Osteoblastic cells indirectly induce osteoclastogenesis in the bone microenvironment by expressing paracrine factors, such as RANKL and M-CSF, leading to increased bone resorption. These cytokines can be regulated by a variety of intracellular pathways that include G protein-coupled receptor signaling. To explore how enhanced signaling of the Gαq/11 pathway in osteoblast lineage cells may mediate osteoclast formation, we co-cultured wild-type (WT) pre-osteoclasts with BMSCs derived from either WT or transgenic mice with osteoblast-specific overexpression of Gα11 (G11-Tg). G11-Tg co-cultures had elevated osteoclast numbers with greater resorptive capacity and increased expression of Rankl, Rankl:Opg and M-csf than co-cultures with WT BMSCs. As well, co-cultures with G11-Tg BMSCs required a higher concentration of OPG to inhibit osteoclast formation and less angiotensin II to increase osteoclast size. These indicate that G11-Tg osteoblasts drive the increased osteoclast formation and osteopenia seen in G11-Tg mice. Pamidronate treatment of G11-Tg mice restored the trabecular bone loss phenotype, as bone mineral density, bone volume, trabecular number, separation, and expressions of osteoblastic and osteoclastic genes were comparable to wild-type parameters. These changes were characterized by enhanced accumulation of calcified cartilage in trabecular bone, demonstrating that resorption of the cartilaginous intermediate by osteoclasts are more affected by bisphosphonate treatment in G11-Tg mice. In conclusion, overexpression of Gα11 in osteoblastic cells promotes osteoclastogenesis by upregulation of Rankl and M-csf, and bone loss by increased osteoclast resorption of the trabecular bone and cartilaginous matrix.
- trabecular bone
- Copyright © 2016, American Journal of Physiology - Endocrinology and Metabolism