Bone transport accelerates diabetic foot ulcer healing via TGF-β1-mediated angiogenic and osteo-immune coupling.

Diabetic foot ulcer (DFU), often complicated by peripheral artery disease and local ischemia, remains a major clinical challenge. Bone transport (BT) is a surgical technique known to promote both osteogenesis and angiogenesis, and has shown promise in facilitating DFU healing. However, the underlying molecular mechanisms, especially the role of the TGF‑β1 signaling pathway, are not yet fully understood. Seventy-five Sprague-Dawley rats with ischemic diabetic foot ulcers (DFUs) were randomly assigned to three groups: sham (osteotomy without distraction), BT, and BT with TGF-β1 pathway inhibition (BTI). Wound healing was evaluated using serial wound measurement and histology. The contribution of the TGF-β1 pathway was assessed using proteomics, ELISA, RT-qPCR, and immunohistochemistry.The BT group exhibited accelerated wound closure, greater dermal thickness, and enhanced re-epithelialization compared to the sham and BTI groups. Proteomic analysis revealed upregulation of TGF-β1 and TGFBR1 expression in BT-treated wounds, accompanied by activation of the TGF-β1/TGFBR1 pathway. Notably, BT also triggered a systemic immune response, including complement activation and inflammatory regulation, indicating the involvement of both innate and adaptive immunity. Consistently, serum concentrations of TGF-β1 and VEGF were increased in the BT group than the other two groups, paralleled by elevated local expression of TGF-β1, TGFBR1, VEGF, and α-SMA at the wound sites. These pro-healing effects were markedly attenuated in the BTI group. BT stimulated the release of osteokines and growth factors, including TGF-β1, which activated the TGF-β1/TGFBR1 pathway to couple osteogenesis with angiogenesis and immunomodulation, thereby promoting diabetic wound repair. Targeting the TGF-β1/TGFBR1 pathway is likely a promising treatment for enhancing diabetic wound healing.