Ablation of Gsα signaling in osteoclast progenitor cells adversely affects skeletal bone maintenance.

Gsα, the alpha stimulatory subunit of heterotrimeric G proteins that activates downstream signaling through the adenylyl cyclase and cAMP/PKA pathway, plays an important role in bone development and remodeling. The role of Gsα in mesenchymal stem cell (MSC) differentiation to osteoblasts has been demonstrated in several mouse models of Gsα inactivation. Previously, using mice with heterozygous germline deletion of Gsα (Gnas+/p-), we identified a novel additional role for Gsα in bone remodeling, and showed the importance of Gnas in maintaining bone quality by regulating osteoclast differentiation and function. In this study, we show that postnatal deletion of Gsα (CreERT2;Gnasfl/fl) leads to reduction in trabecular bone quality parameters and increased trabecular osteoclast numbers. Furthermore, mice with deletion of Gsα specifically in cells of the macrophage/osteoclast lineage (LysM-Cre;Gnasfl/fl) showed reduced trabecular bone quality and increased trabecular osteoclasts, but to a reduced extent compared to the CreERT2;Gnasfl/fl global knockout. This demonstrates that while Gsα has a cell autonomous role in osteclasts in regulating bone quality, Gsα expression in other cell types additionally contribute. In both of these mouse models, cortical bone was more subtly affected than trabecular bone. Our results support that Gsα is required postnatally to maintain trabecular bone quality and that Gsα function to maintain trabecular bone is regulated in part through a specific activity in osteoclasts.