Gα12 regulates osteoclastogenesis by modulating NFATc1 expression.

The G12 family of G protein alpha subunits has been shown to participate in the regulation of various physiological processes. However, the role of G alpha 12 in bone physiology has not been well described. Here, by micro-CT analysis, we discovered that G alpha 12-knockout mice have an osteopetrotic phenotype. Histological examination showed lower osteoclast number in femoral tissue of G alpha 12-knockout mice compared to wild-type mice. Additionally, in vitro osteoclastic differentiation of precursor cells with receptor activator of nuclear factor-kappa B ligand (RANKL) showed that G alpha 12 deficiency decreased the number of osteoclast generated and the bone resorption activity. The induction of nuclear factor of activated T-cell c1 (NFATc1), the key transcription factor of osteoclastogenesis, and the activation of RhoA by RANKL was also significantly suppressed by G alpha 12 deficiency. We further found that the RANKL induction of NFATc1 was not dependent on RhoA signalling, while osteoclast precursor migration and bone resorption required RhoA in the G alpha 12-mediated regulation of osteoclasts. Therefore, G alpha 12 plays a role in differentiation through NFATc1 and in cell migration and resorption activity through RhoA during osteoclastogenesis.