Gαi1/3 Is a Novel Regulatory Target for RANKL Signal Transduction and Osteoporosis

Osteoporosis, characterized by progressive bone loss and increased fracture risk, is a growing concern as the population ages. Current treatments, though advanced, remain limited, underscoring the necessity for novel therapeutic targets. Recent studies have shown that the immune system plays a key role in osteoporosis, with osteoclasts driving bone resorption. Gαi proteins, critical mediators of immune signaling, are implicated in osteoclastogenesis, but their precise role remains unclear. It is demonstrated that Gαi1/3 was highly expressed in osteoclast precursors and mature osteoclasts, with elevated levels in the bone marrow of osteoporotic patients and ovariectomized (OVX) mice. Conditional knockout of Gαi1/3 in osteoclast precursors mitigates OVX-induced bone loss, improving bone mass and structure. Gαi1/3-deficient bone marrow monocytes and macrophages exhibit impaired osteoclast formation and reduced bone resorption. In contrast, overexpression of Gαi1/3 enhances osteoclast differentiation and function. In addition, the 173 Asp residue of Gαi3 is identified as crucial for RANK-TRAF6 binding during RANKL signaling. Inhibition of Gαi1/3 mimics the protective effects of denosumab, a treatment for osteoporosis, in mice. The findings position Gαi1/3 as a critical regulator of osteoclastogenesis and suggest it as a promising therapeutic target for osteoporosis.