摘要Heterotopic ossification(HO)is a pathological process that commonly arises following severe polytrauma,characterized by the anomalous differentiation of mesenchymal progenitor cells and resulting in the formation of ectopic bone in non-skeletal tissues.This abnormal bone growth contributes to pain and reduced mobility,especially when adjacent to a joint.Our prior observations suggested an essential role of NGF(Nerve Growth Factor)-responsive TrkA(Tropomyosin Receptor Kinase A)-expressing peripheral nerves in regulating abnormal osteochondral differentiation following tendon injury.Here,we utilized a recently developed mouse model of hip arthroplasty-induced HO to further validate the role of peripheral nerve regulation of traumatic HO.Nerve ingrowth was either modulated using a knockin transgenic animals with point mutation in TrkA,or local treatment with an FDA-approved formulation of long acting Bupivacaine which prevents peripheral nerve growth.Results demonstrate exuberant sensory and sympathetic nerve growth within the peri-articular HO site,and that both methods to reduce local innervation significantly reduced heterotopic bone formation.TrkA inhibition led to a 34%reduction in bone volume,while bupivacaine treatment resulted in a 50%decrease.Mechanistically,alterations in TGFβ and FGF signaling activation accompanied both methods of local denervation,and a shift in macrophages from M1 to M2 phenotypes was observed.In sum,these studies reinforce the observations that peripheral nerves play a role in the etiopathogenesis of HO,and that targeting local nerves represents a potential therapeutic approach for disease prevention.