Lineage allocation of the marrow mesenchymal stem cells (MSCs) to osteoblasts and adipocytes is dependent on both Wnt signaling and PPARã2 activity. Activation of PPARã2, an essential regulator of energy metabolism and insulin sensitivity, stimulates adipocyte and suppresses osteoblast differentiation and bone formation, and correlates with decreased bone mass and increased fracture rate. In contrast, activation of Wnt signaling promotes osteoblast differentiation, augments bone accrual and reduces total body fat. This study examined the cross-talk between PPARã2 and â-catenin, a key mediator of canonical Wnt signaling, on MSC lineage determination. Rosiglitazone-activated PPARã2 induced rapid proteolytic degradation of â-catenin, which was prevented by either inhibiting glycogen synthase kinase 3 beta (GSK3â) activity, or blocking pro-adipocytic activity of PPARã2 using selective antagonist GW9662 or mutation within PPARã2 protein. Stabilization of â-catenin suppressed PPARã2 pro-adipocytic but not anti-osteoblastic activity. Moreover, â-catenin stabilization decreased PPARã2-mediated insulin signaling as measured by insulin receptor and FoxO1 gene expression, and protein levels of phosphorylated Akt (pAkt). Cellular knockdown of â-catenin with siRNA increased expression of adipocyte but did not affect osteoblast gene markers. Interestingly, the expression of Wnt10b was suppressed by anti-osteoblastic, but not by pro-adipocytic activity of PPARã2. Moreover, â-catenin stabilization in the presence of activated PPARã2 did not restore Wnt10b expression indicating a dominant role of PPARã2 in negative regulation of pro-osteoblastic activity of Wnt signaling. In conclusion, â-catenin and PPARã2 are in cross-talk which results in sequestration of pro-adipocytic and insulin sensitizing activity. The anti-osteoblastic activity of PPARã2 is independent of this interaction.
Adipocytes Anilides