Cathepsin K is a critical protease in synovial fibroblast-mediated collagen degradation
Cathepsin K is a critical protease in synovial fibroblast-mediated collagen degradation
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DOI：
10.1016/s0002-9440(10)63068-4
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发表时间：
2001-12-01
影响因子：
6
通讯作者：
Brömme, D
中科院分区：
文献类型：
--
作者：
Hou, WS;Li, ZQ;Brömme, D
滑膜成纤维细胞（SFs）在类风湿关节炎（RA）的发病机制中起关键作用，并直接参与关节破坏。sf基质金属蛋白酶和组织蛋白酶都与软骨降解有关，尽管它们的身份和个体贡献尚不清楚。本研究的目的是研究组织蛋白酶K在sf中的表达，组织蛋白酶K的表达与疾病严重程度的关系，以及组织蛋白酶K在成纤维细胞介导的胶原降解中的作用。疣状;21例患者的关节标本显示滑膜SFs中组织蛋白酶K高表达。滑膜绒毛的细胞壁和基质，以及较少程度的cd68阳性细胞。在软骨和骨降解部位一致观察到组织蛋白酶k阳性的SFs。作为衡量个体患者RA严重程度的指标，组织蛋白酶K在炎症滑膜下和血管化区域的表达水平与汉诺威功能能力问卷的结果呈高度显著负相关（r = 0.78, P = 0.003; r = 0.70, P = 0.012）。相比之下，汉诺威功能能力问卷与组织蛋白酶S没有相关性，组织蛋白酶S的表达仅限于cd -68阳性的巨噬细胞样滑膜细胞。组织蛋白酶K在ra - sf原代细胞培养中也有表达。软骨盘上的SFs共培养显示成纤维细胞样细胞吞噬胶原原纤维的能力；在有效的组织蛋白酶K抑制剂存在的情况下，其溶酶体内水解被阻止，而对组织蛋白酶L， B，组织蛋白酶K在关节软骨和软骨下骨侵蚀中具有选择性和关键作用，这一发现进一步证实了组织蛋白酶K具有强大的聚合蛋白降解活性，并且组织蛋白酶K产生的聚合蛋白裂解产物特异性地增强了组织蛋白酶K对I型和H型胶原的胶原溶解活性。这项研究首次证明了组织蛋白酶K在风湿性关节炎中sf软骨降解中的关键作用，其作用与其在破骨细胞中的众所周知的活性相当。
Synovial fibroblasts (SFs) play a critical role in the pathogenesis of rheumatoid arthritis (RA) and are directly involved in joint destruction. Both SF-resident matrix metalloproteases and cathepsins have been implicated in cartilage degradation although their identities and individual contributions remain unclear. The aims of this study were to investigate the expression of cathepsin K in SFs, the correlation between cathepsin K expression and disease severity, and the contribution of cathepsin K to fibroblast-mediated collagen degradation. Immunostaining; of joint specimens of 21 patients revealed high expression of cathepsin K in SFs in the synovial. lining and the stroma of synovial villi, and to a lesser extent in CD68-positive cells of the synovial lining. Cathepsin K-positive SFs were consistently observed at sites of cartilage and bone degradation. Expression levels of cathepsin K in the sublining and vascularized areas of inflamed synovia showed a highly significant negative correlation with results derived from the Hannover Functional Capacity Questionnaire (r = 0.78, P = 0.003; and r = 0.70, P 0.012, respectively) as a measure of the severity of RA in individual patients. For comparison, there was no correlation between Hannover Functional Capacity Questionnaire and cathepsin S whose expression is limited to CD-68-positive macrophage-like synoviocytes. The expression of cathepsin K was also demonstrated in primary cell cultures of RA-SFs. Co-cultures of SFs on cartilage disks revealed the ability of fibroblast-like cells to phagocytose collagen fibrils; whose intralysosomal hydrolysis was prevented in the presence of a potent cathepsin K inhibitor but not by an inhibitor effective against cathepsins L, B, and S. The selective and critical role of cathepsin K in articular cartilage and subchondral bone erosion was further corroborated by the finding that cathepsin K has a potent aggrecan-degrading activity and that cathepsin K-generated aggrecan cleavage products specifically potentiate the collagenolytic activity of cathepsin K toward type I and H collagens. This study demonstrates for the first time a critical role of cathepsin K in cartilage degradation by SFs in RA that is comparable to its well-known activity in osteoclasts.