Estrogen-related receptor γ negatively regulates osteoclastogenesis and protects against inflammatory bone loss

Estrogen-related receptor γ (ERRγ) is an orphan nuclear receptor that plays an important role in various metabolic processes under physiological and pathophysiological conditions. Here, we report that ERRγ functions as a negative regulator in receptor activator of nuclear factor κΒ ligand (RANKL)-induced osteoclast differentiation. We observed that ERRγ was strongly expressed in osteoclast precursors, bone marrow-derived macrophages (BMMs) while its expression was significantly reduced by RANKL during osteoclastogenesis. Overexpression of ERRγ in BMMs suppressed the formation of multinucleated osteoclasts and attenuated the induction of c-Fos and nuclear factor of activated T cells c1, which are critical modulators in osteoclastogenesis. Similarly, the treatment of ERRγ agonists, N-(4-(diethylaminobenzylidenyl)-N'-(4-hydroxybenzoyl)-hydrazine (DY131) or GSK4716, also inhibited osteoclast generation and the expression of these key modulators. On the other hand, shRNA-mediated knockdown of ERRγ accelerated the formation of bone-resorbing cells and the expression of osteoclastogenic markers. Forced expression of ERRγ blocked RANKL-stimulated phosphorylation of the nuclear factor κB (NF-κB) inhibitor IκBα and suppressed NF-κB transcriptional activity induced by RANKL or the NF-κB subunit p65. Furthermore, by employing a pharmacological approach, we showed that the ERRγ agonist DY131 protected against inflammatory bone loss induced by lipopolysaccharide in vivo. Together, our findings reveal that ERRγ is a pivotal regulator in RANKL-mediated osteoclastogenesis and suggest that ERRγ may have potential as a therapeutic target for pathological bone loss.