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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. G\u03b1i proteins, critical mediators of immune signaling, are implicated in osteoclastogenesis, but their precise role remains unclear. It is demonstrated that G\u03b1i1\/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 G\u03b1i1\/3 in osteoclast precursors mitigates OVX\u2010induced bone loss, improving bone mass and structure. G\u03b1i1\/3\u2010deficient bone marrow monocytes and macrophages exhibit impaired osteoclast formation and reduced bone resorption. In contrast, overexpression of G\u03b1i1\/3 enhances osteoclast differentiation and function. In addition, the 173 Asp residue of G\u03b1i3 is identified as crucial for RANK\u2010TRAF6 binding during RANKL signaling. Inhibition of G\u03b1i1\/3 mimics the protective effects of denosumab, a treatment for osteoporosis, in mice. The findings position G\u03b1i1\/3 as a critical regulator of osteoclastogenesis and suggest it as a promising therapeutic target for osteoporosis.<\/jats:p>","DOI":"10.1002\/advs.202510836","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T08:49:23Z","timestamp":1770886163000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["G\u03b1i1\/3 Is a Novel Regulatory Target for RANKL Signal Transduction and Osteoporosis"],"prefix":"10.1002","volume":"13","author":[{"given":"Chaowen","family":"Bai","sequence":"first","affiliation":[{"name":"Department of Orthopedics The Second Affiliated Hospital of Soochow University  Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingchao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics The Second Affiliated Hospital of Soochow University  Suzhou 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