Activation of PPARsα,β/δ,and γ impairs TGF-β1-induced collagens' production and modulates the TIMP-1/MMPs balance in three-dimensional cultured chondrocytes

Background and purpose. we investigated the potency of peroxisome proliferators-activated receptors (ppars) α,β/δ,and agonists to modulate transforming growth factor-β1 (tgf-β1-) induced collagen production or changes in tissue inhibitor of matrix metalloproteinase- (timp-) 1/matrix metalloproteinase (mmp) balance in rat chondrocytes embedded in alginate beads. experimental approach. collagen production was evaluated by quantitative sirius red staining,while timp-1 protein levels and global mmp (-1,-2,-3,-7,and -9) or specific mmp-13 activities were measured by elisa and fluorigenic assays in culture media,respectively. levels of mrna for type ii collagen,timp-1,and mmp-3 & 13 were quantified by real-time pcr. key results. tgf-β1 increased collagen deposition and type ii collagen mrna levels,while inducing timp-1 mrna and protein expression. in contrast,it decreased global mmp or specific mmp-13 activities,while decreasing mmp-3 or mmp-13 mrna levels. ppar agonists reduced most of the effects of tgf-β1 on changes in collagen metabolism and timp-1/mmp balance in rat in a ppar-dependent manner,excepted for wy14643 on mmp activities. conclusions and implications. ppar agonists reduce tgf-β1-modulated ecm turnover and inhibit chondrocyte activities crucial for collagen biosynthesis,and display a different inhibitory profile depending on selectivity for ppar isotypes. copyright © 2010 paul-emile poleni et al.