Bone Lymphatic Endothelial Cells Form a Distinct Skeletal Population and Drive Skeletal Repair

Abstract

Bone regeneration relies on specialized vascular niches, yet the contribution of lymphatic vessels across distinct skeletal sites remains poorly understood. Here, we identify bone lymphatics as an essential component of the regenerative microenvironment in the mandible and long bones. We demonstrate that bone lymphatic endothelial cells (LECs) constitute a specialized endothelial population that is transcriptionally and spatially distinct from periosteal LECs. During skeletal repair, bone LECs reactivate a regenerative transcriptional programme, and promote mandibular and fracture healing. In osteonecrosis of the jaw and periodontitis, bone lymphatic-associated signalling is disrupted, identifying impaired lymphatic function as a shared feature of mandibular disease. Therapeutic activation of VEGFC-FLT4 signalling during injury or mandibular disease restores lymphangiogenesis, enhances osteogenesis, and markedly improves bone regeneration. Together, our findings advance the paradigm-shifting role of bone lymphatics positive regulators of bone regeneration and identify lymphatic activation as a promising therapeutic strategy to enhance bone regeneration in mandibular diseases.