Billinghurst R C, Dahlberg L, Ionescu M, Reiner A, Bourne R, Rorabeck C, Mitchell P, Hambor J, Diekmann O, Tschesche H, Chen J, Van Wart H, Poole A R
Department of Surgery, McGill University, Montreal, Quebec, Canada.
J Clin Invest. 1997 Apr 1;99(7):1534-45. doi: 10.1172/JCI119316.
We demonstrate the direct involvement of increased collagenase activity in the cleavage of type II collagen in osteoarthritic human femoral condylar cartilage by developing and using antibodies reactive to carboxy-terminal (COL2-3/4C(short)) and amino-terminal (COL2-1/4N1) neoepitopes generated by cleavage of native human type II collagen by collagenase matrix metalloproteinase (MMP)-1 (collagenase-1), MMP-8 (collagenase-2), and MMP-13 (collagenase-3). A secondary cleavage followed the initial cleavage produced by these recombinant collagenases. This generated neoepitope COL2-1/4N2. There was significantly more COL2-3/4C(short) neoepitope in osteoarthritis (OA) compared to adult nonarthritic cartilages as determined by immunoassay of cartilage extracts. A synthetic preferential inhibitor of MMP-13 significantly reduced the unstimulated release in culture of neoepitope COL2-3/4C(short) from human osteoarthritic cartilage explants. These data suggest that collagenase(s) produced by chondrocytes is (are) involved in the cleavage and denaturation of type II collagen in articular cartilage, that this is increased in OA, and that MMP-13 may play a significant role in this process.
我们通过研发并使用与胶原酶基质金属蛋白酶（MMP）-1（胶原酶-1）、MMP-8（胶原酶-2）和MMP-13（胶原酶-3）切割天然人II型胶原所产生的羧基末端（COL2-3/4C（短链））和氨基末端（COL2-1/4N1）新表位反应的抗体，证明了骨关节炎患者股骨髁软骨中胶原酶活性增加在II型胶原切割过程中的直接作用。这些重组胶原酶产生的初始切割之后会发生二次切割，从而产生新表位COL2-1/4N2。通过对软骨提取物进行免疫测定发现，与成人非关节炎软骨相比，骨关节炎（OA）中COL2-3/4C（短链）新表位明显更多。一种MMP-13的合成选择性抑制剂显著降低了人骨关节炎软骨外植体在培养中未受刺激时新表位COL2-3/4C（短链）的释放。这些数据表明，软骨细胞产生的胶原酶参与了关节软骨中II型胶原的切割和变性，在OA中这种情况会增加，并且MMP-13可能在此过程中发挥重要作用。
