{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:28:01Z","timestamp":1791419281207,"version":"4.3.3"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T00:00:00Z","timestamp":1665532800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"James Laboratory by Musculoskeletal Transplant Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,11,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Heterotopic ossification (HO) is a dynamic, complex pathologic process that often occurs after severe polytrauma trauma, resulting in an abnormal mesenchymal stem cell differentiation leading to ectopic bone growth in soft-tissues including tendons, ligaments, and muscles. The abnormal bone structure and location induce pain and loss of mobility. Recently, we observed that NGF (Nerve growth factor)-responsive TrkA (Tropomyosin receptor kinase A)-expressing nerves invade sites of soft-tissue trauma, and this is a necessary feature for heterotopic bone formation at sites of injury. Here, we assayed the effects of the partial TrkA agonist Gambogic amide (GA) in peritendinous heterotopic bone after extremity trauma. Mice underwent HO induction using the burn\/tenotomy model with or without systemic treatment with GA, followed by an examination of the injury site via radiographic imaging, histology, and immunohistochemistry. Single-cell RNA Sequencing confirmed an increase in neurotrophin signaling activity after HO-inducing extremity trauma. Next, TrkA agonism led to injury site hyper-innervation, more brisk expression of cartilage antigens within the injured tendon, and a shift from FGF to TGF\u03b2 signaling activity among injury site cells. Nine weeks after injury, this culminated in higher overall levels of heterotopic bone among GA-treated animals. In summary, these studies further link injury site hyper-innervation with increased vascular ingrowth and ultimately heterotopic bone after trauma. In the future, modulation of TrkA signaling may represent a potent means to prevent the trauma-induced heterotopic bone formation and improve tissue regeneration.<\/jats:p>","DOI":"10.1093\/stcltm\/szac073","type":"journal-article","created":{"date-parts":[[2022,9,16]],"date-time":"2022-09-16T16:48:55Z","timestamp":1663346935000},"page":"1165-1176","source":"Crossref","is-referenced-by-count":24,"title":["TrkA+ Neurons Induce Pathologic Regeneration After Soft Tissue Trauma"],"prefix":"10.1093","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2300-4018","authenticated-orcid":false,"given":"Masnsen","family":"Cherief","sequence":"first","affiliation":[{"name":"Department of Pathology, Johns Hopkins University , Baltimore, MD , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2218-6654","authenticated-orcid":false,"given":"Stefano","family":"Negri","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins University , Baltimore, MD , USA"},{"name":"Department of Orthopaedics and Traumatology, University of Verona , Verona , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qizhi","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins University , Baltimore, MD , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chase A","family":"Pagani","sequence":"additional","affiliation":[{"name":"Center for Organogenesis and Trauma, Department of Surgery, University of Texas Southwestern , Dallas, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seungyong","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins University , Baltimore, MD , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunzhi Peter","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Stanford University , Stanford, CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas L","family":"Clemens","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Johns Hopkins University , Baltimore, MD , USA"},{"name":"Baltimore Veterans Administration Medical Center , Baltimore, MD , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Levi","sequence":"additional","affiliation":[{"name":"Center for Organogenesis and Trauma, Department of Surgery, University of Texas Southwestern , Dallas, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron W","family":"James","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins University , Baltimore, MD , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,10,12]]},"reference":[{"key":"2022111808205130100_CIT0001","doi-asserted-by":"crossref","first-page":"5428","DOI":"10.1111\/jcmm.15240","article-title":"Heterotopic ossification of tendon and ligament","volume":"24","author":"Zhang","year":"2020","journal-title":"J Cell Mol Med"},{"key":"2022111808205130100_CIT0002","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1080\/16501970510027628","article-title":"Heterotopic ossification: a review","volume":"37","author":"Vanden Bossche","year":"2005","journal-title":"J Rehabil Med."},{"key":"2022111808205130100_CIT0003","doi-asserted-by":"crossref","first-page":"e10172","DOI":"10.1002\/jbm4.10172","article-title":"Heterotopic ossification: a comprehensive review","volume":"3","author":"Meyers","year":"2019","journal-title":"JBMR 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