Elucidation of the mechanism of aggrecan degradation and epigenetic regulation of aggrecanase expression in osteoarthritic cartilage

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We investigated the mechanism of mechanical stress-induced expression and regulation of aggrecanases and examined the role of runt-related transcription factor 2 (RUNX-2) in chondrocyte-like cells. A uni-axial cyclic tensile strain (CTS) (0.5 Hz, 10% stretch) induced expression of RUNX-2, MMP-13, ADAMTS-4, -5, and -9 by SW1353 cells. Overexpression of RUNX-2 up-regulated expression of MMP-13 and ADAMTS-5, whereas RUNX-2 siRNA resulted in significant downregulation of mechanically-induced MMP-13 and ADAMTS-5 expression. CTS induced activation of p38 MAPK, and CTS induction of RUNX-2, MMP-13 and ADAMTS-5 mRNA was down-regulated by the selective p38 MAPK inhibitor SB203580 but not by the p44/42 MAPK inhibitor U0126, or the JNK MAPK inhibitor JNK inhibitor II. These results suggested that RUNX-2 might have a role as a key downstream mediator of p38's ability to regulate mechanical stress-induced MMP-13 and ADAMTS-5 expression. Furthermore, histone deacetylase (HDAC) inhibitor, trichostatin A and MS-275 downregulated the expression of mechanically-induced RUNX-2 and ADAMTS-5. The epigenetic regulation of RUNX-2 transcriptional factor by HDAC inhibitor might be beneficial for the suppression of cartilage degeneration of early phase of osteoarthritis.