Gαs signaling in skeletal development, homeostasis and diseases

Skeletal development is exquisitely controlled both spatially and temporally by cell signaling networks. Gαs 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. Gαs, encoded by the GNAS gene in humans, plays critical roles in skeletal development and homeostasis by regulating commitment, differentiation and maturation of skeletal cells. Gαs-mediated signaling interacts with the Wnt and Hedgehog signaling pathways, both crucial regulators of skeletal development, remodeling and injury repair. Genetic mutations that disrupt Gαs 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 Gαs signaling during skeletal development and homeostasis, and the pathological mechanisms underlying skeletal diseases caused by GNAS mutations.