Estrogen-related receptor α regulates osteoblast differentiation via Wnt/β-catenin signaling

Based on its homology to the estrogen receptor and its roles in osteoblast and chondrocyte differentiation, the orphan nuclear receptor estrogen-related receptor alpha (ERR alpha (ESRRA)) is an intriguing therapeutic target for osteoporosis and other bone diseases. The objective of this study was to better characterize the molecular mechanisms by which ERR alpha modulates osteoblastogenesis. Experiments from multiple systems demonstrated that ERR alpha modulates Wnt signaling, a crucial pathway for proper regulation of bone development. This was validated using a Wnt-luciferase reporter, where ERR alpha showed co-activator-dependent (peroxisome proliferator-activated receptor gamma co-activator 1 alpha, PGC-1 alpha) stimulatory effects. Interestingly, knockdown of ERR alpha expression also enhanced WNT signaling. In combination, these data indicated that ERR alpha could serve to either activate or repress Wnt signaling depending on the presence or absence of its co-activator PGC-1 alpha. The observed Wnt pathway modulation was cell intrinsic and did not alter beta-catenin nuclear translocation but was dependent on DNAbinding of ERR alpha. We also found that expression of active ERR alpha correlated with Wnt pathway effects on osteoblastic differentiation in two cell types, consistent with a role for ERR alpha in modulating the Wnt pathway. In conclusion, this work identifies ERR alpha, in conjunction with co-activators such as PGC-1 alpha, as a new regulator of the Wnt-signaling pathway during osteoblast differentiation, through a cell-intrinsic mechanism not affecting beta-catenin nuclear translocation. Journal of Molecular Endocrinology (2012) 48, 177-191