PPARgamma2 expression in growth plate chondrocytes is regulated by p38 and GSK-3

Although peroxisome proliferator activated receptor (PPAR)gamma remains a critical regulator of preadipocyte differentiation, new roles have been discovered in inflammation, bone morphogenesis, endothelial function, cancer, longevity and atherosclerosis. Despite the demonstration of PPARgamma expression in chondrocytes, its role and the pathways affecting its expression and activity in chondrocytes remain largely unknown. We investigated the effects of PPARgamma activation on chondrocyte differentiation and its participation in chondrocyte lipid metabolism. PPARgamma2 expression is highly regulated during chondrocyte differentiation in vivo and in vitro PPARgamma activation with troglitazone resulted in increased Indian hedgehog expression and reduced collagen X expression, confirming previously described roles in the inhibition of differentiation. However, the major effect of PPARgamma2 in chondrocytes appears to be on lipid metabolism. During differentiation chondrocytes increase expression of the lipid-associated metabolizing protein, Lpl, which is accompanied by increased gene expression of PPARgamma. PPARgamma expression is suppressed by p38 activity, but requires GSK-3 activity. Furthermore, Lpl expression is regulated by p38 and GSK-3 signalling. This is the first study demonstrating a relationship between PPARgamma2 expression and chondrocyte lipid metabolism and its regulation by p38 and GSK-3 signalling.