Autocrine regulation of collagenase 3 (matrix metalloproteinase 13) during osteoarthritis

Objective. To correlate the increased collagenase production previously seen in chondrocytes isolated from osteoarthritic (OA) lesions and the expression of cytokines and cytokine receptors, Methods. Chondrocytes were isolated from OA cartilage and characterized for synthesis of collagenases, cytokines, and cytokine receptors by Northern and Western blot analyses, RNA protection assay, and flow cytometry, Results. Chondrocytes located in cartilage proximal to the macroscopic OA lesions bound more tumor necrosis factor alpha (TNF alpha) and interleukin-1 beta (IL-1 beta) compared with chondrocytes isolated from morphologically normal cartilage from the same joint. In response to TNF alpha stimulation, messenger RNA (mRNA) levels for the IL-1 receptor I (IL-1RI), IL-1RII, TNF receptor II (TNFR II), and IL-6 receptor as well as the level of proinflammatory cytokines, such as IL-1 alpha, IL-1 beta, lymphotoxin beta, TNF alpha, and IL-6, also increased. In contrast, treatment with transforming growth factor beta 1 (TGF beta 1) resulted in down-regulation of matrix metalloproteinase 1 (MMP-1) and MMP-13 concomitant with a reduction in the levels of mRNA for IL-1RI, IL-1RII, TNFRI, and TNFRII and proinflammatory cytokine levels. In contrast, the levels of mRNA for TGF beta receptor I, TGF beta 1, and TGF beta 3 were up-regulated. Conclusion. These data show that TGF beta 1 has antagonistic effects upon OA chondrocytes, in contrast to the effects seen with TNF alpha, The cyclical course of OA, where a period of active disease is followed by a period of remission, can be explained by a sequential pattern of cytokine stimulation followed by a feedback inhibition of autocrine cytokine production and cytokine receptor expression, thus affecting collagenase synthesis.