Pharmacologic or genetic targeting of peripheral nerves prevents peri-articular traumatic heterotopic ossification  

作　　者：Manyu Zhu Ji-Hye Yea Zhao Li Qizhi Qin Mingxin Xu Xin Xing Stefano Negri Mary Archer Monisha Mittal Benjamin Levi Aaron W.James 

机构地区：[1]Department of Pathology,Johns Hopkins University,Baltimore,MD 21205,USA [2]Orthopedic Unit,University of Verona,Verona,Italy [3]Department of Surgery,Center for Organogenesis and Trauma,University of Texas Southwestern Medical Center,Dallas,TX 75390,USA

出　　处：《Bone Research》2024年第4期863-876,共14页骨研究(英文版)

基　　金：supported by NIH/NIAMS (P01 AG066603,R01 AR079171,R01 AR079171-07S1,R21AR078919);NIH/NIDCR (R01 DE031488,R01 DE031028);Alex’s Lemonade Stand Foundation (22-26743);American Cancer Society (DBG-23-1155131-01-IBCD);the Maryland Stem Cell Research Foundation (2021-MSCRFD-5641);Department of Defense (USAMRAA HT9425-24-1-0051);supported by NIH/NIAMS (R01 AR079171-07,R01 AR079171-07S1)。

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 TGFβand 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.

关 键 词：NERVES TRAUMATIC alterations 

分 类 号：R681[医药卫生—骨科学]