Soluble Sema4D From γδ T Cells Exerts Osteoblast Inhibition via Plexin‐B/mTOR Signalling Contributing to Pathogenesis of Bisphosphonate‐Related Osteonecrosis of the Jaws

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe complication in patients undergoing long-term bisphosphonate therapy, while our knowledge on the pathogenesis of BRONJ is far from sufficient. Gamma delta (γδ) T cells predominantly distribute in mucosal tissues and play an important role in both immune modulation and bone metabolism; however, the mechanism of γδ T cells in the pathogenesis of BRONJ has not been elucidated. Here, we induced BRONJ-like lesions in wild-type (WT) and T-cell receptor delta-deficient (TCRδ^-/-) mice via intraperitoneal zoledronate injection. Our findings revealed that γδ T cells infiltrating BRONJ lesions suppressed osteoblast differentiation, whereas γδ T cell depletion in TCRδ^-/- mice restored osteogenic function and significantly reduced BRONJ lesion incidence. Mechanistically, we identified matrix metalloproteinase 3 (MMP3) secreted by activated γδ T cells as a critical enzyme cleaving membrane-bound Sema4D (mSema4D) into soluble Sema4D (sSema4D). This cleavage product bound to Plexin-B1/2 receptors on osteoblasts, activating the mTOR signalling pathway to inhibit osteogenic differentiation (ALP/Runx2 downregulation). To promote the repair of BRONJ lesions, we engineered a dual-functional composite hydrogel (Gel-BG@ab) combining PLGA-PEG-PLGA with mesoporous bioactive glass (BG) and anti-Sema4D antibodies. This composite hydrogel achieved sustained antibody release, effectively neutralising sSema4D, restoring osteoblast activity and reducing the formation of BRONJ-like lesions in vivo. This study provides evidence of MMP3-Sema4D-Plexin-B1/2/mTOR crosstalk in BRONJ and introduces a targeted biomaterial strategy to disrupt pathogenic feedback loops. The Gel-BG@ab is the integration of immunomodulation and regenerative medicine, providing both theoretical and technical insights for the immune-material combination therapy of BRONJ.