A Rras2-BMPR2 feedback loop sustains osteogenesis and represents a therapeutic target for osteoporosis.

Ras-related protein 2 (Rras2) mutations are linked to Noonan syndrome, a disorder characterized by skeletal dysplasia and growth deficits. However, the role of Rras2 in bone homeostasis remains poorly defined, hindering the development of clinical interventions. Here, we show that Rras2 deficiency in mice leads to osteopenia, reduced bone strength, and impaired osteogenesis, recapitulating the clinical features of human patients. Mechanistically, Rras2 promotes osteogenic differentiation of bone marrow mesenchymal stem cells and supports bone regeneration. At the molecular level, Rras2 sustains BMP signaling by blocking Smurf1-dependent ubiquitination and degradation of BMPR2; in turn, BMP signaling enhances Rras2 transcription. Osteoporotic mice exhibit marked reduction in Rras2 expression in bone, and adeno-associated virus 9 (AAV9)-mediated restoration of Rras2 rescues bone loss. Our findings identify a Rras2-BMPR2 positive feedback loop that is critical for bone homeostasis and provide a therapeutic avenue for osteoporosis and Noonan syndrome.