G protein-coupled receptors and heterotrimeric G proteins in skeletal development, homeostasis, and disease

G protein signaling, encompassing G protein-coupled receptors (GPCRs), heterotrimeric G proteins, and their downstream effectors and regulators, plays a pivotal role in bone development, remodeling, and disease. In humans, mutations in specific GPCRs or G protein subunits impair skeletal development and metabolism, causing characteristic skeletal dysplasias and metabolic bone disorders. This review synthesizes recent advances in G protein and GPCR functions in osteoblasts and osteoclasts, integrating insights from key signaling pathways, mouse models, and human genetic studies. It critically evaluates the distinct roles of the four major G protein classes (Gαs, Gq/11, Gi/o, and G12/13) and provides in-depth analysis of prominent GPCRs involved in physiological bone formation and remodeling, including PTH1R, the calcitonin receptor, CaSR, relaxin family peptide receptors, cannabinoid receptors, Frizzled receptors, proton-sensing receptors, orphan receptors, lactate sensor receptors, free fatty acid receptors, and sphingosine-1-phosphate receptors. The review also examines pathway modulation by regulators of G protein signaling (RGS proteins) and GTPase-activating proteins (GAPs). Finally, it outlines emerging therapeutic approaches and future directions for targeting G protein signaling in bone biology and related diseases.