Gα_s signaling in skeletal development, homeostasis and diseases

Skeletal development is exquisitely controlled both spatially and temporally by cell signaling networks. Gα_s is the stimulatory α-subunit in a heterotrimeric G protein complex transducing the signaling of G-protein-coupled receptors (GPCRs), responsible for controlling both skeletal development and homeostasis. Gα_s, encoded by the GNAS gene in humans, plays critical roles in skeletal development and homeostasis by regulating commitment, differentiation and maturation of skeletal cells. Gα_s-mediated signaling interacts with the Wnt and Hedgehog signaling pathways, both crucial regulators of skeletal development, remodeling and injury repair. Genetic mutations that disrupt Gα_s functions cause human disorders with severe skeletal defects, such as fibrous dysplasia of bone and heterotopic bone formation. This chapter focuses on the crucial roles of Gα_s signaling during skeletal development and homeostasis, and the pathological mechanisms underlying skeletal diseases caused by GNAS mutations.