A Critical Role for Collagen II in Cartilage Matrix Degradation: Collagen II Induces Pro-Inflammatory Cytokines and MMPs in Primary Human Chondrocytes

We report a process that results in the acceleration of matrix degradation in human articular cartilage a phenomenon commonly observed in ostcoarthritis (OA). The study was conducted by (1) examining the potential of collagen II in modulating the gene expression profile of primary human chondrocytes (PHCs), and (2) investigating the involvement of pro-inflammatory signaling cascades. We first tested the collagen II-dependent induction of pro-inflammatory cytokines and matrix metalloproteinases (MMPs) in PHCs. PHCs were incubated with or without monomeric (i.e., nonfibrillar) collagen II. Cells were then analyzed by RT-PCR for the expression of MMP1, MMP3, MMP13, MMP14, and IL-1 beta was used to quantify IL-6 and IL-8 release. To examine the influence of collagen II signaling, specifically the role of MAPK p38, a p38-inhibitor was added prior to collagen treatment. Changes in I kappa B concentration were monitored by immunoblot analysis to detect NF kappa B signaling. Results indicated that incubation of PHCs with Collagen II did produce a dose-dependent induction of MMP1, MMP3, MMP13, MMP14, as well as cytokine IL-1 beta, IL-6, and IL-8. At the same time, inhibiton of p38 and I kappa B degradation revealed that collagen II-dependent gene induction also involves MAPK p38 and NF kappa B signaling. Thus, we provide evidence for a collagen II-dependent feed-forward mechanism whereby collagen II induces first MMPS and pro-inflammatory cytokines and then release of collagen II fragments from mature collagen II fibers. This in turn, induces more pro-inflammatory cytokines and MMPs, and the process is repeated. which results in the acceleration and perpetuation of cartilage matrix degradation. (C) 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:65-70, 2009