aut-sei=Kubota
en-aut-mei=Satoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=KubokiTakuo
en-aut-sei=Kuboki
en-aut-mei=Takuo
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

affil-num=1
en-affil=Advanced Research Center for Oral and Craniofacial Sciences (ARCOCS), Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=2
en-affil=Advanced Research Center for Oral and Craniofacial Sciences (ARCOCS), Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=3
en-affil=Laboratory of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=4
en-affil=Laboratory of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=5
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=6
en-affil=Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=7
en-affil=Advanced Research Center for Oral and Craniofacial Sciences (ARCOCS), Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=
en-keyword=S-adenosylmethionine
kn-keyword=S-adenosylmethionine
en-keyword=chondrocyte differentiation
kn-keyword=chondrocyte differentiation
en-keyword=CCN2
kn-keyword=CCN2
en-keyword=polyamine
kn-keyword=polyamine
en-keyword=ODC
kn-keyword=ODC
en-keyword=gene expression
kn-keyword=gene expression
END

start-ver=1.4
cd-journal=joma
no-vol=17
cd-vols=
no-issue=4
article-no=
start-page=1501
end-page=1515
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2023
dt-pub=20230911
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Expression and function of CCN2-derived circRNAs in chondrocytes
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Cellular communication network factor 2 (CCN2) molecules promote endochondral ossification and articular cartilage regeneration, and circular RNAs (circRNAs), which arise from various genes and regulate gene expression by adsorbing miRNAs, are known to be synthesized from CCN2 in human vascular endothelial cells and other types of cells. However, in chondrocytes, not only the function but also the presence of CCN2-derived circRNA remains completely unknown. In the present study, we investigated the expression and function of CCN2-derived circRNAs in chondrocytes. Amplicons smaller than those from known CCN2-derived circRNAs were observed using RT-PCR analysis that could specifically amplify CCN2-derived circRNAs in human chondrocytic HCS-2/8 cells. The nucleotide sequences of the PCR products indicated novel circRNAs in the HCS-2/8 cells that were different from known CCN2-derived circRNAs. Moreover, the expression of several Ccn2-derived circRNAs in murine chondroblastic ATDC5 cells was confirmed and observed to change alongside chondrocytic differentiation. Next, one of these circRNAs was knocked down in HCS-2/8 cells to investigate the function of the human CCN2-derived circRNA. As a result, CCN2-derived circRNA knockdown significantly reduced the expression of aggrecan mRNA and proteoglycan synthesis. Our data suggest that CCN2-derived circRNAs are expressed in chondrocytes and play a role in chondrogenic differentiation.
en-copyright=
kn-copyright=

en-aut-name=KatoSoma
en-aut-sei=Kato
en-aut-mei=Soma
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=KawataKazumi
en-aut-sei=Kawata
en-aut-mei=Kazumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=NishidaTakashi
en-aut-sei=Nishida
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=MizukawaTomomi
en-aut-sei=Mizukawa
en-aut-mei=Tomomi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=IidaSeiji
en-aut-sei=Iida
en-aut-mei=Seiji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=KubotaSatoshi
en-aut-sei=Kubota
en-aut-mei=Satoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

affil-num=1
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=2
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=3
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=4
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=5
en-affil=Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=6
en-affil=Department of Oral Maxillofacial Reconstructive Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=7
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=
en-keyword=Chondrocyte
kn-keyword=Chondrocyte
en-keyword=CCN2
kn-keyword=CCN2
en-keyword=Circular RNA
kn-keyword=Circular RNA
en-keyword=ACAN
kn-keyword=ACAN
en-keyword=Chondrocytic differentiation
kn-keyword=Chondrocytic differentiation
END

start-ver=1.4
cd-journal=joma
no-vol=17
cd-vols=
no-issue=2
article-no=
start-page=353
end-page=359
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2023
dt-pub=20230206
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Do not overwork: cellular communication network factor 3 for life in cartilage
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Cellular communication network factor (CCN) 3, which is one of the founding members of the CCN family, displays diverse functions. However, this protein generally represses the proliferation of a variety of cells. Along with skeletal development, CCN3 is produced in cartilaginous anlagen, growth plate cartilage and epiphysial cartilage. Interestingly, CCN3 is drastically induced in the growth plates of mice lacking CCN2, which promotes endochondral ossification. Notably, chondrocytes in these mutant mice with elevated CCN3 production also suffer from impaired glycolysis and energy metabolism, suggesting a critical role of CCN3 in cartilage metabolism. Recently, CCN3 was found to be strongly induced by impaired glycolysis, and in our study, we located an enhancer that mediated CCN3 regulation via starvation. Subsequent investigations specified regulatory factor binding to the X-box 1 (RFX1) as a transcription factor mediating this CCN3 regulation. Impaired glycolysis is a serious problem, resulting in an energy shortage in cartilage without vasculature. CCN3 produced under such starved conditions restricts energy consumption by repressing cell proliferation, leading chondrocytes to quiescence and survival. This CCN3 regulatory system is indicated to play an important role in articular cartilage maintenance, as well as in skeletal development. Furthermore, CCN3 continues to regulate cartilage metabolism even during the aging process, probably utilizing this regulatory system. Altogether, CCN3 seems to prevent "overwork" by chondrocytes to ensure their sustainable life in cartilage by sensing energy metabolism. Similar roles are suspected to exist in relation to systemic metabolism, since CCN3 is found in the bloodstream.
en-copyright=
kn-copyright=

en-aut-name=KubotaSatoshi
en-aut-sei=Kubota
en-aut-mei=Satoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=KawakiHarumi
en-aut-sei=Kawaki
en-aut-mei=Harumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=PerbalBernard
en-aut-sei=Perbal
en-aut-mei=Bernard
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=KawataKazumi
en-aut-sei=Kawata
en-aut-mei=Kazumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=HattoriTakako
en-aut-sei=Hattori
en-aut-mei=Takako
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=NishidaTakashi
en-aut-sei=Nishida
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

affil-num=1
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=2
en-affil=Department of Oral Biochemistry, Asahi University School of Dentistry
kn-affil=

affil-num=3
en-affil=International CCN Society
kn-affil=

affil-num=4
en-affil=Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences/Dental School
kn-affil=

affil-num=5
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=6
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=7
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=
en-keyword=CCN family
kn-keyword=CCN family
en-keyword=CCN3
kn-keyword=CCN3
en-keyword=cartilage
kn-keyword=cartilage
en-keyword=chondrocytes
kn-keyword=chondrocytes
en-keyword=energy metabolism
kn-keyword=energy metabolism
END

start-ver=1.4
cd-journal=joma
no-vol=23
cd-vols=
no-issue=23
article-no=
start-page=15311
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2022
dt-pub=20221204
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Elevated Expression of CCN3 in Articular Cartilage Induces Osteoarthritis in Hip Joints Irrespective of Age and Weight Bearing
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Osteoarthritis (OA) occurs not only in the knee but also in peripheral joints throughout the whole body. Previously, we have shown that the expression of cellular communication network factor 3 (CCN3), a matricellular protein, increases with age in knee articular cartilage, and the misexpression of CCN3 in cartilage induces senescence-associated secretory phenotype (SASP) factors, indicating that CCN3 promotes cartilage senescence. Here, we investigated the correlation between CCN3 expression and OA degenerative changes, principally in human femoral head cartilage. Human femoral heads obtained from patients who received total hip arthroplasty were categorized into OA and femoral neck fracture (normal) groups without significant age differences. Gene expression analysis of RNA obtained from femoral head cartilage revealed that CCN3 and MMP-13 expression in the non-weight-bearing part was significantly higher in the OA group than in the normal group, whereas the weight-bearing OA parts and normal cartilage showed no significant differences in the expression of these genes. The expression of COL10A1, however, was significantly higher in weight-bearing OA parts compared with normal weight-bearing parts, and was also higher in weight-bearing parts compared with non-weight-bearing parts in the OA group. In contrast, OA primary chondrocytes from weight-bearing parts showed higher expression of CCN3, p16, ADAMTS4, and IL-1 beta than chondrocytes from the corresponding normal group, and higher ADAMTS4 and IL-1 beta in the non-weight-bearing part compared with the corresponding normal group. Acan expression was significantly lower in the non-weight-bearing group in OA primary chondrocytes than in the corresponding normal chondrocytes. The expression level of CCN3 did not show significant differences between the weight-bearing part and non-weight-bearing part in both OA and normal primary chondrocytes. Immunohistochemical analysis showed accumulated CCN3 and aggrecan neoepitope staining in both the weight-bearing part and non-weight-bearing part in the OA group compared with the normal group. The CCN3 expression level in cartilage had a positive correlation with the Mankin score. X-ray analysis of cartilage-specific CCN3 overexpression mice (Tg) revealed deformation of the femoral and humeral head in the early stage, and immunohistochemical analysis showed accumulated aggrecan neoepitope staining as well as CCN3 staining and the roughening of the joint surface in Tg femoral and humeral heads. Primary chondrocytes from the Tg femoral head showed enhanced expression of Ccn3, Adamts5, p16, Il-6, and Tnf alpha, and decreased expression of Col2a1 and -an. These findings indicate a correlation between OA degenerative changes and the expression of CCN3, irrespective of age and mechanical loading. Furthermore, the Mankin score indicates that the expression level of Ccn3 correlates with the progression of OA.
en-copyright=
kn-copyright=

en-aut-name=HiroseKazuki
en-aut-sei=Hirose
en-aut-mei=Kazuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=KuwaharaMiho
en-aut-sei=Kuwahara
en-aut-mei=Miho
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=NakataEiji
en-aut-sei=Nakata
en-aut-mei=Eiji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=TetsunagaTomonori
en-aut-sei=Tetsunaga
en-aut-mei=Tomonori
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=YamadaKazuki
en-aut-sei=Yamada
en-aut-mei=Kazuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=SaigaKenta
en-aut-sei=Saiga
en-aut-mei=Kenta
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=OzakiToshifumi
en-aut-sei=Ozaki
en-aut-mei=Toshifumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=KubotaSatoshi
en-aut-sei=Kubota
en-aut-mei=Satoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=HattoriTakako
en-aut-sei=Hattori
en-aut-mei=Takako
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

affil-num=1
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=2
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=3
en-affil=Department of Orthopaedic Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=4
en-affil=Department of Orthopaedic Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=5
en-affil=Department of Orthopaedic Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=6
en-affil=Department of Orthopaedic Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=7
en-affil=Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School/Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=8
en-affil=Department of Orthopaedic Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=9
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=10
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=
en-keyword=hip osteoarthritis
kn-keyword=hip osteoarthritis
en-keyword=cartilage
kn-keyword=cartilage
en-keyword=cellular communication network factor 3 (CCN3)
kn-keyword=cellular communication network factor 3 (CCN3)
en-keyword=senescence-associatedsecretory phenotype (SASP)
kn-keyword=senescence-associatedsecretory phenotype (SASP)
en-keyword=p16
kn-keyword=p16
en-keyword=ADAMTA4/5
kn-keyword=ADAMTA4/5
en-keyword=IL-6
kn-keyword=IL-6
en-keyword=TNFa
kn-keyword=TNFa
en-keyword=aging
kn-keyword=aging
en-keyword=Mankinscore
kn-keyword=Mankinscore
en-keyword=weight-bearing
kn-keyword=weight-bearing
en-keyword=non-weight-bearing
kn-keyword=non-weight-bearing
END

start-ver=1.4
cd-journal=joma
no-vol=23
cd-vols=
no-issue=15
article-no=
start-page=8592
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2022
dt-pub=20220802
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Fibroblast Growth Factors and Cellular Communication Network Factors: Intimate Interplay by the Founding Members in Cartilage
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Fibroblast growth factors (FGFs) constitute a large family of signaling molecules that act in an autocrine/paracrine, endocrine, or intracrine manner, whereas the cellular communication network factors (CCN) family is composed of six members that manipulate extracellular signaling networks. FGFs and CCNs are structurally and functionally distinct, except for the common characteristics as matricellular proteins. Both play significant roles in the development of a variety of tissues and organs, including the skeletal system. In vertebrates, most of the skeletal parts are formed and grow through a process designated endochondral ossification, in which chondrocytes play the central role. The growth plate cartilage is the place where endochondral ossification occurs, and articular cartilage is left to support the locomotive function of joints. Several FGFs, including FGF-2, one of the founding members of this family, and all of the CCNs represented by CCN2, which is required for proper skeletal development, can be found therein. Research over a decade has revealed direct binding of CCN2 to FGFs and FGF receptors (FGFRs), which occasionally affect the biological outcome via FGF signaling. Moreover, a recent study uncovered an integrated regulation of FGF and CCN genes by FGF signaling. In this review, after a brief introduction of these two families, molecular and genetic interactions between CCN and FGF family members in cartilage, and their biological effects, are summarized. The molecular interplay represents the mutual involvement of the other in their molecular functions, leading to collaboration between CCN2 and FGFs during skeletal development.
en-copyright=
kn-copyright=

en-aut-name=KubotaSatoshi
en-aut-sei=Kubota
en-aut-mei=Satoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=AoyamaEriko
en-aut-sei=Aoyama
en-aut-mei=Eriko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=NishidaTakashi
en-aut-sei=Nishida
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

affil-num=1
en-affil=Department of Biochemistry and Molecular Dentistry, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=2
en-affil=Advanced Research Center for Oral and Craniofacial Sciences, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=3
en-affil=Advanced Research Center for Oral and Craniofacial Sciences, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=4
en-affil=Department of Biochemistry and Molecular Dentistry, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=
en-keyword=fibroblast growth factor
kn-keyword=fibroblast growth factor
en-keyword=cellular communication network factor
kn-keyword=cellular communication network factor
en-keyword=cartilage
kn-keyword=cartilage
en-keyword=skeletal development
kn-keyword=skeletal development
en-keyword=CCN2
kn-keyword=CCN2
END

start-ver=1.4
cd-journal=joma
no-vol=22
cd-vols=
no-issue=17
article-no=
start-page=9204
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2021
dt-pub=20210825
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Effect of Angiotensin II on Chondrocyte Degeneration and Protection via Differential Usage of Angiotensin II Receptors
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=The renin-angiotensin system (RAS) controls not only systemic functions, such as blood pressure, but also local tissue-specific events. Previous studies have shown that angiotensin II receptor type 1 (AT(1)R) and type 2 (AT(2)R), two RAS components, are expressed in chondrocytes. However, the angiotensin II (ANG II) effects exerted through these receptors on chondrocyte metabolism are not fully understood. In this study, we investigated the effects of ANG II and AT(1)R blockade on chondrocyte proliferation and differentiation. Firstly, we observed that ANG II significantly suppressed cell proliferation and glycosaminoglycan content in rat chondrocytic RCS cells. Additionally, ANG II decreased CCN2, which is an anabolic factor for chondrocytes, via increased MMP9. In Agtr1a-deficient RCS cells generated by the CRISPR-Cas9 system, Ccn2 and Aggrecan (Acan) expression increased. Losartan, an AT(1)R antagonist, blocked the ANG II-induced decrease in CCN2 production and Acan expression in RCS cells. These findings suggest that AT(1)R blockade reduces ANG II-induced chondrocyte degeneration. Interestingly, AT(1)R-positive cells, which were localized on the surface of the articular cartilage of 7-month-old mice expanded throughout the articular cartilage with aging. These findings suggest that ANG II regulates age-related cartilage degeneration through the ANG II-AT(1)R axis.
en-copyright=
kn-copyright=

en-aut-name=NishidaTakashi
en-aut-sei=Nishida
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=AkashiSho
en-aut-sei=Akashi
en-aut-mei=Sho
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=KubotaSatoshi
en-aut-sei=Kubota
en-aut-mei=Satoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

affil-num=1
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=2
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=3
en-affil=Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=4
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=岡山大学大学院医歯薬学総合研究科
en-keyword=angiotensin II
kn-keyword=angiotensin II
en-keyword=cellular communication network factor 2 (CCN2)
kn-keyword=cellular communication network factor 2 (CCN2)
en-keyword=renin-angiotensin system (RAS)
kn-keyword=renin-angiotensin system (RAS)
en-keyword=losartan
kn-keyword=losartan
en-keyword=angiotensin II type I receptor (AT(1)R)
kn-keyword=angiotensin II type I receptor (AT(1)R)
END

start-ver=1.4
cd-journal=joma
no-vol=
cd-vols=
no-issue=
article-no=
start-page=
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2021
dt-pub=20210303
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=RFX1‐mediated CCN3 induction that may support chondrocyte survival under starved conditions
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Cellular communication network factor (CCN) family members are multifunctional matricellular proteins that manipulate and integrate extracellular signals. In our previous studies investigating the role of CCN family members in cellular metabolism, we found three members that might be under the regulation of energy metabolism. In this study, we confirmed that CCN2 and CCN3 are the only members that are tightly regulated by glycolysis in human chondrocytic cells. Interestingly, CCN3 was induced under a variety of impaired glycolytic conditions. This CCN3 induction was also observed in two breast cancer cell lines with a distinct phenotype, suggesting a basic role of CCN3 in cellular metabolism. Reporter gene assays indicated a transcriptional regulation mediated by an enhancer in the proximal promoter region. As a result of analyses in silico, we specified regulatory factor binding to the X‐box 1 (RFX1) as a candidate that mediated the transcriptional activation by impaired glycolysis. Indeed, the inhibition of glycolysis induced the expression of RFX1, and RFX1 silencing nullified the CCN3 induction by impaired glycolysis. Subsequent experiments with an anti‐CCN3 antibody indicated that CCN3 supported the survival of chondrocytes under impaired glycolysis. Consistent with these findings in vitro, abundant CCN3 production by chondrocytes in the deep zones of developing epiphysial cartilage, which are located far away from the synovial fluid, was confirmed in vivo. Our present study uncovered that RFX1 is the mediator that enables CCN3 induction upon cellular starvation, which may eventually assist chondrocytes in retaining their viability, even when there is an energy supply shortage.
en-copyright=
kn-copyright=

en-aut-name=MizukawaTomomi
en-aut-sei=Mizukawa
en-aut-mei=Tomomi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=NishidaTakashi
en-aut-sei=Nishida
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=AkashiSho
en-aut-sei=Akashi
en-aut-mei=Sho
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=KawataKazumi
en-aut-sei=Kawata
en-aut-mei=Kazumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=KikuchiSumire
en-aut-sei=Kikuchi
en-aut-mei=Sumire
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=KawakiHarumi
en-aut-sei=Kawaki
en-aut-mei=Harumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=KamiokaHiroshi
en-aut-sei=Kamioka
en-aut-mei=Hiroshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=KubotaSatoshi
en-aut-sei=Kubota
en-aut-mei=Satoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

affil-num=1
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=2
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=3
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama Japan
kn-affil=

affil-num=4
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama Japan
kn-affil=

affil-num=5
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama Japan
kn-affil=

affil-num=6
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama Japan
kn-affil=

affil-num=7
en-affil=Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School
kn-affil=

affil-num=8
en-affil=Department of Orthodontics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=9
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=
END

start-ver=1.4
cd-journal=joma
no-vol=15
cd-vols=
no-issue=1
article-no=
start-page=81
end-page=91
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2021
dt-pub=202114
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Bipartite regulation of cellular communication network factor 2 and fibroblast growth factor 1 genes by fibroblast growth factor 1 through histone deacetylase 1 and fork head box protein A1
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract= Fibroblast growth factor 1 (FGF-1) is the first FGF family member, and it induces proliferation of fibroblasts and other types of the cells. However, recent studies are uncovering unexpected functions of this molecule. Our previous study redefined this growth factor as a catabolic molecule produced in cartilage upon metabolic insult. Indeed, FGF-1 was found to repress the gene expression of cellular communication network factor 2 (CCN2), which protects and regenerates cartilage, amplifying its own production through positive feedback regulation. In the present study, we investigated the molecular mechanism of this bipartite CCN2 repression and FGF1 activation by FGF-1 in chondrocytes. Repression of CCN2 and induction of FGF1 in human chondrocytic cells were both partly abolished by valproic acid, an inhibitor of histone deacetylase 1 (HDAC1), indicating the involvement of chromatin remodeling by histone acetylation in this system. In contrast, RNA degradation analysis suggested no contribution of post-transcriptional regulation of the mRNA stability to the effects conferred by FGF-1. Suspecting a regulation by a specific transcription factor, we next sought a candidate in silico from a large dataset. As a result, we found fork head box protein A1 (FOXA1) as the transcription factor that bound to both CCN2 and FGF1 loci. Functional analysis demonstrated that FOXA1 silencing significantly attenuated the CCN2 repression and FGF1 induction caused by FGF1. These findings collectively indicate that the bipartite regulation by FGF-1 is enabled by the combination of chromatin remodeling by HDACs and transcriptional modulation by FOXA1 with unknown transcriptional coactivators of opposite functionalities.
en-copyright=
kn-copyright=

en-aut-name=ElseoudiAbdellatif
en-aut-sei=Elseoudi
en-aut-mei=Abdellatif
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=NishidaTakashi
en-aut-sei=Nishida
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=MizukawaTomomi
en-aut-sei=Mizukawa
en-aut-mei=Tomomi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=HattoriTakako
en-aut-sei=Hattori
en-aut-mei=Takako
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=KawataKazumi
en-aut-sei=Kawata
en-aut-mei=Kazumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=TahaEman A.
en-aut-sei=Taha
en-aut-mei=Eman A.
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=KubotaSatoshi
en-aut-sei=Kubota
en-aut-mei=Satoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

affil-num=1
en-affil=Department of Biochemistry and Molecular Dentistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=2
en-affil=Department of Biochemistry and Molecular Dentistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=3
en-affil=Department of Biochemistry and Molecular Dentistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=4
en-affil=Department of Biochemistry and Molecular Dentistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=5
en-affil=Department of Biochemistry and Molecular Dentistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=6
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=7
en-affil=Advanced Research Center for Oral and Craniofacial Sciences, Dental School, Okayama University
kn-affil=

affil-num=8
en-affil=Department of Biochemistry and Molecular Dentistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=
en-keyword=FGF-1
kn-keyword=FGF-1
en-keyword=CCN2
kn-keyword=CCN2
en-keyword=Osteoarthritis
kn-keyword=Osteoarthritis
en-keyword=Chondrocytes
kn-keyword=Chondrocytes
en-keyword=Cartilage 
kn-keyword=Cartilage 
END

start-ver=1.4
cd-journal=joma
no-vol=9
cd-vols=
no-issue=1
article-no=
start-page=1769373
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2020
dt-pub=20200531
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Triple knockdown of CDC37, HSP90‐alpha and HSP90‐beta diminishes extracellular vesicles‐driven malignancy events and macrophage M2 polarization in oral cancer
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Evidence has been accumulating to indicate that extracellular vesicles (EVs), including exosomes, released by cancer cells can foster tumour progression. The molecular chaperones – CDC37, HSP90α and HSP90β play key roles in cancer progression including epithelial‐mesenchymal transition (EMT), although their contribution to EVs‐mediated cell–cell communication in tumour microenvironment has not been thoroughly examined. Here we show that triple depletion of the chaperone trio attenuates numerous cancer malignancy events exerted through EV release. Metastatic oral cancer‐derived EVs (MEV) were enriched with HSP90α HSP90β and cancer‐initiating cell marker CD326/EpCAM. Depletion of these chaperones individually induced compensatory increases in the other chaperones, whereas triple siRNA targeting of these molecules markedly diminished the levels of the chaperone trio and attenuated EMT. MEV were potent agents in initiating EMT in normal epithelial cells, a process that was attenuated by the triple chaperone depletion. The migration, invasion, and in vitro tumour initiation of oral cancer cells were significantly promoted by MEV, while triple depletion of CDC37/HSP90α/β reversed these MEV‐driven malignancy events. In metastatic oral cancer patient‐derived tumours, HSP90β was significantly accumulated in infiltrating tumour‐associated macrophages (TAM) as compared to lower grade oral cancer cases. HSP90‐enriched MEV‐induced TAM polarization to an M2 phenotype, a transition known to support cancer progression, whereas the triple chaperone depletion attenuated this effect. Mechanistically, the triple chaperone depletion in metastatic oral cancer cells effectively reduced MEV transmission into macrophages. Hence, siRNA‐mediated knockdown of the chaperone trio (CDC37/HSP90α/HSP90β) could potentially be a novel therapeutic strategy to attenuate several EV‐driven malignancy events in the tumour microenvironment.
en-copyright=
kn-copyright=

en-aut-name=OnoKisho
en-aut-sei=Ono
en-aut-mei=Kisho
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=Sogawa Chiharu
en-aut-sei=Sogawa
en-aut-mei= Chiharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=KawaiHotaka
en-aut-sei=Kawai
en-aut-mei=Hotaka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=Manh Tien Tran
en-aut-sei=Manh Tien Tran
en-aut-mei=
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=TahaEman A.
en-aut-sei=Taha
en-aut-mei=Eman A.
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=LuYanyin
en-aut-sei=Lu
en-aut-mei=Yanyin
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=May Wathone Oo
en-aut-sei=May Wathone Oo
en-aut-mei=
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=OkushaYuka
en-aut-sei=Okusha
en-aut-mei=Yuka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=OkamuraHirohiko
en-aut-sei=Okamura
en-aut-mei=Hirohiko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=IbaragiSoichiro
en-aut-sei=Ibaragi
en-aut-mei=Soichiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=KozakiKen-Ichi
en-aut-sei=Kozaki
en-aut-mei=Ken-Ichi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

en-aut-name=NagatsukaHitoshi
en-aut-sei=Nagatsuka
en-aut-mei=Hitoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=13
ORCID=

en-aut-name=SasakiAkira
en-aut-sei=Sasaki
en-aut-mei=Akira
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=14
ORCID=

en-aut-name=OkamotoKuniaki
en-aut-sei=Okamoto
en-aut-mei=Kuniaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=15
ORCID=

en-aut-name=CalderwoodStuart K.
en-aut-sei=Calderwood
en-aut-mei=Stuart K.
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=16
ORCID=

en-aut-name=EguchiTakanori
en-aut-sei=Eguchi
en-aut-mei=Takanori
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=17
ORCID=

affil-num=1
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=2
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=3
en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=4
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=5
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=6
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=7
en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=8
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=9
en-affil=Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=10
en-affil=Department of Oral and Maxillofacial Surgery, Okayama University Hospital
kn-affil=

affil-num=11
en-affil=Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=12
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=13
en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=14
en-affil=Department of Oral and Maxillofacial Surgery, Okayama University Hospital
kn-affil=

affil-num=15
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=16
en-affil=Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School
kn-affil=

affil-num=17
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=
en-keyword=Extracellular vesicles
kn-keyword=Extracellular vesicles
en-keyword=epithelial‐mesenchymal transition
kn-keyword=epithelial‐mesenchymal transition
en-keyword=tumour‐associated macrophage
kn-keyword=tumour‐associated macrophage
en-keyword=CDC37
kn-keyword=CDC37
en-keyword=HSP90
kn-keyword=HSP90
en-keyword=tetraspanin
kn-keyword=tetraspanin
en-keyword=oral cancer
kn-keyword=oral cancer
END

start-ver=1.4
cd-journal=joma
no-vol=21
cd-vols=
no-issue=20
article-no=
start-page=7556
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2020
dt-pub=20201013
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=CCN3 (NOV) Drives Degradative Changes in Aging Articular Cartilage
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Aging is a major risk factor of osteoarthritis, which is characterized by the degeneration of articular cartilage. CCN3, a member of the CCN family, is expressed in cartilage and has various physiological functions during chondrocyte development, differentiation, and regeneration. Here, we examine the role of CCN3 in cartilage maintenance. During aging, the expression of Ccn3 mRNA in mouse primary chondrocytes from knee cartilage increased and showed a positive correlation with p21 and p53 mRNA. Increased accumulation of CCN3 protein was confirmed. To analyze the effects of CCN3 in vitro, either primary cultured human articular chondrocytes or rat chondrosarcoma cell line (RCS) were used. Artificial senescence induced by H2O2 caused a dose-dependent increase in Ccn3 gene and CCN3 protein expression, along with enhanced expression of p21 and p53 mRNA and proteins, as well as SA-beta gal activity. Overexpression of CCN3 also enhanced p21 promoter activity via p53. Accordingly, the addition of recombinant CCN3 protein to the culture increased the expression of p21 and p53 mRNAs. We have produced cartilage-specific CCN3-overexpressing transgenic mice, and found degradative changes in knee joints within two months. Inflammatory gene expression was found even in the rib chondrocytes of three-month-old transgenic mice. Similar results were observed in human knee articular chondrocytes from patients at both mRNA and protein levels. These results indicate that CCN3 is a new senescence marker of chondrocytes, and the overexpression of CCN3 in cartilage may in part promote chondrocyte senescence, leading to the degeneration of articular cartilage through the induction of p53 and p21.
en-copyright=
kn-copyright=

en-aut-name=KuwaharaMiho
en-aut-sei=Kuwahara
en-aut-mei=Miho
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=KadoyaKoichi
en-aut-sei=Kadoya
en-aut-mei=Koichi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=KondoSei
en-aut-sei=Kondo
en-aut-mei=Sei
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=FuShanqi
en-aut-sei=Fu
en-aut-mei=Shanqi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=MiyakeYoshiko
en-aut-sei=Miyake
en-aut-mei=Yoshiko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=OgoAyako
en-aut-sei=Ogo
en-aut-mei=Ayako
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=OnoMitsuaki
en-aut-sei=Ono
en-aut-mei=Mitsuaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=FurumatsuTakayuki
en-aut-sei=Furumatsu
en-aut-mei=Takayuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=NakataEiji
en-aut-sei=Nakata
en-aut-mei=Eiji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=SasakiTakako
en-aut-sei=Sasaki
en-aut-mei=Takako
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=MinagiShogo
en-aut-sei=Minagi
en-aut-mei=Shogo
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

en-aut-name=KubotaSatoshi
en-aut-sei=Kubota
en-aut-mei=Satoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=13
ORCID=

en-aut-name=HattoriTakako
en-aut-sei=Hattori
en-aut-mei=Takako
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=14
ORCID=

affil-num=1
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=2
en-affil=Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=3
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=4
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=5
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=6
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=7
en-affil=Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=8
en-affil=Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=9
en-affil=Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=10
en-affil=Department of Biochemistry, Faculty of Medicine, Oita University
kn-affil=

affil-num=11
en-affil=Department of Occlusal and Oral Functional Rehabilitation, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=12
en-affil=Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School/Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=13
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=14
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=
en-keyword=cellular communication network factor 3
kn-keyword=cellular communication network factor 3
en-keyword=CCN3
kn-keyword=CCN3
en-keyword=NOV
kn-keyword=NOV
en-keyword=primary chondrocytes
kn-keyword=primary chondrocytes
en-keyword=aging
kn-keyword=aging
en-keyword=oxidative stress
kn-keyword=oxidative stress
en-keyword=senescence
kn-keyword=senescence
en-keyword=p21
kn-keyword=p21
en-keyword=p53
kn-keyword=p53
en-keyword=SASP
kn-keyword=SASP
END

start-ver=1.4
cd-journal=joma
no-vol=62
cd-vols=
no-issue=3
article-no=
start-page=280
end-page=288
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2020
dt-pub=20200811
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Regulation of cellular communication network factor 2 (CCN2) in breast cancer cells via the cell-type dependent interplay between CCN2 and glycolysis
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Objectives: Anti-osteoclastic treatments for breast cancer occasionally cause medication-related osteonecrosis of the jaw. Moreover, elevated glycolytic activity, which is known as the Warburg effect, is usually observed in these breast cancer cells. Previously, we found that cellular communication network factor 2 (CCN2) production and glycolysis enhanced each other in chondrocytes. Here, we evaluated the interplay between CCN2 and glycolysis in breast cancer cells, as we suspected a possible involvement of CCN2 in the Warburg effect in highly invasive breast cancer cells. <br/>
Methods: Two human breast cancer cell lines with a distinct phenotype were used. Glycolysis was inhibited by using 2 distinct compounds, and gene silencing was performed using siRNA. Glycolysis and the expression of relevant genes were monitored via colorimetric assays and quantitative RT-PCR, respectively. <br/>
Results: Although CCN2 expression was almost completely silenced when treating invasive breast cancer cells with a siRNA cocktail against CCN2, glycolytic activity was not affected. Notably, the expression of glycolytic enzyme genes, which was repressed by CCN2 deficiency in chondrocytes, tended to increase upon CCN2 silencing in breast cancer cells. Inhibition of glycolysis, which resulted in the repression of CCN2 expression in chondrocytic cells, did not alter or strongly enhanced CCN2 expression in the invasive and non-invasive breast cancer cells, respectively. <br/>
Conclusions: High CCN2 expression levels play a critical role in the invasion and metastasis of breast cancer. Thus, a collapse in the intrinsic repressive machinery of CCN2 due to glycolysis may induce the acquisition of an invasive phenotype in breast cancer cells. 
en-copyright=
kn-copyright=

en-aut-name=AkashiSho
en-aut-sei=Akashi
en-aut-mei=Sho
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=NishidaTakashi
en-aut-sei=Nishida
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=MizukawaTomomi
en-aut-sei=Mizukawa
en-aut-mei=Tomomi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=KawataKazumi
en-aut-sei=Kawata
en-aut-mei=Kazumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=IidaSeiji
en-aut-sei=Iida
en-aut-mei=Seiji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=KubotaSatoshi
en-aut-sei=Kubota
en-aut-mei=Satoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

affil-num=1
en-affil=  Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=2
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=3
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=4
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=5
en-affil=Department of Oral and Maxillofacial Reconstructive Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=6
en-affil=  Department of Oral and Maxillofacial Reconstructive Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=7
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=
en-keyword=Bone metastasis
kn-keyword=Bone metastasis
en-keyword=Breast cancer
kn-keyword=Breast cancer
en-keyword=CCN2
kn-keyword=CCN2
en-keyword=Glycolysis
kn-keyword=Glycolysis
en-keyword=Warburg effect
kn-keyword=Warburg effect
END

start-ver=1.4
cd-journal=joma
no-vol=21
cd-vols=
no-issue=8
article-no=
start-page=
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2020
dt-pub=20200416
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Roles of Interaction between CCN2 and Rab14 in Aggrecan Production by Chondrocytes
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=To identify proteins that cooperate with cellular communication network factor 2 (CCN2), we carried out GAL4-based yeast two-hybrid screening using a cDNA library derived from the chondrocytic cell line HCS-2/8. Rab14 GTPase (Rab14) polypeptide was selected as a CCN2-interactive protein. The interaction between CCN2 and Rab14 in HCS-2/8 cells was confirmed using the in situ proximity ligation assay. We also found that CCN2 interacted with Rab14 through its IGFBP-like domain among the four domains in CCN2 protein. To detect the colocalization between CCN2 and Rab14 in the cells in detail, CCN2, wild-type Rab14 (Rab14WT), a constitutive active form (Rab14CA), and a dominant negative form (Rab14DN) of Rab14 were overexpressed in monkey kidney-tissue derived COS7 cells. Ectopically overexpressed Rab14 showed a diffuse cytosolic distribution in COS7 cells; however, when Rab14WT was overexpressed with CCN2, the Rab14WT distribution changed to dots that were evenly distributed within the cytosol, and both Rab14 and CCN2 showed clear colocalization. When Rab14CA was overexpressed with CCN2, Rab14CA and CCN2 also showed good localization as dots, but their distribution was more widespread within cytosol. The coexpression of Rab14DN and CCN2 also showed a dotted codistribution but was more concentrated in the perinuclear area. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis revealed that the reduction in RAB14 or CCN2 mRNA by their respective siRNA significantly enhanced the expression of ER stress markers, BIP and CHOP mRNA in HCS-2/8 chondrocytic cells, suggesting that ER and Golgi stress were induced by the inhibition of membrane vesicle transfer via the suppression of CCN2 or Rab14. Moreover, to study the effect of the interaction between CCN2 and its interactive protein Rab14 on proteoglycan synthesis, we overexpressed Rab14WT or Rab14CA or Rab14DN in HCS-2/8 cells and found that the overexpression of Rab14DN decreased the extracellular proteoglycan accumulation more than the overexpression of Rab14WT/CA did in the chondrocytic cells. These results suggest that intracellular CCN2 is associated with Rab14 on proteoglycan-containing vesicles during their transport from the Golgi apparatus to endosomes in chondrocytes and that this association may play a role in proteoglycan secretion by chondrocytes.
en-copyright=
kn-copyright=

en-aut-name=HoshijimaMitsuhiro
en-aut-sei=Hoshijima
en-aut-mei=Mitsuhiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=HattoriTakako
en-aut-sei=Hattori
en-aut-mei=Takako
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=AoyamaEriko
en-aut-sei=Aoyama
en-aut-mei=Eriko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=NishidaTakashi
en-aut-sei=Nishida
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=KubotaSatoshi
en-aut-sei=Kubota
en-aut-mei=Satoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=KamiokaHiroshi
en-aut-sei=Kamioka
en-aut-mei=Hiroshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

affil-num=1
en-affil=Department of Orthodontics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=2
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=3
en-affil=Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School/Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=4
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=5
en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=6
en-affil=Department of Orthodontics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=7
en-affil=Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School/Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=
en-keyword=cellular communication network factor 2
kn-keyword=cellular communication network factor 2
en-keyword=CCN2
kn-keyword=CCN2
en-keyword=CTGF
kn-keyword=CTGF
en-keyword=Rab14
kn-keyword=Rab14
en-keyword=yeast two-hybrid
kn-keyword=yeast two-hybrid
en-keyword=chondrocyte
kn-keyword=chondrocyte
en-keyword=ER stress
kn-keyword=ER stress
en-keyword=aggrecan
kn-keyword=aggrecan
END

start-ver=1.4
cd-journal=joma
no-vol=12
cd-vols=
no-issue=4
article-no=
start-page=881
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2020
dt-pub=20200404
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (CCN2/CTGF): CRISPR against Cancer
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Matrix metalloproteinase 3 (MMP3) plays multiple roles in extracellular proteolysis as well as intracellular transcription, prompting a new definition of moonlighting metalloproteinase (MMP), according to a definition of protein moonlighting (or gene sharing), a phenomenon by which a protein can perform more than one function. Indeed, connective tissue growth factor (CTGF, aka cellular communication network factor 2 (CCN2)) is transcriptionally induced as well as cleaved by MMP3. Moreover, several members of the MMP family have been found within tumor-derived extracellular vesicles (EVs). We here investigated the roles of MMP3-rich EVs in tumor progression, molecular transmission, and gene regulation. EVs derived from a rapidly metastatic cancer cell line (LuM1) were enriched in MMP3 and a C-terminal half fragment of CCN2/CTGF. MMP3-rich, LuM1-derived EVs were disseminated to multiple organs through body fluid and were pro-tumorigenic in an allograft mouse model, which prompted us to define LuM1-EVs as oncosomes in the present study. Oncosome-derived MMP3 was transferred into recipient cell nuclei and thereby trans-activated the CCN2/CTGF promoter, and induced CCN2/CTGF production in vitro. TRENDIC and other cis-elements in the CCN2/CTGF promoter were essential for the oncosomal responsivity. The CRISPR/Cas9-mediated knockout of MMP3 showed significant anti-tumor effects such as the inhibition of migration and invasion of tumor cells, and a reduction in CCN2/CTGF promoter activity and fragmentations in vitro. A high expression level of MMP3 or CCN2/CTGF mRNA was prognostic and unfavorable in particular types of cancers including head and neck, lung, pancreatic, cervical, stomach, and urothelial cancers. These data newly demonstrate that oncogenic EVs-derived MMP is a transmissive trans-activator for the cellular communication network gene and promotes tumorigenesis at distant sites.
en-copyright=
kn-copyright=

en-aut-name=OkushaYuka
en-aut-sei=Okusha
en-aut-mei=Yuka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=EguchiTakanori
en-aut-sei=Eguchi
en-aut-mei=Takanori
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=TranManh T.
en-aut-sei=Tran
en-aut-mei=Manh T.
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=SogawaChiharu
en-aut-sei=Sogawa
en-aut-mei=Chiharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=YoshidaKaya
en-aut-sei=Yoshida
en-aut-mei=Kaya
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=ItagakiMami
en-aut-sei=Itagaki
en-aut-mei=Mami
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=TahaEman A.
en-aut-sei=Taha
en-aut-mei=Eman A.
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=OnoKisho
en-aut-sei=Ono
en-aut-mei=Kisho
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=AoyamaEriko
en-aut-sei=Aoyama
en-aut-mei=Eriko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=OkamuraHirohiko
en-aut-sei=Okamura
en-aut-mei=Hirohiko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=KozakiKen-Ichi
en-aut-sei=Kozaki
en-aut-mei=Ken-Ichi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=CalderwoodStuart K.
en-aut-sei=Calderwood
en-aut-mei=Stuart K.
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=13
ORCID=

en-aut-name=OkamotoKuniaki
en-aut-sei=Okamoto
en-aut-mei=Kuniaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=14
ORCID=

affil-num=1
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=2
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=3
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=4
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=5
en-affil=Department of Oral Healthcare Education, Institute of Biomedical Sciences, Tokushima University Graduate School
kn-affil=

affil-num=6
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=7
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=8
en-affil=Department of Oral and Maxillofacial Surgery, Okayama University Hospital
kn-affil=

affil-num=9
en-affil=Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=10
en-affil=Department of Oral Morphology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine
kn-affil=

affil-num=11
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=12
en-affil=Division of Molecular and Cellular Biology, Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School
kn-affil=

affil-num=13
en-affil=Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=14
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=
en-keyword=matrix metalloproteinase
kn-keyword=matrix metalloproteinase
en-keyword=moonlighting metalloproteinase (MMP)
kn-keyword=moonlighting metalloproteinase (MMP)
en-keyword=protein moonlighting
kn-keyword=protein moonlighting
en-keyword=transcription factor
kn-keyword=transcription factor
en-keyword=extracellular vesicles
kn-keyword=extracellular vesicles
en-keyword=oncosome
kn-keyword=oncosome
en-keyword=genome editing
kn-keyword=genome editing
en-keyword=CRISPR
kn-keyword=CRISPR
en-keyword=cellular communication network factor
kn-keyword=cellular communication network factor
en-keyword=CCN2/CTGF 
kn-keyword=CCN2/CTGF 
END

start-ver=1.4
cd-journal=joma
no-vol=12
cd-vols=
no-issue=2
article-no=
start-page=523
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2020
dt-pub=20200224
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3/DAT and Reducing STAT3
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Tumor growth, progression, and therapy resistance are crucial factors in the prognosis of cancer. The properties of three-dimensional (3D) tumor-like organoids (tumoroids) more closely resemble in vivo tumors compared to two-dimensionally cultured cells and are therefore effectively used for assays and drug screening. We here established a repurposed drug for novel anticancer research and therapeutics using a 3D tumoroid-based screening system. We screened six pharmacologically active compounds by using an original tumoroid-based multiplex phenotypic screening system with a matrix metalloproteinase 9 (MMP9) promoter-driven fluorescence reporter for the evaluation of both tumoroid formation and progression. The antiparkinson drug benztropine was the most effective compound uncovered by the screen. Benztropine significantly inhibited in vitro tumoroid formation, cancer cell survival, and MMP9 promoter activity. Benztropine also reduced the activity of oncogenic signaling transducers and trans-activators for MMP9, including STAT3, NF-kappa B, and beta-catenin, and the properties of cancer stem cells/cancer-initiating cells. Benztropine and GBR-12935 directly targeted the dopamine transporter DAT/SLC6A3, whose genetic alterations such as amplification were correlated with poor prognosis for cancer patients. Benztropine also inhibited the tumor growth, circulating tumor cell (CTC) number, and rate of metastasis in a tumor allograft model in mice. In conclusion, we propose the repurposing of benztropine for anticancer research and therapeutics that can suppress tumor progression, CTC, and metastasis of aggressive cancers by reducing key pro-tumorigenic factors.
en-copyright=
kn-copyright=

en-aut-name=SogawaChiharu
en-aut-sei=Sogawa
en-aut-mei=Chiharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=EguchiTakanori
en-aut-sei=Eguchi
en-aut-mei=Takanori
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=TranManh Tien
en-aut-sei=Tran
en-aut-mei=Manh Tien
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=IshigeMasayuki
en-aut-sei=Ishige
en-aut-mei=Masayuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=TrinKilian
en-aut-sei=Trin
en-aut-mei=Kilian
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=OkushaYuka
en-aut-sei=Okusha
en-aut-mei=Yuka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=TahaEman Ahmed
en-aut-sei=Taha
en-aut-mei=Eman Ahmed
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=LuYanyin
en-aut-sei=Lu
en-aut-mei=Yanyin
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=KawaiHotaka
en-aut-sei=Kawai
en-aut-mei=Hotaka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=SogawaNorio
en-aut-sei=Sogawa
en-aut-mei=Norio
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=CalderwoodStuart K.
en-aut-sei=Calderwood
en-aut-mei=Stuart K.
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

en-aut-name=OkamotoKuniaki
en-aut-sei=Okamoto
en-aut-mei=Kuniaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=13
ORCID=

en-aut-name=KozakiKen-Ichi
en-aut-sei=Kozaki
en-aut-mei=Ken-Ichi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=14
ORCID=

affil-num=1
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=2
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=3
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=4
en-affil=On-Chip Biotechnologies, Co., Ltd.
kn-affil=

affil-num=5
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=6
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=7
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=8
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=9
en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=10
en-affil=Department of Dental Pharmacology, Matsumoto Dental University
kn-affil=

affil-num=11
en-affil=Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=12
en-affil=Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School
kn-affil=

affil-num=13
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=

affil-num=14
en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
kn-affil=
en-keyword=drug repositioning/repurposing
kn-keyword=drug repositioning/repurposing
en-keyword=three-dimensional (3D) culture
kn-keyword=three-dimensional (3D) culture
en-keyword=tumoroids
kn-keyword=tumoroids
en-keyword=dopamine transporter (DAT)
kn-keyword=dopamine transporter (DAT)
en-keyword=benztropine
kn-keyword=benztropine
en-keyword=signal transducer and activator of transcription (STAT)
kn-keyword=signal transducer and activator of transcription (STAT)
en-keyword=circulating tumor cell (CTC)
kn-keyword=circulating tumor cell (CTC)
END

start-ver=1.4
cd-journal=joma
no-vol=519
cd-vols=
no-issue=2
article-no=
start-page=309
end-page=315
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2019
dt-pub=20191105
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Jiadifenolide induces the expression of cellular communication network factor (CCN) genes, and CCN2 exhibits neurotrophic activity in neuronal precursor cells derived from human induced pluripotent stem cells
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract= Jiadifenolide has been reported to have neurotrophin-like activity in primary rat cortical neurons, and also possesses neurotrophic effects in neuronal precursor cells derived from human induced pluripotent stem cells (hiPSCs), as we have previously reported. However, the molecular mechanisms by which jiadifenolide exerts its neurotrophic effects in rat and human neurons are unknown. Thus, we aimed to investigate the molecular mechanisms and pathways by which jiadifenolide promotes neurotrophic effects. Here, we found that jiadifenolide activated cellular communication network factor (CCN) signaling pathways by up-regulating mRNA level expression of CCN genes in human neuronal cells. We also found that CCN2 (also known as connective tissue growth factor, CTGF) protein promotes neurotrophic effects through activation of the p44/42 mitogen-activated protein kinase signaling pathway. This is the first discovery which links neurotrophic activity with CCN signaling.
en-copyright=
kn-copyright=

en-aut-name=ShojiMasaki
en-aut-sei=Shoji
en-aut-mei=Masaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=UedaMasako
en-aut-sei=Ueda
en-aut-mei=Masako
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=NishiokaMegumi
en-aut-sei=Nishioka
en-aut-mei=Megumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=MinatoHiroki
en-aut-sei=Minato
en-aut-mei=Hiroki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=SekiMasahide
en-aut-sei=Seki
en-aut-mei=Masahide
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=HaradaKenichi
en-aut-sei=Harada
en-aut-mei=Kenichi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=KuboMiwa
en-aut-sei=Kubo
en-aut-mei=Miwa
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=FukuyamaYoshiyasu
en-aut-sei=Fukuyama
en-aut-mei=Yoshiyasu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=SuzukiYutaka
en-aut-sei=Suzuki
en-aut-mei=Yutaka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=AoyamaEriko
en-aut-sei=Aoyama
en-aut-mei=Eriko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=11
ORCID=

en-aut-name=KuzuharaTakashi
en-aut-sei=Kuzuhara
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=12
ORCID=

affil-num=1
en-affil=Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University
kn-affil=

affil-num=2
en-affil=Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University
kn-affil=

affil-num=3
en-affil=Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University
kn-affil=

affil-num=4
en-affil=Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University
kn-affil=

affil-num=5
en-affil=
kn-affil=

affil-num=6
en-affil=Laboratory of Biophysical Chemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University
kn-affil=

affil-num=7
en-affil=Laboratory of Biophysical Chemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University
kn-affil=

affil-num=8
en-affil=Laboratory of Biophysical Chemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University
kn-affil=

affil-num=9
en-affil=Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo
kn-affil=

affil-num=10
en-affil=Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School/Graduate School of Medicine Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=11
en-affil=Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School/Graduate School of Medicine Dentistry and Pharmaceutical Sciences
kn-affil=

affil-num=12
en-affil=Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University
kn-affil=
en-keyword=CCN signaling pathway
kn-keyword=CCN signaling pathway
en-keyword=CCN2
kn-keyword=CCN2
en-keyword=Jiadifenolide
kn-keyword=Jiadifenolide
en-keyword=Neurotrophin
kn-keyword=Neurotrophin
en-keyword=iPS
kn-keyword=iPS
END

start-ver=1.4
cd-journal=joma
no-vol=8
cd-vols=
no-issue=3
article-no=
start-page=
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2013
dt-pub=20130328
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Cartilage-Specific Over-Expression of CCN Family Member 2/Connective Tissue Growth Factor (CCN2/CTGF) Stimulates Insulin-Like Growth Factor Expression and Bone Growth
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Previously we showed that CCN family member 2/connective tissue growth factor (CCN2) promotes the proliferation, differentiation, and maturation of growth cartilage cells in vitro. To elucidate the specific role and molecular mechanism of CCN2 in cartilage development in vivo, in the present study we generated transgenic mice overexpressing CCN2 and analyzed them with respect to cartilage and bone development. Transgenic mice were generated expressing a ccn2/lacZ fusion gene in cartilage under the control of the 6 kb-Col2a1-enhancer/promoter. Changes in cartilage and bone development were analyzed histologically and immunohistologically and also by micro CT. Primary chondrocytes as well as limb bud mesenchymal cells were cultured and analyzed for changes in expression of cartilage-related genes, and non-transgenic chondrocytes were treated in culture with recombinant CCN2. Newborn transgenic mice showed extended length of their long bones, increased content of proteoglycans and collagen II accumulation. Micro-CT analysis of transgenic bones indicated increases in bone thickness and mineral density. Chondrocyte proliferation was enhanced in the transgenic cartilage. In in vitro short-term cultures of transgenic chondrocytes, the expression of col2a1, aggrecan and ccn2 genes was substantially enhanced; and in long-term cultures the expression levels of these genes were further enhanced. Also, in vitro chondrogenesis was strongly enhanced. IGF-I and IGF-II mRNA levels were elevated in transgenic chondrocytes, and treatment of non-transgenic chondrocytes with recombinant CCN2 stimulated the expression of these mRNA. The addition of CCN2 to non-transgenic chondrocytes induced the phosphorylation of IGFR, and ccn2-overexpressing chondrocytes showed enhanced phosphorylation of IGFR. Our data indicates that the observed effects of CCN2 may be mediated in part by CCN2-induced overexpression of IGF-I and IGF-II. These findings indicate that CCN2-overexpression in transgenic mice accelerated the endochondral ossification processes, resulting in increased length of their long bones. Our results also indicate the possible involvement of locally enhanced IGF-I or IGF-II in this extended bone growth.
en-copyright=
kn-copyright=

en-aut-name=TomitaNao
en-aut-sei=Tomita
en-aut-mei=Nao
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=HattoriTakako
en-aut-sei=Hattori
en-aut-mei=Takako
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=ItohShinsuke
en-aut-sei=Itoh
en-aut-mei=Shinsuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=AoyamaEriko
en-aut-sei=Aoyama
en-aut-mei=Eriko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=YaoMayumi
en-aut-sei=Yao
en-aut-mei=Mayumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=YamashiroTakashi
en-aut-sei=Yamashiro
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

affil-num=1
en-affil=
kn-affil=Okayama Univ, Sch Dent, Dept Biochem & Mol Dent

affil-num=2
en-affil=
kn-affil=Okayama Univ, Sch Dent, Dept Biochem & Mol Dent

affil-num=3
en-affil=
kn-affil=Okayama Univ, Sch Dent, Dept Biochem & Mol Dent

affil-num=4
en-affil=
kn-affil=Okayama Univ, Sch Dent, Biodent Res Ctr

affil-num=5
en-affil=
kn-affil=Okayama Univ, Sch Dent, Dept Biochem & Mol Dent

affil-num=6
en-affil=
kn-affil=Okayama Univ, Sch Dent, Dept Orthodont, Grad Sch Med Dent & Pharmaceut Sci

affil-num=7
en-affil=
kn-affil=Okayama Univ, Sch Dent, Dept Biochem & Mol Dent
END

start-ver=1.4
cd-journal=joma
no-vol=8
cd-vols=
no-issue=8
article-no=
start-page=
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2013
dt-pub=20130812
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=CCN Family Member 2/Connective Tissue Growth Factor (CCN2/CTGF) Has Anti-Aging Effects That Protect Articular Cartilage from Age-Related Degenerative Changes
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=To examine the role of connective tissue growth factor CCN2/CTGF (CCN2) in the maintenance of the articular cartilaginous phenotype, we analyzed knee joints from aging transgenic mice (TG) overexpressing CCN2 driven by the Col2a1 promoter. Knee joints from 3-, 14-, 40-, and 60-day-old and 5-, 12-, 18-, 21-, and 24-month-old littermates were analyzed. Ccn2-LacZ transgene expression in articular cartilage was followed by X-gal staining until 5 months of age. Overexpression of CCN2 protein was confirmed through all ages in TG articular cartilage and in growth plates. Radiographic analysis of knee joints showed a narrowing joint space and other features of osteoarthritis in 50% of WT, but not in any of the TG mice. Transgenic articular cartilage showed enhanced toluidine blue and safranin-O staining as well as chondrocyte proliferation but reduced staining for type X and I collagen and MMP-13 as compared with those parameters for WT cartilage. Staining for aggrecan neoepitope, a marker of aggrecan degradation in WT articular cartilage, increased at 5 and 12 months, but disappeared at 24 months due to loss of cartilage; whereas it was reduced in TG articular cartilage after 12 months. Expression of cartilage genes and MMPs under cyclic tension stress (CTS) was measured by using primary cultures of chondrocytes obtained from wild-type (WT) rib cartilage and TG or WT epiphyseal cartilage. CTS applied to primary cultures of mock-transfected rib chondrocytes from WT cartilage and WT epiphyseal cartilage induced expression of Col1a1, ColXa1, Mmp-13, and Mmp-9 mRNAs; however, their levels were not affected in CCN2-overexpressing chondrocytes and TG epiphyseal cartilage. In conclusion, cartilage-specific overexpression of CCN2 during the developmental and growth periods reduced age-related changes in articular cartilage. Thus CCN2 may play a role as an anti-aging factor by stabilizing articular cartilage.
en-copyright=
kn-copyright=

en-aut-name=ItohShinsuke
en-aut-sei=Itoh
en-aut-mei=Shinsuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=HattoriTakako
en-aut-sei=Hattori
en-aut-mei=Takako
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=TomitaNao
en-aut-sei=Tomita
en-aut-mei=Nao
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=AoyamaEriko
en-aut-sei=Aoyama
en-aut-mei=Eriko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=YutaniYasutaka
en-aut-sei=Yutani
en-aut-mei=Yasutaka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=YamashiroTakashi
en-aut-sei=Yamashiro
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

affil-num=1
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Biochem & Mol Dent

affil-num=2
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Biochem & Mol Dent

affil-num=3
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Biochem & Mol Dent

affil-num=4
en-affil=
kn-affil=Okayama Univ, Sch Dent, Biodental Res Ctr

affil-num=5
en-affil=
kn-affil=Yutani Orthopaed Clin

affil-num=6
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Orthodont

affil-num=7
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Biochem & Mol Dent
END

start-ver=1.4
cd-journal=joma
no-vol=14
cd-vols=
no-issue=6
article-no=
start-page=1089
end-page=1098
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2008
dt-pub=200806
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Promotion of Bone Regeneration by CCN2 Incorporated into Gelatin Hydrogel
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=CCN family protein 2/connective tissue growth factor (CCN2/CTGF) is a unique molecule that promotes the entire endochondral ossification process and regeneration of damaged articular cartilage. Also, CCN2 has been shown to enhance the adhesion and migration of bone marrow stromal cells as well as the growth and differentiation of osteoblasts; hence, its utility in bone regeneration has been suggested. Here, we evaluated the effect of CCN2 on the regeneration of an intractable bone defect in a rat model. First, we prepared two recombinant CCN2s of different origins, and the one showing the stronger effect on osteoblasts in vitro was selected for further evaluation, based on the result of an in vitro bioassay. Next, to obtain a sustained effect, the recombinant CCN2 was incorporated into gelatin hydrogel that enabled the gradual release of the factor. Evaluation in vivo indicated that CCN2 continued to be released at least for up to 14 days after its incorporation. Application of the gelatin hydrogel-CCN2 complex, together with a collagen scaffold to the bone defect prepared in a rat femur resulted in remarkable induction of osteoblastic mineralization markers within 2 weeks. Finally, distinct enhancement of bone regeneration was observed 3 weeks after the application of the complex. These results confirm the utility of CCN2 in the regeneration of intractable bone defects in vivo when the factor is incorporated into gelatin hydrogel.
en-copyright=
kn-copyright=

en-aut-name=KikuchiTakeshi
en-aut-sei=Kikuchi
en-aut-mei=Takeshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=KubotaSatoshi
en-aut-sei=Kubota
en-aut-mei=Satoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=AsaumiKoji
en-aut-sei=Asaumi
en-aut-mei=Koji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=KawakiHarumi
en-aut-sei=Kawaki
en-aut-mei=Harumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=NishidaTakashi
en-aut-sei=Nishida
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=KawataKazumi
en-aut-sei=Kawata
en-aut-mei=Kazumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=MitaniShigeru
en-aut-sei=Mitani
en-aut-mei=Shigeru
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=TabataYasuhiko
en-aut-sei=Tabata
en-aut-mei=Yasuhiko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=OzakiToshifumi
en-aut-sei=Ozaki
en-aut-mei=Toshifumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

affil-num=1
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Biochem & Mol Dent

affil-num=2
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Biochem & Mol Dent

affil-num=3
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Orthopaed Surg

affil-num=4
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Biochem & Mol Dent

affil-num=5
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Biochem & Mol Dent

affil-num=6
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Biochem & Mol Dent

affil-num=7
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Orthopaed Surg

affil-num=8
en-affil=
kn-affil=Kyoto Univ, Inst Frontier Med Sci, Dept Biomat

affil-num=9
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Orthopaed Surg

affil-num=10
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Biochem & Mol Dent
END

start-ver=1.4
cd-journal=joma
no-vol=279
cd-vols=
no-issue=19
article-no=
start-page=3597
end-page=3584
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2012
dt-pub=201210
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Roles of heterotypic CCN2/CTGF-CCN3/NOV and homotypic CCN2-CCN2 interactions in expression of the differentiated phenotype of chondrocytes
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=To identify proteins that regulate CCN2 activity, we carried out GAL4-based yeast two-hybrid screening with a cDNA library derived from a chondrocytic cell line, HCS-2/8. CCN2/CTGF and CCN3/NOV polypeptides were picked up as CCN2-binding proteins, and CCN2CCN2 and CCN2CCN3 binding domains were identified. Direct binding between CCN2 and CCN3 was confirmed by coimmunoprecipitation in vitro and in vivo and surface plasmon resonance, and the calculated dissociation constants (Kd) were 1.17 x 10-9 m for CCN2 and CCN2, and 1.95 x 10-9 m for CCN2 and CCN3. Ectopically overexpressed green fluorescent proteinCCN2 and HaloCCN3 in COS7 cells colocalized, as determined by direct fluorescence analysis. We present evidence that CCN2CCN3 interactions modulated CCN2 activity such as enhancement of ACAN and col2a1 expression. Curiously, CCN2 enhanced, whereas CCN3 inhibited, the expression of aggrecan and col2a1 mRNA in HCS-2/8 cells, and combined treatment with CCN2 and CCN3 abolished the inhibitory effect of CCN3. These effects were neutralized with an antibody against the von Willebrand factor type C domain of CCN2 (11H3). This antibody diminished the binding between CCN2 and CCN2, but enhanced that between CCN3 and CCN2. Our results suggest that CCN2 could form homotypic and heterotypic dimers with CCN2 and CCN3, respectively. Strengthening the binding between CCN2 and CCN3 with the 11H3 antibody had an enhancing effect on aggrecan expression in chondrocytes, suggesting that CCN2 had an antagonizing effect by binding to CCN3.
en-copyright=
kn-copyright=

en-aut-name=HoshijimaMitsuhiro
en-aut-sei=Hoshijima
en-aut-mei=Mitsuhiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=HattoriTakako
en-aut-sei=Hattori
en-aut-mei=Takako
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=AoyamaEriko
en-aut-sei=Aoyama
en-aut-mei=Eriko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=NishidaTakashi
en-aut-sei=Nishida
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=YamashiroTakashi
en-aut-sei=Yamashiro
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

affil-num=1
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Biochem & Mol Dent

affil-num=2
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Biochem & Mol Dent

affil-num=3
en-affil=
kn-affil=Okayama Univ, Sch Dent, Biodent Res Ctr

affil-num=4
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Biochem & Mol Dent

affil-num=5
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Orthodont & Dentofacial Orthoped

affil-num=6
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Biochem & Mol Dent
en-keyword=ACAN
kn-keyword=ACAN
en-keyword=CCN2
kn-keyword=CCN2
en-keyword=CTGF
kn-keyword=CTGF
en-keyword=CCN3
kn-keyword=CCN3
en-keyword=NOV
kn-keyword=NOV
en-keyword=chondrocyte
kn-keyword=chondrocyte
en-keyword=dimerization
kn-keyword=dimerization
END

start-ver=1.4
cd-journal=joma
no-vol=409
cd-vols=
no-issue=2
article-no=
start-page=247
end-page=252
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2011
dt-pub=20110603
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Mechanical stretch increases CCN2/CTGF expression in anterior cruciate ligament-derived cells
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Anterior cruciate ligament (ACL)-to-bone interface serves to minimize the stress concentrations that would arise between two different tissues. Mechanical stretch plays an important role in maintaining cell-specific features by inducing CCN family 2/connective tissue growth factor (CCN2/CTGF). We previously reported that cyclic tensile strain (CTS) stimulates alpha 1(I) collagen (COL1A1) expression in human ACL-derived cells. However, the biological function and stress-related response of CCN2/CTGF were still unclear in ACL fibroblasts. In the present study, CCN2/CTGF was observed in ACL-to-bone interface, but was not in the midsubstance region by immunohistochemical analyses. CTS treatments induced higher increase of CCN2/CTGF expression and secretion in interface cells compared with midsubstance cells. COL1A1 expression was not influenced by CCN2/CTGF treatment in interface cells despite CCN2/CTGF stimulated COL1A1 expression in midsubstance cells. However, CCN2/CTGF stimulated the proliferation of interface cells. Our results suggest that distinct biological function of stretch-induced CCN2/CTGF might regulate region-specific phenotypes of ACL-derived cells.
en-copyright=
kn-copyright=

en-aut-name=MiyakeYoshiaki
en-aut-sei=Miyake
en-aut-mei=Yoshiaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=FurumatsuTakayuki
en-aut-sei=Furumatsu
en-aut-mei=Takayuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=KubotaSatoshi
en-aut-sei=Kubota
en-aut-mei=Satoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=KawataKazumi
en-aut-sei=Kawata
en-aut-mei=Kazumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=OzakiToshifumi
en-aut-sei=Ozaki
en-aut-mei=Toshifumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

affil-num=1
en-affil=
kn-affil=Department of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences

affil-num=2
en-affil=
kn-affil=Department of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences

affil-num=3
en-affil=
kn-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences

affil-num=4
en-affil=
kn-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences

affil-num=5
en-affil=
kn-affil=Department of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences

affil-num=6
en-affil=
kn-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
en-keyword=CCN2/CTGF
kn-keyword=CCN2/CTGF
en-keyword=Anterior cruciate ligament
kn-keyword=Anterior cruciate ligament
en-keyword=Cyclic tensile strain
kn-keyword=Cyclic tensile strain
en-keyword=Collagen
kn-keyword=Collagen
en-keyword=Ligament-to-bone interface
kn-keyword=Ligament-to-bone interface
END

start-ver=1.4
cd-journal=joma
no-vol=366
cd-vols=
no-issue=1
article-no=
start-page=110
end-page=116
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2008
dt-pub=20080201
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Inhibition of tumor-stromal interaction through HGF/Met signaling by valproic acid
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Hepatocyte growth factor (HGF), which is produced by surrounding stromal cells, including fibroblasts and endothelial cells, has been shown to be a significant factor responsible for cancer cell invasion mediated by tumor-stromal interactions. We found in this study that the anti-tumor agent valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, strongly inhibited tumor-stromal interaction. VPA inhibited HGF production in fibroblasts induced by epidermal growth factor (EGF), platelet-derived growth factor, basic fibroblast growth factor, phorbol 12-myristate 13-acetate (PMA) and prostaglandin E-2 without any appreciable cytotoxic effect. Other HDAC inhibitors, including butyric acid and trichostatin A (TSA), showed similar inhibitory effects on HGF production stimulated by various inducers. Up-regulations of HGF gene expression induced by PMA and EGF were also suppressed by VPA and TSA. Furthermore, VPA significantly inhibited HGF-induced invasion of HepG2 hepatocellular carcinoma cells. VPA, however, did not affect the increases in phosphorylation of MAPK and Akt in HGF-treated HepG2 cells. These results demonstrated that VPA inhibited two critical processes of tumor-stromal interaction, induction of fibroblastic HGF production and HGF-induced invasion of HepG2 cells, and suggest that those activities serve for other anti-tumor mechanisms of VPA besides causing proliferation arrest, differentiation, and/or apoptosis of tumor cells.
en-copyright=
kn-copyright=

en-aut-name=MatsumotoYohsuke
en-aut-sei=Matsumoto
en-aut-mei=Yohsuke
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=MotokiTakahiro
en-aut-sei=Motoki
en-aut-mei=Takahiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=KubotaSatoshi
en-aut-sei=Kubota
en-aut-mei=Satoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=TsubouchiHirohito
en-aut-sei=Tsubouchi
en-aut-mei=Hirohito
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=GohdaEiichi
en-aut-sei=Gohda
en-aut-mei=Eiichi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

affil-num=1
en-affil=
kn-affil=Department of Immunochemistry, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=2
en-affil=
kn-affil=Department of Immunochemistry, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=3
en-affil=
kn-affil=Department of Biochemistry and Molecular Dentistry, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=4
en-affil=
kn-affil=Department of Biochemistry and Molecular Dentistry, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=5
en-affil=
kn-affil=Digestive Disease and Life-style Related Disease, Health Research Human and Environmental Sciences, Kagoshima University, Graduate School of Medicine and Dental Sciences

affil-num=6
en-affil=
kn-affil=Department of Immunochemistry, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
en-keyword=hepatocyte growth factor
kn-keyword=hepatocyte growth factor
en-keyword=valproic acid
kn-keyword=valproic acid
en-keyword=histone deacetylase inhibitor
kn-keyword=histone deacetylase inhibitor
en-keyword=butyric acid
kn-keyword=butyric acid
en-keyword=trichostatin A
kn-keyword=trichostatin A
en-keyword=induction
kn-keyword=induction
en-keyword=tumor invasion
kn-keyword=tumor invasion
en-keyword=dermal fibroblast
kn-keyword=dermal fibroblast
END

start-ver=1.4
cd-journal=joma
no-vol=3
cd-vols=
no-issue=1
article-no=
start-page=
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2005
dt-pub=20050415
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Comparable response of ccn1 with ccn2 genes upon arthritis: An in vitro evaluation with a human chondrocytic cell line stimulated by a set of cytokines
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=<p><b>Background:</b> The chondrosarcoma-derived HCS-2/8 has been known to be an excellent model of human articular chondrocytes. By mimicking the arthritic conditions through the treatment of HCS-2/8 cells with cytokines, we estimated the gene expression response of ccn1 and ccn2 during the course of joint inflammation in vitro.<br />
<b>Results:</b> In order to mimic the initiation of inflammation, HCS-2/8 cells were treated with tumor necrosis factor (TNF)-α. To induce pro-inflammatory or reparative responses, TGF-β was employed. Effects of an anti-inflammatory glucocorticoid were also evaluated. After stimulation, expression levels of ccn1 and ccn2 were quantitatively analyzed. Surprisingly, not only ccn2, but also ccn1 expression was repressed upon TNF-α stimulation, whereas both mRNAs were uniformly induced by transforming growth factor (TGF)-β and a glucocorticoid.<br />
<b>Conclusion:</b> These results describing the same response during the course of inflammation suggest similar and co-operative roles of these 2 ccn family members in the course of arthritis.</p>
en-copyright=
kn-copyright=

en-aut-name=MoritaniNorifumi H
en-aut-sei=Moritani
en-aut-mei=Norifumi H
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=KubotaSatoshi
en-aut-sei=Kubota
en-aut-mei=Satoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=SugaharaToshio
en-aut-sei=Sugahara
en-aut-mei=Toshio
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

affil-num=1
en-affil=
kn-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine and Dentistry

affil-num=2
en-affil=
kn-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine and Dentistry

affil-num=3
en-affil=
kn-affil=Department of Oral and Maxillofacial Reconstructive Surgery, Okayama University Graduate School of Medicine and Dentistry

affil-num=4
en-affil=
kn-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine and Dentistry
END

start-ver=1.4
cd-journal=joma
no-vol=203
cd-vols=
no-issue=2
article-no=
start-page=447
end-page=456
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2004
dt-pub=200412
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Connective Tissue Growth Factor Causes Persistent Proα2(I) Collagen Gene Expression Induced by Transforming Growth Factor-β in a Mouse Fibrosis Model
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Skin fibrotic disorders such as systemic sclerosis (SSc) are characterized by an excessive production of extracellular matrix (ECM) and understood to develop under the influence of certain growth factors. Connective tissue growth factor (CTGF) is a cysteine-rich mitogenic peptide that is implicated in various fibrotic disorders and induced in fibroblasts after activation with transforming growth factor-beta (TGF-beta). To better understand the mechanisms of persistent fibrosis seen in SSc, we previously established an animal model of skin fibrosis induced by exogenous application of growth factors. In this model, TGF-beta transiently induced subcutaneous fibrosis and serial injections of CTGF after TGF-beta caused persistent fibrosis. To further define the mechanisms of skin fibrosis induced by TGF-beta and CTGF in vivo, we investigated in this study, the effects of growth factors on the promoter activity of the pro alpha 2 (1) collagen (COL1A2) gene in skin fibrosis. For this purpose, we utilized transgenic reporter mice harboring the -17 kb promoter sequence of the mouse COL1A2 linked to either a firefly luciferase gene or a bacterial P-galactosidase gene. Serial injections of CTGF after TGF-beta resulted in a sustained elevation of COL1A2 mRNA expression and promoter activity compared with consecutive injection of TGF-beta alone on day 8. We also demonstrated that the number of fibroblasts with activated COL1A2 transcription was increased by serial injections of CTGF after TGF-beta in comparison with the injection of TGF-beta alone. Furthermore, the serial injections recruited mast cells and macrophages. The number of mast cells reached a maximum on day 4 and remained relatively high up to day 8. In contrast to the kinetics of mast cells, the number of macrophages was increased on day 4 and continued to rise during the subsequent consecutive CTGF injections until day 8. These results suggested that CTGF maintains TGF-beta-induced skin fibrosis by sustaining COL1A2 promoter activation and increasing the number of activated fibroblasts. The infiltrated mast cells and macrophages may also contribute to the maintenance of fibrosis.
en-copyright=
kn-copyright=

en-aut-name=ChujoSonoko
en-aut-sei=Chujo
en-aut-mei=Sonoko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=ShirasakiFumiaki
en-aut-sei=Shirasaki
en-aut-mei=Fumiaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=KawaraShigeru
en-aut-sei=Kawara
en-aut-mei=Shigeru
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=InagakiYutaka
en-aut-sei=Inagaki
en-aut-mei=Yutaka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=KinbaraTakuro
en-aut-sei=Kinbara
en-aut-mei=Takuro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=InaokiMakoto
en-aut-sei=Inaoki
en-aut-mei=Makoto
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=TakeharaKazuhiko
en-aut-sei=Takehara
en-aut-mei=Kazuhiko
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

affil-num=1
en-affil=
kn-affil=Department of Dermatology, Kanazawa University Graduate School of Medical Science

affil-num=2
en-affil=
kn-affil=Department of Dermatology, Kanazawa University Graduate School of Medical Science

affil-num=3
en-affil=
kn-affil=Department of Dermatology, National Kanazawa Hospital

affil-num=4
en-affil=
kn-affil=Department of Community Health, Tokai University School of Medicine

affil-num=5
en-affil=
kn-affil=Department of Dermatology, Kanazawa University Graduate School of Medical Science

affil-num=6
en-affil=
kn-affil=Department of Dermatology, Kawasaki Medical School

affil-num=7
en-affil=
kn-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine and Dentistry

affil-num=8
en-affil=
kn-affil=Department of Dermatology, Kanazawa University Graduate School of Medical Science
en-keyword=systemic sclerosis
kn-keyword=systemic sclerosis
en-keyword=fibrosis
kn-keyword=fibrosis
en-keyword=transforming growth factor-?
kn-keyword=transforming growth factor-?
en-keyword=connective tissue growth factor
kn-keyword=connective tissue growth factor
END

start-ver=1.4
cd-journal=joma
no-vol=3
cd-vols=
no-issue=1
article-no=
start-page=
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2005
dt-pub=20051005
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Effect of connective tissue growth factor (CCN2/CTGF) on proliferation and differentiation of mouse periodontal ligament-derived cells
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=<p><b>Background:</b> CCN2/CTGF is known to be involved in tooth germ development and periodontal tissue remodeling, as well as in mesenchymal tissue development and regeneration. In this present study, we investigated the roles of CCN2/CTGF in the proliferation and differentiation of periodontal ligament cells (murine periodontal ligament-derived cell line: MPL) in vitro.<br />
<b>Results:</b> In cell cultures of MPL, the mRNA expression of the CCN2/CTGF gene was stronger in sparse cultures than in confluent ones and was significantly enhanced by TGF-β. The addition of Recombinant CCN2/CTGF (rCCN2) to MPL cultures stimulated DNA synthesis and cell growth in a dose-dependent manner. Moreover, rCCN2 addition also enhanced the mRNA expression of alkaline phosphatase (ALPase), type I collagen, and periostin, the latter of which is considered to be a specific marker of the periosteum and periodontium; whereas it showed little effect on the mRNA expression of typical osteoblastic markers, e.g., osteopontin and osteocalcin. Finally, rCCN2/CTGF also stimulated ALPase activity and collagen synthesis.<br />
<b>Conclusion:</b> These results taken together suggest important roles of CCN2/CTGF in the development and regeneration of periodontal tissue including the periodontal ligament.</p>
en-copyright=
kn-copyright=

en-aut-name=AsanoMasahiro
en-aut-sei=Asano
en-aut-mei=Masahiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=KubotaSatoshi
en-aut-sei=Kubota
en-aut-mei=Satoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=NakanishiTohru
en-aut-sei=Nakanishi
en-aut-mei=Tohru
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=NishidaTakashi
en-aut-sei=Nishida
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=YamaaiTomoichiro
en-aut-sei=Yamaai
en-aut-mei=Tomoichiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=YosimichiGen
en-aut-sei=Yosimichi
en-aut-mei=Gen
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=OhyamaKazumi
en-aut-sei=Ohyama
en-aut-mei=Kazumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=SugimotoTomosada
en-aut-sei=Sugimoto
en-aut-mei=Tomosada
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=MurayamaYoji
en-aut-sei=Murayama
en-aut-mei=Yoji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

affil-num=1
en-affil=
kn-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=2
en-affil=
kn-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=3
en-affil=
kn-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=4
en-affil=
kn-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=5
en-affil=
kn-affil=Department of Oral Functional Anatomy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=6
en-affil=
kn-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=7
en-affil=
kn-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=8
en-affil=
kn-affil=Department of Oral Functional Anatomy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=9
en-affil=
kn-affil=Department of Periodontal Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=10
en-affil=
kn-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
END

start-ver=1.4
cd-journal=joma
no-vol=62
cd-vols=
no-issue=2
article-no=
start-page=119
end-page=126
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2008
dt-pub=200804
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Interleukin-4 downregulates the cyclic tensile stress-induced matrix metalloproteinases-13 and cathepsin b expression by rat normal chondrocytes
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=<p>Mechanical stress plays a key role in the pathogenesis of cartilage destruction seen in osteoarthritis (OA). We investigated the effect of cyclic tensile stress (CTS) on the anabolic and catabolic gene expression of rat cultured normal chondrocytes using the Flexercell strain unit. The effects of interleukin (IL)-4, a chondroprotective cytokine, on the changes in gene expression induced by CTS were also investigated. CTS (7% elongation at 0.5 Hz) for 24 h did not affect the expression of aggrecan and type II collagen, whereas CTS significantly upregulated matrix metalloproteinase (MMP)-13 and cathepsin B mRNA expression by chondrocytes. IL-1beta expression was also signifi cantly upregulated by CTS up to 12 h. The upregulation of MMP-13 was observed at 3 h, which was earlier than that of IL-1beta. Furthermore, pre-treatment with IL-4 (10 ng/ml) suppressed both MMP-13 and cathepsin B induction by mechanical stress, as well as CTS-induced IL-1beta expression. Our results suggest that IL-4 might have a therapeutic value in the treatment of OA by downregulation of mechanical stress-induced MMP-13 and cathepsin B expression by chondrocytes.</p>
en-copyright=
kn-copyright=

en-aut-name=DoiHideyuki
en-aut-sei=Doi
en-aut-mei=Hideyuki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=NishidaKeiichiro
en-aut-sei=Nishida
en-aut-mei=Keiichiro
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=YorimitsuMasanori
en-aut-sei=Yorimitsu
en-aut-mei=Masanori
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=KomiyamaTakamitsu
en-aut-sei=Komiyama
en-aut-mei=Takamitsu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=KadotaYasutaka
en-aut-sei=Kadota
en-aut-mei=Yasutaka
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=TetsunagaTomonori
en-aut-sei=Tetsunaga
en-aut-mei=Tomonori
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=YoshidaAki
en-aut-sei=Yoshida
en-aut-mei=Aki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

en-aut-name=KubotaSatoshi
en-aut-sei=Kubota
en-aut-mei=Satoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
ORCID=

en-aut-name=OzakiToshifumi
en-aut-sei=Ozaki
en-aut-mei=Toshifumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=10
ORCID=

affil-num=1
en-affil=
kn-affil=Departments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=2
en-affil=
kn-affil=Departments of Human Morphology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=3
en-affil=
kn-affil=Departments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=4
en-affil=
kn-affil=Departments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=5
en-affil=
kn-affil=Departments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=6
en-affil=
kn-affil=Departments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=7
en-affil=
kn-affil=Departments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=8
en-affil=
kn-affil=Departments of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=9
en-affil=
kn-affil=Departments of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences

affil-num=10
en-affil=
kn-affil=Departments of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
en-keyword=IL-4
kn-keyword=IL-4
en-keyword=MMP
kn-keyword=MMP
en-keyword=cathepsin B
kn-keyword=cathepsin B
en-keyword=mechanical stress
kn-keyword=mechanical stress
en-keyword=aggrecanase
kn-keyword=aggrecanase
END

start-ver=1.4
cd-journal=joma
no-vol=60
cd-vols=
no-issue=5
article-no=
start-page=267
end-page=277
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2006
dt-pub=200610
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Expression of Neurotrophins and Their Receptors Tropomyosin-related kinases (Trk) under Tension-stress during Distraction Osteogenesis
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=The localization and expression of neurotrophins and their receptors during distraction osteogenesis was investigated in 72 male rat femurs (11 weeks old) to further clarify the concurrence of cellular and molecular events of new bone formation. After osteotomy, a 7-day lag phase was followed by distraction at the rate of 0.25 mm/12 h for 21 days (distraction phase), and a 7-day consolidation phase. The localization of neurotrophins (NGF, BDNF and NT-3) and their receptors tropomyosinrelated kinases (TRKA, TRKB and TRKC) by immunostaining showed positive staining in bone forming cells in each stage, although the presence and staining intensity varied by cell type and phase. The expressions of NGF, BDNF and NT-3 by real-time polymerase chain reaction (real-time PCR) showed that the peak of the mRNA expression of NGF occurred 10 days after distraction. NT-3 increased during bone extension, but decreased when distraction stopped. In contrast, BDNF continued to increase gradually throughout the distraction and consolidation phases. These findings suggest that neurotrophins and their receptors may play different roles in endochondral and intramembranous ossification in distraction osteogenesis. The tension stress caused by distraction may stimulate the expression of neurotrophins and their receptors, and promote osteogenesis.
en-copyright=
kn-copyright=

en-aut-name=AigaAyako
en-aut-sei=Aiga
en-aut-mei=Ayako
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=1
ORCID=

en-aut-name=AsaumiKoji
en-aut-sei=Asaumi
en-aut-mei=Koji
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
ORCID=

en-aut-name=LeeYou Jin
en-aut-sei=Lee
en-aut-mei=You Jin
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=3
ORCID=

en-aut-name=KadotaHiroaki
en-aut-sei=Kadota
en-aut-mei=Hiroaki
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=4
ORCID=

en-aut-name=MitaniShigeru
en-aut-sei=Mitani
en-aut-mei=Shigeru
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
ORCID=

en-aut-name=OzakiToshifumi
en-aut-sei=Ozaki
en-aut-mei=Toshifumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=6
ORCID=

en-aut-name=TakigawaMasaharu
en-aut-sei=Takigawa
en-aut-mei=Masaharu
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=7
ORCID=

affil-num=1
en-affil=
kn-affil=Okayama University

affil-num=2
en-affil=
kn-affil=Okayama University

affil-num=3
en-affil=
kn-affil=Chosun University

affil-num=4
en-affil=
kn-affil=Okayama University

affil-num=5
en-affil=
kn-affil=Okayama University

affil-num=6
en-affil=
kn-affil=Okayama University

affil-num=7
en-affil=
kn-affil=Okayama University
en-keyword=neurotrophin
kn-keyword=neurotrophin
en-keyword=Trk
kn-keyword=Trk
en-keyword=distraction osteogenesis
kn-keyword=distraction osteogenesis
en-keyword=mechanical stress
kn-keyword=mechanical stress
END