Gαi1/3 Are Essential for BMP2-Induced Osteogenesis by Bridging BMP Receptors to the Gab1 Signaling Complex

BMP2 serves as a pivotal regulator of skeletal development, homeostasis, and repair. Previously, we demonstrated that Gαi1/3 (G protein subunit alpha i1/3) is not only involved in G protein-coupled receptor (GPCR) signal transduction but also acts as a key mediator of tyrosine kinase receptor signaling. However, its role in bone formation and BMP2 signaling remains elusive. In this study, we report that the expression of Gαi1/3 is significantly downregulated in the bone tissue of patients with senile osteoporosis. Gαi1/3 double knockout mice exhibited delayed skeletal development and reduced bone mass. Mechanistically, Gαi1/3 is required for BMP2 signal transduction, as its deletion impaired BMP2 downstream signaling. In BMSCs (bone marrow-derived mesenchymal stem cells), Gαi1/3 knockout suppressed BMP2-induced osteogenesis, while overexpression enhanced it. In the femoral fracture model, knockdown of Gαi1/3 in BMSCs reduced the ability of BMP2 to promote fracture healing. Furthermore, in neonatal mice with conditional knockout of Gαi1/3 in BMSCs, skeletal development was delayed. Gab1 is indispensable for Gαi1/3-mediated BMP2 signaling, as Gαi1/3 binds to both the BMP2 receptor and Gab1 to mediate BMP2 biological function. Collectively, our findings reveal the critical role of the Gαi1/3-Gab1 axis in BMP2 signaling and osteogenesis, providing potential therapeutic targets for osteoporosis and bone repair.