Abstract

Based on its homology to the estrogen receptor and its roles in osteoblast and chondrocyte differentiation, the orphan nuclear receptor estrogen-related receptor α (ERRα (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 ERRα modulates osteoblastogenesis. Experiments from multiple systems demonstrated that ERRα modulates Wnt signaling, a crucial pathway for proper regulation of bone development. This was validated using a Wnt-luciferase reporter, where ERRα showed co-activator-dependent (peroxisome proliferator-activated receptor gamma co-activator 1α, PGC-1α) stimulatory effects. Interestingly, knockdown of ERRα expression also enhanced WNT signaling. In combination, these data indicated that ERRα could serve to either activate or repress Wnt signaling depending on the presence or absence of its co-activator PGC-1α. The observed Wnt pathway modulation was cell intrinsic and did not alter β-catenin nuclear translocation but was dependent on DNA binding of ERRα. We also found that expression of active ERRα correlated with Wnt pathway effects on osteoblastic differentiation in two cell types, consistent with a role for ERRα in modulating the Wnt pathway. In conclusion, this work identifies ERRα, in conjunction with co-activators such as PGC-1α, as a new regulator of the Wnt-signaling pathway during osteoblast differentiation, through a cell-intrinsic mechanism not affecting β-catenin nuclear translocation.