コラーゲン分解系と疾患

組織のコラーゲン沈着にはコラーゲン合成系と分解系の不均衡によって生ずる｡従来,主としてコラーゲン合成系が注目されていたが,最近の研究の進歩により,コラーゲン分解系が重要な役割を演ずることが明らかになってきた｡コラーゲンの分解系には細胞内と細胞外の二つの経路が存在する｡それぞれcollagenolytic cathepsinおよびmatrix metalloproteinases( MMP)がコラーゲン分解能を有する重要な酵素である｡その調節因子については細胞外の経路についての解明か進んでいる｡MMPの遺伝子の発現にはサイトカインや成長因子が関与し,IL-1やTNF-αは強力な誘導因子である｡一旦,遺伝子か発現すれば,MMPは合成され,細胞外に不活性型(latent form)で分泌される｡不活性型のMMPが活性化する過程にはplasminogen activator inhibitorやtissue inhibitors of metalloproteinases(TIMP)などの阻害因子が存在し,MMP活性を調節する｡TIMPの遺伝子の発現にもサイトカインや成長因子が関与する｡MMPがTIMPを上回るような病態では組織破壊が,逆にTIMPがMMPを上回るような病態では綿維化が生ずる｡コラーゲン分解能の障害が線維化の維持や不可逆性に関与することが推察される。

Fibrosis is the result of net accumulation of collagen in the organ. This may occur as a consequence of alterations in the synthesis of collagen, their degradation, or both. Recent investigations revealed that a decrease in collagen degradation plays a crucial role in fibrogenesis. Two pathways exist in collagen degradation : extracellular and intracellular. Each pathway has an important enzyme; that is, matrix metalloproteinases (MMP) and collagenolytic cathepsin, respectively. Collagenolytic activity is regulated at several levels. Expression of MMP and tissue inhibitors of metalloproteinase (TIMP), which act as inhibitors of MMP, is regulated independently by a number of cytokines and growth factors. MMP, which is synthesized in the cell, is secreted in a latent form. Activation of the latent MMP is controlled by TIMP and plasminogen activator inhibitor. TIMP also inhibits activated MMP which can degrade connective tissue matrices including collagens. In the condition where TIMP is predominant over MMP, activity of collagen breakdown is reduced, and consequently collagen deposition occurrs.