G protein-coupled receptor signaling in osteogenic bone mesenchymal stem/stromal cells

Skeletal integrity is maintained throughout the lifespan by tightly coordinated actions of cells in the bone microenvironment. In healthy bone, matrix resorption by osteoclasts is balanced by new matrix synthesis by osteoblasts. Tipping this balance to favor resorption depletes bone mineral and disrupts microarchitecture, eventually leading to osteoporosis. Bone mesenchymal stem/stromal cells (BMSCs) are the progenitors of osteoblasts and play a central role in maintaining bone mass. With age and disease, BMSC number and function decline. Defining mechanisms that restore the mesenchymal progenitor population may yield targets for new osteoporosis therapeutics. G protein-coupled receptors (GPCRs) are a major class of receptors through which systemic hormones, neural inputs, mechanical cues, and local paracrine factors converge to regulate BMSC fate, survival, and differentiation. Although GPCRs are the target of approximately one-third of all drugs, only a small number of GPCR-mediated anabolic therapies are currently available to treat osteoporosis. Here, we synthesize the current understanding of classical GPCR signaling pathways in BMSCs and discuss how their dysregulation contributes to bone loss. We further highlight emerging non-classical GPCR targets and effectors that may work to expand the healthy BMSC pool, thereby enhancing bone formation. Defining druggable GPCR signaling axes in BMSCs is a promising strategy to develop safe and effective anabolic therapeutics for osteoporosis.