TY - JOUR
T1 - TrkA+Neurons Induce Pathologic Regeneration After Soft Tissue Trauma
AU - Cherief, Masnsen
AU - Negri, Stefano
AU - Qin, Qizhi
AU - Pagani, Chase A.
AU - Lee, Seungyong
AU - Yang, Yunzhi Peter
AU - Clemens, Thomas L.
AU - Levi, Benjamin
AU - James, Aaron W.
N1 - Funding Information:
We thank the JHU microscopy facility for its technical assistance. AWJ is funded by NIH/NIAMS (R01 AR070773, R01 AR068316, R01 AR079171), NIH/NIDCR (R21 DE027922), USAMRAA through the Peer Reviewed Medical Research Program (W81XWH-18-1-0121, W81XWH-18-1-0336), Peer Reviewed Orthopaedic Research Program (W81XWH-20-10795) and Broad Agency Announcement (W81XWH-18-10613), American Cancer Society (Research Scholar Grant, RSG-18-027-01-CSM), and the Maryland Stem Cell Research Foundation. BL is funded by the NIH (NIH1R01AR071379, R01 AR079171) and USAMRAA through the Peer Reviewed Orthopaedic Research Program (W81XWH-20-10795). TLC was supported by the NIH/ NIAMS (R01 AR068934), NIH/NIDCR (R21 DE027922), and the VA (Merit Award and Senior Research Career Scientist Award). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health or Department of Defense. Research unrelated to the work presented herein was supported in the James Laboratory by Musculoskeletal Transplant Foundation (MTF) Biologics and Novadip Biosciences.
Publisher Copyright:
© 2022 The Author(s). Published by Oxford University Press.
PY - 2022/11
Y1 - 2022/11
N2 - 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.
AB - 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.
KW - Gambogic amide
KW - NGF
KW - TrkA
KW - ectopic bone
KW - endochondral ossification
KW - heterotopic bone
KW - mesenchymal stem cells
KW - nerve growth factor
KW - osteogenesis
KW - sensory innervation
UR - http://www.scopus.com/inward/record.url?scp=85142402493&partnerID=8YFLogxK
U2 - 10.1093/stcltm/szac073
DO - 10.1093/stcltm/szac073
M3 - Article
C2 - 36222619
AN - SCOPUS:85142402493
SN - 2157-6564
VL - 11
SP - 1165
EP - 1176
JO - Stem Cells Translational Medicine
JF - Stem Cells Translational Medicine
IS - 11
ER -