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-ΐ (TGF-ΐ) 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-ΐ. Interestingly, CCN6 combined with BMP2 increased the gene expression of receptor activator of nuclear factor-ΘB 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=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=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=23
cd-vols=
no-issue=11
article-no=
start-page=5887
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2022
dt-pub=20220524
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Molecular and Genetic Interactions between CCN2 and CCN3 behind Their Yin-Yang Collaboration
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Cellular communication network factor (CCN) 2 and 3 are the members of the CCN family that conduct the harmonized development of a variety of tissues and organs under interaction with multiple biomolecules in the microenvironment. Despite their striking structural similarities, these two members show contrastive molecular functions as well as temporospatial emergence in living tissues. Typically, CCN2 promotes cell growth, whereas CCN3 restrains it. Where CCN2 is produced, CCN3 disappears. Nevertheless, these two proteins collaborate together to execute their mission in a yin-yang fashion. The apparent functional counteractions of CCN2 and CCN3 can be ascribed to their direct molecular interaction and interference over the cofactors that are shared by the two. Recent studies have revealed the mutual negative regulation systems between CCN2 and CCN3. Moreover, the simultaneous and bidirectional regulatory system of CCN2 and CCN3 is also being clarified. It is of particular note that these regulations were found to be closely associated with glycolysis, a fundamental procedure of energy metabolism. Here, the molecular interplay and metabolic gene regulation that enable the yin-yang collaboration of CCN2 and CCN3 typically found in cartilage development/regeneration and fibrosis are described.
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=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=HattoriTakako
en-aut-sei=Hattori
en-aut-mei=Takako
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, 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=
en-keyword=cellular communication network factor
kn-keyword=cellular communication network factor
en-keyword=CCN2
kn-keyword=CCN2
en-keyword=CCN3
kn-keyword=CCN3
en-keyword=cartilage
kn-keyword=cartilage
en-keyword=fibrosis
kn-keyword=fibrosis
en-keyword=glycolysis
kn-keyword=glycolysis
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=ͺRεwεw@γςw€Θ
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=56
cd-vols=
no-issue=1
article-no=
start-page=119
end-page=126
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2020
dt-pub=20201009
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Roles of CCN2 as a mechano-sensing regulator of chondrocyte differentiation
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Cellular communication network factor 2 (CCN2) is a cysteine-rich secreted matricellular protein that regulates various cellular functions including cell differentiation. CCN2 is highly expressed under several types of mechanical stress, such as stretch, compression, and shear stress, in mesenchymal cells including chondrocytes, osteoblasts, and fibroblasts. In particular, CCN2 not only promotes cell proliferation and differentiation of various cells but also regulates the stability of mRNA of TRPV4, a mechanosensitive ion channel in chondrocytes. Of note, CCN2 behaves like a biomarker to sense suitable mechanical stress, because CCN2 expression is down-regulated when chondrocytes are subjected to excessive mechanical stress. These findings suggest that CCN2 is a mechano-sensing regulator. CCN2 expression is regulated by the activation of various mechano-sensing signaling pathways, e.g., mechanosensitive ion channels, integrin-focal adhesion-actin dynamics, Rho GTPase family members, Hippo-YAP signaling, and G protein-coupled receptors. This review summarizes the characterization of mechanoreceptors involved in CCN2 gene regulation and discusses the role of CCN2 as a mechano-sensing regulator of mesenchymal cell differentiation, with particular focus on chondrocytes.
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=KubotaSatoshi
en-aut-sei=Kubota
en-aut-mei=Satoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
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=
en-keyword=Mechanoreceptors
kn-keyword=Mechanoreceptors
en-keyword=Cellular communication network factor 2 (CCN2)
kn-keyword=Cellular communication network factor 2 (CCN2)
en-keyword=Mechanical stress
kn-keyword=Mechanical stress
en-keyword=Chondrocytes
kn-keyword=Chondrocytes
END
start-ver=1.4
cd-journal=joma
no-vol=56
cd-vols=
no-issue=1
article-no=
start-page=119
end-page=126
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2020
dt-pub=202011
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Roles of CCN2 as a mechano-sensing regulator of chondrocyte differentiation
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Cellular communication network factor 2 (CCN2) is a cysteine-rich secreted matricellular protein that regulates various cellular functions including cell differentiation. CCN2 is highly expressed under several types of mechanical stress, such as stretch, compression, and shear stress, in mesenchymal cells including chondrocytes, osteoblasts, and fibroblasts. In particular, CCN2 not only promotes cell proliferation and differentiation of various cells but also regulates the stability of mRNA of TRPV4, a mechanosensitive ion channel in chondrocytes. Of note, CCN2 behaves like a biomarker to sense suitable mechanical stress, because CCN2 expression is down-regulated when chondrocytes are subjected to excessive mechanical stress. These findings suggest that CCN2 is a mechano-sensing regulator. CCN2 expression is regulated by the activation of various mechano-sensing signaling pathways, e.g., mechanosensitive ion channels, integrin-focal adhesion-actin dynamics, Rho GTPase family members, Hippo-YAP signaling, and G protein-coupled receptors. This review summarizes the characterization of mechanoreceptors involved in CCN2 gene regulation and discusses the role of CCN2 as a mechano-sensing regulator of mesenchymal cell differentiation, with particular focus on chondrocytes.
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=KubotaSatoshi
en-aut-sei=Kubota
en-aut-mei=Satoshi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
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=
en-keyword=Mechanoreceptors
kn-keyword=Mechanoreceptors
en-keyword=Cellular communication network factor 2 (CCN2)
kn-keyword=Cellular communication network factor 2 (CCN2)
en-keyword=Mechanical stress
kn-keyword=Mechanical stress
en-keyword=Chondrocytes
kn-keyword=Chondrocytes
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.
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.
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.
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=21
cd-vols=
no-issue=5
article-no=
start-page=1564
end-page=
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2020
dt-pub=20200225
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Retrotransposons Manipulating Mammalian Skeletal Development in Chondrocytes
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Retrotransposons are genetic elements that copy and paste themselves in the host genome through transcription, reverse-transcription, and integration processes. Along with their proliferation in the genome, retrotransposons inevitably modify host genes around the integration sites, and occasionally create novel genes. Even now, a number of retrotransposons are still actively editing our genomes. As such, their profound role in the evolution of mammalian genomes is obvious; thus, their contribution to mammalian skeletal evolution and development is also unquestionable. In mammals, most of the skeletal parts are formed and grown through a process entitled endochondral ossification, in which chondrocytes play central roles. In this review, current knowledge on the evolutional, physiological, and pathological roles of retrotransposons in mammalian chondrocyte differentiation and cartilage development is summarized. The possible biological impact of these mobile genetic elements in the future is also discussed.
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=IshikawaTakanori
en-aut-sei=Ishikawa
en-aut-mei=Takanori
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=2
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=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=NishidaTakashi
en-aut-sei=Nishida
en-aut-mei=Takashi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=5
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 Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
kn-affil=
en-keyword=retrotransposon
kn-keyword=retrotransposon
en-keyword=endogenous retrovirus
kn-keyword=endogenous retrovirus
en-keyword=chondrocyte
kn-keyword=chondrocyte
en-keyword=cartilage
kn-keyword=cartilage
en-keyword=skeletal development
kn-keyword=skeletal development
END
start-ver=1.4
cd-journal=joma
no-vol=115
cd-vols=
no-issue=5
article-no=
start-page=854
end-page=865
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2014
dt-pub=201405
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=CCN2 as a Novel Molecule Supporting Energy Metabolism of Chondrocytes
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=CCN2/connective tissue growth factor (CTGF) is a unique molecule that promotes both chondrocytic differentiation and proliferation through its matricellular interaction with a number of extracellular biomolecules. This apparently contradictory functional property of CCN2 suggests its certain role in basic cellular activities such as energy metabolism, which is required for both proliferation and differentiation. Comparative metabolomic analysis of costal chondrocytes isolated from wild-type and Ccn2-null mice revealed overall impaired metabolism in the latter. Among the numerous metabolites analyzed, stable reduction in the intracellular level of ATP, GTP, CTP, or UTP was observed, indicating a profound role of CCN2 in energy metabolism. Particularly, the cellular level of ATP was decreased by more than 50% in the Ccn2-null chondrocytes. The addition of recombinant CCN2 (rCCN2) to cultured Ccn2-null chondrocytes partly redeemed the cellular ATP level attenuated by Ccn2 deletion. Next, in order to investigate the mechanistic background that mediates the reduction in ATP level in these Ccn2-null chondrocytes, we performed transcriptome analysis. As a result, several metabolism-associated genes were found to have been up-regulated or down-regulated in the mutant mice. Up-regulation of a number of ribosomal protein genes was observed upon Ccn2 deletion, whereas a few genes required for aerobic and anaerobic ATP production were down-regulated in the Ccn2-null chondrocytes. Among such genes, reduction in the expression of the enolase 1 gene was of particular note. These findings uncover a novel functional role of CCN2 as a metabolic supporter in the growth-plate chondrocytes, which is required for skeletogenesis in mammals.
en-copyright=
kn-copyright=
en-aut-name=Maeda-UematsuAya
en-aut-sei=Maeda-Uematsu
en-aut-mei=Aya
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=KawakiHarumi
en-aut-sei=Kawaki
en-aut-mei=Harumi
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=MiyakeYoshiaki
en-aut-sei=Miyake
en-aut-mei=Yoshiaki
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=
en-aut-name=MoritaniNorifumi
en-aut-sei=Moritani
en-aut-mei=Norifumi
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=8
ORCID=
en-aut-name=LyonsKaren M.
en-aut-sei=Lyons
en-aut-mei=Karen M.
kn-aut-name=
kn-aut-sei=
kn-aut-mei=
aut-affil-num=9
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=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=
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, 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 Orthopaed Surg
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 Biochem & Mol Dent
affil-num=8
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Oral & Maxillofacial Reconstruct Surg
affil-num=9
en-affil=
kn-affil=Univ Calif Los Angeles, Sch Med, Dept Orthoped Surg
affil-num=10
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Oral & Maxillofacial Reconstruct Surg
affil-num=11
en-affil=
kn-affil=Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Biochem & Mol Dent
en-keyword=CCN2
kn-keyword=CCN2
en-keyword=CTGF
kn-keyword=CTGF
en-keyword=CARTILAGE
kn-keyword=CARTILAGE
en-keyword=CHONDROCYTES
kn-keyword=CHONDROCYTES
en-keyword=METABOLISM
kn-keyword=METABOLISM
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=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=
Background: 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.
Results: 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-ΐ. 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.
Conclusion: These results taken together suggest important roles of CCN2/CTGF in the development and regeneration of periodontal tissue including the periodontal ligament.