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.