Myocyte-Specific Enhancer Factor 2A Potentiates Osteoclastic Differentiation in Osteoporosis by Inducing Endothelin Receptor Type A.

Activation of endothelin receptor type A (EDNRA) has been revealed to induce osteoclastic bone resorption during orthodontic treatment. In this study, we investigated the mechanisms by which EDNRA potentiates osteoclastic differentiation in ovariectomy (OVX)-induced mice with osteoporosis (OP)-like symptoms. The effects of knocking down EDNRA on OP in mice were observed using micro-CT, HE staining, TRAP staining, RT-qPCR, and immunoblotting. The effects of the knockdown of EDNRA in osteoclastic differentiation of bone marrow macrophages (BMs) were investigated by TRAP staining, F-actin staining, RT-qPCR, and immunoblotting. EDNRA was highly expressed in osteoporotic mice, and the knockdown of EDNRA in vivo alleviated osteoporotic phenotypes in OVX-induced mice by inhibiting osteoclast differentiation. BMs with EDNRA knockdown showed repressed MMP1, MMP8, and RANKL protein expression and Nfatc1, Ctsk, C-fos, and Trap mRNA expression. Myocyte-specific enhancer factor 2A (MEF2A) transcriptionally promoted EDNRA expression by binding to the EDNRA promoter. Silencing of MEF2A exerted the same anti-osteoporotic effects, which were reversed by overexpression of EDNRA. Altogether, our findings highlight that MEF2A knockdown alleviates loss of bone mass in the OVX-induced mice by suppressing osteoclast differentiation via inhibition of EDNRA transcription.