TrkA+Neurons Induce Pathologic Regeneration After Soft Tissue Trauma

Masnsen Cherief, Stefano Negri, Qizhi Qin, Chase A. Pagani, Seungyong Lee, Yunzhi Peter Yang, Thomas L. Clemens, Benjamin Levi*, Aaron W. James*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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 TGFβ 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.

Original languageEnglish
Pages (from-to)1165-1176
Number of pages12
JournalStem Cells Translational Medicine
Issue number11
StatePublished - Nov 2022
Externally publishedYes


  • Gambogic amide
  • NGF
  • TrkA
  • ectopic bone
  • endochondral ossification
  • heterotopic bone
  • mesenchymal stem cells
  • nerve growth factor
  • osteogenesis
  • sensory innervation


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