The Orphan Nuclear Receptor Estrogen Receptor-related Receptor γ Negatively Regulates BMP2-induced Osteoblast Differentiation and Bone Formation

Estrogen receptor-related receptor gamma(ERR gamma/ERR3/NR3B3) is a member of the orphan nuclear receptor with important functions in development and homeostasis. Recently it has been reported that ERR alpha is involved in osteoblast differentiation and bone formation. In the present study we examined the role of ERR gamma in osteoblast differentiation. Here, we showed that ERR gamma is expressed in osteoblast progenitors and primary osteoblasts, and its expression is increased temporarily by BMP2. Overexpression of ERR gamma reduced BMP2-induced alkaline phosphatase activity and osteocalcin production as well as calcified nodule formation, whereas inhibition of ERR gamma expression significantly enhanced BMP2-induced osteogenic differentiation and mineralization, suggesting that endogenous ERR gamma plays an important role in osteoblast differentiation. In addition, ERR gamma significantly repressed Runx2 transactivity on osteocalcin and bone sialoprotein promoters. We also observed that ERR gamma physically interacts with Runx2 in vitro and in vivo and competes with p300 to repress Runx2 transactivity. Notably, intramuscular injection of ERR gamma strongly inhibited BMP2-induced ectopic bone formation in a dose-dependent manner. Taken together, these results suggest that ERR gamma is a novel negative regulator of osteoblast differentiation and bone formation via its regulation of Runx2 transactivity.