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When the Nervous System Turns Skeletal Muscles into Bones: How to Solve the Conundrum of Neurogenic Heterotopic Ossification

  • Skeletal Biology and Regulation (MR Forwood and A Robling, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Neurogenic heterotopic ossification (NHO) is the abnormal formation of extra-skeletal bones in periarticular muscles after damage to the central nervous system (CNS) such as spinal cord injury (SCI), traumatic brain injury (TBI), stroke, or cerebral anoxia. The purpose of this review is to summarize recent developments in the understanding of NHO pathophysiology and pathogenesis. Recent animal models of NHO and recent findings investigating the communication between CNS injury, tissue inflammation, and upcoming NHO therapeutics are discussed.

Recent Findings

Animal models of NHO following TBI or SCI have shown that NHO requires the combined effects of a severe CNS injury and soft tissue damage, in particular muscular inflammation and the infiltration of macrophages into damaged muscles plays a key role. In the context of a CNS injury, the inflammatory response to soft tissue damage is exaggerated and persistent with excessive signaling via substance P-, oncostatin M-, and TGF-β1-mediated pathways.

Summary

This review provides an overview of the known animal models and mechanisms of NHO and current therapeutic interventions for NHO patients. While some of the inflammatory mechanisms leading to NHO are common with other forms of traumatic and genetic heterotopic ossifications (HO), NHOs uniquely involve systemic changes in response to CNS injury. Future research into these CNS-mediated mechanisms is likely to reveal new targetable pathways to prevent NHO development in patients.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Ohlmeier M, Suero EM, Aach M, Meindl R, Schildhauer TA, Citak M. Muscle localization of heterotopic ossification following spinal cord injury. Spine J. 2017;17(10):1519–22. https://doi.org/10.1016/j.spinee.2017.04.021.

    Article  PubMed  Google Scholar 

  2. Genet F, Jourdan C, Schnitzler A, Lautridou C, Guillemot D, Judet T, et al. Troublesome heterotopic ossification after central nervous system damage: a survey of 570 surgeries. PLoS One. 2011;6(1):e16632. https://doi.org/10.1371/journal.pone.0016632.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Dejerine M, Ceillier A, Dejerine Y. Para-osteo-arthropathies des paraplegiques par lesion medullaire: Etude anatomique et histologique. Rev Neurol. 1919;26:399–407.

    Google Scholar 

  4. Dejerine M, Ceillier MA. Trois cas d'ostéomes – Ossifications périostés juxta-musculaires chez les paraplegiques par lesion traumatique de la moelle épinière. Rev Neurol. 1918;1:159–74.

    Google Scholar 

  5. Schurch B, Dollfus P. The ‘Dejerines’: an historical review and homage to two pioneers in the field of neurology and their contribution to the understanding of spinal cord pathology. Spinal Cord. 1998;36(2):78–86. https://doi.org/10.1038/sj.sc.3100561.

    Article  CAS  PubMed  Google Scholar 

  6. Forsberg JA, Pepek JM, Wagner S, Wilson K, Flint J, Andersen RC, et al. Heterotopic ossification in high-energy wartime extremity injuries: prevalence and risk factors. J Bone Joint Surg Am. 2009;91(5):1084–91. https://doi.org/10.2106/jbjs.h.00792.

    Article  PubMed  Google Scholar 

  7. Bevevino AJ, Lehman RA Jr, Tintle SM, Kang DG, Dworak TC, Potter BK. Incidence and morbidity of concomitant spine fractures in combat-related amputees. Spine J. 2014;14(4):646–50. https://doi.org/10.1016/j.spinee.2013.06.098.

    Article  PubMed  Google Scholar 

  8. Hoyt BW, Pavey GJ, Potter BK, Forsberg JA. Heterotopic ossification and lessons learned from fifteen years at war: a review of therapy, novel research, and future directions for military and civilian orthopaedic trauma. Bone. 2018;109:3–11. https://doi.org/10.1016/j.bone.2018.02.009.

    Article  PubMed  Google Scholar 

  9. Aubut JA, Mehta S, Cullen N, Teasell RW. A comparison of heterotopic ossification treatment within the traumatic brain and spinal cord injured population: an evidence based systematic review. NeuroRehabilitation. 2011;28(2):151–60. https://doi.org/10.3233/NRE-2011-0643.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Haran M, Bhuta T, Lee B. Pharmacological interventions for treating acute heterotopic ossification. Cochrane Database Syst Rev. 2004(4):Cd003321. https://doi.org/10.1002/14651858.CD003321.pub3.

  11. Dizdar D, Tiftik T, Kara M, Tunc H, Ersoz M, Akkus S. Risk factors for developing heterotopic ossification in patients with traumatic brain injury. Brain Inj. 2013;27(7–8):807–11. https://doi.org/10.3109/02699052.2013.775490.

    Article  PubMed  Google Scholar 

  12. Reznik JE, Biros E, Marshall R, Jelbart M, Milanese S, Gordon S, et al. Prevalence and risk-factors of neurogenic heterotopic ossification in traumatic spinal cord and traumatic brain injured patients admitted to specialised units in Australia. J Musculoskelet Neuronal Interact. 2014;14(1):19–28.

    CAS  PubMed  Google Scholar 

  13. Vanden Bossche L, Vanderstraeten G. Heterotopic ossification: a review. J Rehabil Med. 2005;37(3):129–36. https://doi.org/10.1080/16501970510027628.

    Article  Google Scholar 

  14. Bradleigh LH, Perkash A, Linder SH, Sullivan GH, Bhatt HK, Perkash I. Deep venous thrombosis associated with heterotopic ossification. Arch Phys Med Rehabil. 1992;73(3):293–4.

    CAS  PubMed  Google Scholar 

  15. Salga M, Jourdan C, Durand MC, Hangard C, Denormandie P, Carlier RY, et al. Sciatic nerve compression by neurogenic heterotopic ossification: use of CT to determine surgical indications. Skelet Radiol. 2014;44:233–40. https://doi.org/10.1007/s00256-014-2003-6.

    Article  Google Scholar 

  16. Genet F, Chehensse C, Jourdan C, Lautridou C, Denormandie P, Schnitzler A. Impact of the operative delay and the degree of neurologic sequelae on recurrence of excised heterotopic ossification in patients with traumatic brain injury. J Head Trauma Rehabil. 2012;27(6):443–8. https://doi.org/10.1097/HTR.0b013e31822b54ba.

    Article  PubMed  Google Scholar 

  17. Popovic M, Agarwal A, Zhang L, Yip C, Kreder HJ, Nousiainen MT, et al. Radiotherapy for the prophylaxis of heterotopic ossification: a systematic review and meta-analysis of published data. Radiother Oncol. 2014;113(1):10–7. https://doi.org/10.1016/j.radonc.2014.08.025.

    Article  PubMed  Google Scholar 

  18. Seegenschmiedt MH, Makoski HB, Micke O. German cooperative group on radiotherapy for benign D. Radiation prophylaxis for heterotopic ossification about the hip joint--a multicenter study. Int J Radiat Oncol Biol Phys. 2001;51(3):756–65. https://doi.org/10.1016/s0360-3016(01)01640-6.

    Article  CAS  PubMed  Google Scholar 

  19. Liu JZ, Frisch NB, Barden RM, Rosenberg AG, Silverton CD, Galante JO. Heterotopic ossification prophylaxis after total hip arthroplasty: randomized trial of 400 vs 700 cGy. J Arthroplast. 2017;32(4):1328–34. https://doi.org/10.1016/j.arth.2016.10.030.

    Article  Google Scholar 

  20. Cipriano C, Pill SG, Rosenstock J, Keenan MA. Radiation therapy for preventing recurrence of neurogenic heterotopic ossification. Orthopedics. 2009;32(9). https://doi.org/10.3928/01477447-20090728-33

  21. Museler AC, Grasmucke D, Jansen O, Aach M, Meindl R, Schildhauer TA, et al. In-hospital outcomes following single-dose radiation therapy in the treatment of heterotopic ossification of the hip following spinal cord injury-an analysis of 444 cases. Spinal Cord. 2017;55(3):244–6. https://doi.org/10.1038/sc.2016.112.

    Article  PubMed  Google Scholar 

  22. Lee CH, Shim SJ, Kim HJ, Yang H, Kang YJ. Effects of radiation therapy on established neurogenic heterotopic ossification. Ann Rehabil Med. 2016;40(6):1135–9. https://doi.org/10.5535/arm.2016.40.6.1135.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ploumis A, Belbasis L, Ntzani E, Tsekeris P, Xenakis T. Radiotherapy for prevention of heterotopic ossification of the elbow: a systematic review of the literature. J Shoulder Elb Surg. 2013;22(11):1580–8. https://doi.org/10.1016/j.jse.2013.07.045.

    Article  Google Scholar 

  24. Honore T, Bonan I, Salga M, Denormandie P, Labib A, Genet G, et al. Effectiveness of radiotherapy to prevent recurrence of heterotopic ossification in patients with spinal cord injury and traumatic head injury: a retrospective case-controlled study. J Rehabil Med. 2020. https://doi.org/10.2340/16501977-2692.

  25. Banovac K, Williams JM, Patrick LD, Haniff YM. Prevention of heterotopic ossification after spinal cord injury with indomethacin. Spinal Cord. 2001;39(7):370–4. https://doi.org/10.1038/sj.sc.3101166.

    Article  CAS  PubMed  Google Scholar 

  26. Banovac K, Williams JM, Patrick LD, Levi A. Prevention of heterotopic ossification after spinal cord injury with COX-2 selective inhibitor (rofecoxib). Spinal Cord. 2004;42(12):707–10. https://doi.org/10.1038/sj.sc.3101628.

    Article  CAS  PubMed  Google Scholar 

  27. • Zakrasek EC, Yurkiewicz SM, Dirlikov B, Pence BT, Crew JD. Use of nonsteroidal anti-inflammatory drugs to prevent heterotopic ossification after spinal cord injury: a retrospective chart review. Spinal Cord. 2019;57(3):214–20. https://doi.org/10.1038/s41393-018-0199-3 A retrospective study confirming NSAID prophylaxis reduces prevalence and extent of NHO.

    Article  PubMed  Google Scholar 

  28. Oni JK, Pinero JR, Saltzman BM, Jaffe FF. Effect of a selective COX-2 inhibitor, celecoxib, on heterotopic ossification after total hip arthroplasty: a case-controlled study. Hip Int. 2014;24(3):256–62. https://doi.org/10.5301/hipint.5000109.

    Article  PubMed  Google Scholar 

  29. Kjaersgaard-Andersen P, Schmidt SA. Indomethacin for prevention of ectopic ossification after hip arthroplasty. Acta Orthop Scand. 1986;57(1):12–4. https://doi.org/10.3109/17453678608993206.

    Article  CAS  PubMed  Google Scholar 

  30. Kjaersgaard-Andersen P, Schmidt SA. Total hip arthroplasty. The role of antiinflammatory medications in the prevention of heterotopic ossification. Clin Orthop Relat Res. 1991;263:78–86.

    Google Scholar 

  31. Finerman GA, Stover SL. Heterotopic ossification following hip replacement or spinal cord injury. Two clinical studies with EHDP. Metab Bone Dis Relat Res. 1981;3(4–5):337–42. https://doi.org/10.1016/0221-8747(81)90050-3.

    Article  CAS  PubMed  Google Scholar 

  32. Stover SL, Hahn HR, Miller JM 3rd. Disodium etidronate in the prevention of heterotopic ossification following spinal cord injury (preliminary report). Paraplegia. 1976;14(2):146–56. https://doi.org/10.1038/sc.1976.25.

    Article  CAS  PubMed  Google Scholar 

  33. Banovac K. The effect of etidronate on late development of heterotopic ossification after spinal cord injury. J Spinal Cord Med. 2000;23(1):40–4. https://doi.org/10.1080/10790268.2000.11753507.

    Article  CAS  PubMed  Google Scholar 

  34. Banovac K, Gonzalez F, Wade N, Bowker JJ. Intravenous disodium etidronate therapy in spinal cord injury patients with heterotopic ossification. Paraplegia. 1993;31(10):660–6. https://doi.org/10.1038/sc.1993.106.

    Article  CAS  PubMed  Google Scholar 

  35. Kates SL, Ackert-Bicknell CL. How do bisphosphonates affect fracture healing? Injury. 2016;47(Suppl 1(0 1)):S65–8. https://doi.org/10.1016/s0020-1383(16)30015-8.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Kidd LJ, Cowling NR, Wu AC, Kelly WL, Forwood MR. Bisphosphonate treatment delays stress fracture remodeling in the rat ulna. J Orthop Res. 2011;29(12):1827–33. https://doi.org/10.1002/jor.21464.

    Article  CAS  PubMed  Google Scholar 

  37. Sloan AV, Martin JR, Li S, Li J. Parathyroid hormone and bisphosphonate have opposite effects on stress fracture repair. Bone. 2010;47(2):235–40. https://doi.org/10.1016/j.bone.2010.05.015.

    Article  CAS  PubMed  Google Scholar 

  38. Kan L, Hu M, Gomes WA, Kessler JA. Transgenic mice overexpressing BMP4 develop a fibrodysplasia ossificans progressiva (FOP)-like phenotype. Am J Pathol. 2004;165(4):1107–15. https://doi.org/10.1016/S0002-9440(10)63372-X.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2006;38(5):525–7. https://doi.org/10.1038/ng1783.

    Article  CAS  PubMed  Google Scholar 

  40. Chakkalakal SA, Zhang D, Culbert AL, Convente MR, Caron RJ, Wright AC, et al. An Acvr1 R206H knock-in mouse has fibrodysplasia ossificans progressiva. J Bone Miner Res. 2012;27(8):1746–56. https://doi.org/10.1002/jbmr.1637.

    Article  CAS  PubMed  Google Scholar 

  41. Kaplan FS, Fiori J, De La Peña LS, Ahn J, Billings PC, Shore EM. Dysregulation of the BMP-4 signaling pathway in fibrodysplasia ossificans progressiva. Ann N Y Acad Sci. 2006;1068:54–65. https://doi.org/10.1196/annals.1346.008.

    Article  CAS  PubMed  Google Scholar 

  42. Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, et al. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med. 2015;7(303):303ra137. https://doi.org/10.1126/scitranslmed.aac4358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lees-Shepard JB, Yamamoto M, Biswas AA, Stoessel SJ, Nicholas SE, Cogswell CA, et al. Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva. Nat Commun. 2018;9(1):471. https://doi.org/10.1038/s41467-018-02872-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yu PB, Deng DY, Lai CS, Hong CC, Cuny GD, Bouxsein ML, et al. BMP type I receptor inhibition reduces heterotopic ossification. Nat Med. 2008;14(12):1363–9. https://doi.org/10.1038/nm.1888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kaplan FS, Xu M, Seemann P, Connor JM, Glaser DL, Carroll L, et al. Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum Mutat. 2009;30(3):379–90. https://doi.org/10.1002/humu.20868.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. • Hildebrand L, Stange K, Deichsel A, Gossen M, Seemann P. The fibrodysplasia ossificans progressiva (FOP) mutation p.R206H in ACVR1 confers an altered ligand response. Cell Signal. 2017;29:23–30. https://doi.org/10.1016/j.cellsig.2016.10.001This papers shows the switch in function of BMP ligands signaling occurring as a consequence of the ACVR1R206H mutation which is the most common in FOP patients.

    Article  CAS  PubMed  Google Scholar 

  47. Yano M, Kawao N, Okumoto K, Tamura Y, Okada K, Kaji H. Fibrodysplasia ossificans progressiva-related activated activin-like kinase signaling enhances osteoclast formation during heterotopic ossification in muscle tissues. J Biol Chem. 2014;289(24):16966–77. https://doi.org/10.1074/jbc.M113.526038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hamilton PT, Jansen MS, Ganesan S, Benson RE, Hyde-Deruyscher R, Beyer WF, et al. Improved bone morphogenetic protein-2 retention in an injectable collagen matrix using bifunctional peptides. PLoS One. 2013;8(8):e70715. https://doi.org/10.1371/journal.pone.0070715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Leblanc E, Trensz F, Haroun S, Drouin G, Bergeron E, Penton CM, et al. BMP-9-induced muscle heterotopic ossification requires changes to the skeletal muscle microenvironment. J Bone Miner Res. 2011;26(6):1166–77. https://doi.org/10.1002/jbmr.311.

    Article  CAS  PubMed  Google Scholar 

  50. Li L, Jiang Y, Lin H, Shen H, Sohn J, Alexander PG, et al. Muscle injury promotes heterotopic ossification by stimulating local bone morphogenetic protein-7 production. J Orthop Translat. 2019;18:142–53. https://doi.org/10.1016/j.jot.2019.06.001.

    Article  PubMed  PubMed Central  Google Scholar 

  51. • Convente MR, Chakkalakal SA, Yang E, Caron RJ, Zhang D, Kambayashi T, et al. Depletion of mast cells and macrophages impairs heterotopic ossification in an Acvr1(R206H) mouse model of fibrodysplasia ossificans progressiva. J Bone Miner Res. 2018;33(2):269–82. https://doi.org/10.1002/jbmr.3304This study established that depletion of macrophages or mast cells impaired injury-induced HO in the ACVR1R206H mouse FOP model demonstrating that the innate immune system contributes to HO in FOP.

    Article  CAS  PubMed  Google Scholar 

  52. Haupt J, Xu M, Shore EM. Variable signaling activity by FOP ACVR1 mutations. Bone. 2017;109:232–40. https://doi.org/10.1016/j.bone.2017.10.027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cappato S, Giacopelli F, Ravazzolo R, Bocciardi R. The horizon of a therapy for rare genetic diseases: a “druggable” future for fibrodysplasia ossificans progressiva. Int J Mol Sci. 2018;19(4):989. https://doi.org/10.3390/ijms19040989

  54. Maekawa H, Kawai S, Nishio M, Nagata S, Jin Y, Yoshitomi H, et al. Prophylactic treatment of rapamycin ameliorates naturally developing and episode -induced heterotopic ossification in mice expressing human mutant ACVR1. Orphanet J Rare Dis. 2020;15(1):122. https://doi.org/10.1186/s13023-020-01406-8.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Pulik L, Mierzejewski B, Ciemerych MA, Brzoska E, Legosz P. The survey of cells responsible for heterotopic ossification development in skeletal muscles-human and mouse models. Cells. 2020;9(6):1324. https://doi.org/10.3390/cells9061324

  56. • Genêt F, Kulina I, Vaquette C, Torossian F, Millard S, Pettit AR, et al. Neurological heterotopic ossification following spinal cord injury is triggered by macrophage-mediated inflammation in muscle. J Pathol. 2015;236(2):229–40. https://doi.org/10.1002/path.4519Description of the first clinically relevant mouse model of SCI-NHO that does not involve genetic manipulation or implants containing BMPs.

    Article  CAS  PubMed  Google Scholar 

  57. Citak M, Suero EM, Backhaus M, Aach M, Godry H, Meindl R, et al. Risk factors for heterotopic ossification in patients with spinal cord injury: a case-control study of 264 patients. Spine. 2012;37(23):1953–7. https://doi.org/10.1097/BRS.0b013e31825ee81b.

    Article  PubMed  Google Scholar 

  58. Mounier R, Théret M, Arnold L, Cuvellier S, Bultot L, Göransson O, et al. AMPKα1 regulates macrophage skewing at the time of resolution of inflammation during skeletal muscle regeneration. Cell Metab. 2013;18(2):251–64. https://doi.org/10.1016/j.cmet.2013.06.017.

    Article  CAS  PubMed  Google Scholar 

  59. Brady RD, Zhao MZ, Wong KR, Casilla-Espinosa PM, Yamakawa GR, Wortman RC, et al. A novel rat model of heterotopic ossification after polytrauma with traumatic brain injury. Bone. 2020;133:115263. https://doi.org/10.1016/j.bone.2020.115263.

    Article  PubMed  Google Scholar 

  60. Shi WZ, Ju JY, Xiao HJ, Xue F, Wu J, Pan MM, et al. Dynamics of MMP9, MMP2 and TIMP1 in a rat model of brain injury combined with traumatic heterotopic ossification. Mol Med Rep. 2017;15(4):2129–35. https://doi.org/10.3892/mmr.2017.6275.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Song Y, Bi L, Zhang Z, Huang Z, Hou W, Lu X, et al. Increased levels of calcitonin gene-related peptide in serum accelerate fracture healing following traumatic brain injury. Mol Med Rep. 2012;5(2):432–8. https://doi.org/10.3892/mmr.2011.645.

    Article  CAS  PubMed  Google Scholar 

  62. van Kampen PJ, Martina JD, Vos PE, Hoedemaekers CW, Hendricks HT. Potential risk factors for developing heterotopic ossification in patients with severe traumatic brain injury. J Head Trauma Rehabil. 2011;26(5):384–91. https://doi.org/10.1097/HTR.0b013e3181f78a59.

    Article  PubMed  Google Scholar 

  63. Hendricks HT, Geurts AC, van Ginneken BC, Heeren AJ, Vos PE. Brain injury severity and autonomic dysregulation accurately predict heterotopic ossification in patients with traumatic brain injury. Clin Rehabil. 2007;21(6):545–53. https://doi.org/10.1177/0269215507075260.

    Article  PubMed  Google Scholar 

  64. Meyers C, Lisiecki J, Miller S, Levin A, Fayad L, Ding C, et al. Heterotopic ossification: a comprehensive review. JBMR Plus. 2019;3(4):e10172. https://doi.org/10.1002/jbm4.10172.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Medina A, Shankowsky H, Savaryn B, Shukalak B, Tredget EE. Characterization of heterotopic ossification in burn patients. J Burn Care Res. 2014;35(3):251–6. https://doi.org/10.1097/BCR.0b013e3182957768.

    Article  PubMed  Google Scholar 

  66. Peterson JR, De La Rosa S, Sun H, Eboda O, Cilwa KE, Donneys A, et al. Burn injury enhances bone formation in heterotopic ossification model. Ann Surg. 2014;259(5):993–8. https://doi.org/10.1097/SLA.0b013e318291da85.

    Article  PubMed  Google Scholar 

  67. Hsu GC, Marini S, Negri S, Wang Y, Xu J, Pagani CA, et al. Endogenous CCN family member WISP-1 inhibits trauma-induced heterotopic ossification. JCI Insight. 2020;5. https://doi.org/10.1172/jci.insight.135432.

  68. • Sorkin M, Huber AK, Hwang C, Carson WF, Menon R, Li J, et al. Regulation of heterotopic ossification by monocytes in a mouse model of aberrant wound healing. Nat Commun. 2020;11(1):722. https://doi.org/10.1038/s41467-019-14172-4This paper characterized the inflammatory response, in particular the monocyte/macrophage subpopulations present in injured tissue using a burn and tenotomy-induced HO mouse model confirming the importance of monocyte/macrophages and TGF-β1 in burn-induced HO.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Loder SJ, Agarwal S, Chung MT, Cholok D, Hwang C, Visser N, et al. Characterizing the circulating cell populations in traumatic heterotopic ossification. Am J Pathol. 2018;188(11):2464–73. https://doi.org/10.1016/j.ajpath.2018.07.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. • Hwang C, Pagani CA, Das N, Marini S, Huber AK, Xie L et al. Activin A does not drive post-traumatic heterotopic ossification. Bone. 2020;138:115473. https://doi.org/10.1016/j.bone.2020.115473. The results of this study establishes that anti-activin A neutralizing antibodies have no effect on burn / tenotomy-induced HO.

  71. Qureshi AT, Dey D, Sanders EM, Seavey JG, Tomasino AM, Moss K, et al. Inhibition of mammalian target of rapamycin signaling with rapamycin prevents trauma-induced heterotopic ossification. Am J Pathol. 2017;187(11):2536–45. https://doi.org/10.1016/j.ajpath.2017.07.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Qureshi AT, Crump EK, Pavey GJ, Hope DN, Forsberg JA, Davis TA. Early characterization of blast-related heterotopic ossification in a rat model. Clin Orthop Relat Res. 2015;473(9):2831–9. https://doi.org/10.1007/s11999-015-4240-y.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Kim JM, Yang YS, Park KH, Ge X, Xu R, Li N, et al. A RUNX2 stabilization pathway mediates physiologic and pathologic bone formation. Nat Commun. 2020;11(1):2289. https://doi.org/10.1038/s41467-020-16038-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Zhang Q, Zhang Y, Yan M, Zhu K, Su Q, Pan J, et al. βig-h3 enhances chondrogenesis via promoting mesenchymal condensation in rat Achilles tendon heterotopic ossification model. Aging. 2020;12(8):7030–41. https://doi.org/10.18632/aging.103060.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kusano T, Nakatani M, Ishiguro N, Ohno K, Yamamoto N, Morita M, et al. Desloratadine inhibits heterotopic ossification by suppression of BMP2-Smad1/5/8 signaling. J Orthop Res. 2020. https://doi.org/10.1002/jor.24625.

  76. Rumi MN, Deol GS, Singapuri KP, Pellegrini VD Jr. The origin of osteoprogenitor cells responsible for heterotopic ossification following hip surgery: an animal model in the rabbit. J Orthop Res. 2005;23(1):34–40. https://doi.org/10.1016/j.orthres.2004.05.003.

    Article  PubMed  Google Scholar 

  77. Saclier M, Yacoub-Youssef H, Mackey AL, Arnold L, Ardjoune H, Magnan M, et al. Differentially activated macrophages orchestrate myogenic precursor cell fate during human skeletal muscle regeneration. Stem Cells. 2013;31(2):384–96. https://doi.org/10.1002/stem.1288.

    Article  CAS  PubMed  Google Scholar 

  78. Varga T, Mounier R, Horvath A, Cuvellier S, Dumont F, Poliska S, et al. Highly dynamic transcriptional signature of distinct macrophage subsets during sterile inflammation, resolution, and tissue repair. J Immunol. 2016;196(11):4771–82. https://doi.org/10.4049/jimmunol.1502490.

    Article  CAS  PubMed  Google Scholar 

  79. Hardy D, Besnard A, Latil M, Jouvion G, Briand D, Thépenier C, et al. Comparative study of injury models for studying muscle regeneration in mice. PLoS One. 2016;11(1):e0147198. https://doi.org/10.1371/journal.pone.0147198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Novak ML, Weinheimer-Haus EM, Koh TJ. Macrophage activation and skeletal muscle healing following traumatic injury. J Pathol. 2014;232(3):344–55. https://doi.org/10.1002/path.4301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wang X, Zhao W, Ransohoff RM, Zhou L. Infiltrating macrophages are broadly activated at the early stage to support acute skeletal muscle injury repair. J Neuroimmunol. 2018;317:55–66. https://doi.org/10.1016/j.jneuroim.2018.01.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Blomster LV, Brennan FH, Lao HW, Harle DW, Harvey AR, Ruitenberg MJ. Mobilisation of the splenic monocyte reservoir and peripheral CX3CR1 deficiency adversely affects recovery from spinal cord injury. Exp Neurol. 2013;247(0):226–40. https://doi.org/10.1016/j.expneurol.2013.05.002.

    Article  CAS  PubMed  Google Scholar 

  83. Arnold L, Henry A, Poron F, Baba-Amer Y, van Rooijen N, Plonquet A, et al. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J Exp Med. 2007;204(5):1057–69. https://doi.org/10.1084/jem.20070075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lu H, Huang D, Saederup N, Charo IF, Ransohoff RM, Zhou L. Macrophages recruited via CCR2 produce insulin-like growth factor-1 to repair acute skeletal muscle injury. FASEB J. 2011;25(1):358–69. https://doi.org/10.1096/fj.10-171579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Willenborg S, Lucas T, van Loo G, Knipper JA, Krieg T, Haase I, et al. CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood. 2012;120(3):613–25. https://doi.org/10.1182/blood-2012-01-403386.

    Article  CAS  PubMed  Google Scholar 

  86. Lu H, Huang D, Ransohoff RM, Zhou L. Acute skeletal muscle injury: CCL2 expression by both monocytes and injured muscle is required for repair. FASEB J. 2011;25(10):3344–55. https://doi.org/10.1096/fj.10-178939.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Lemos DR, Babaeijandaghi F, Low M, Chang C-K, Lee ST, Fiore D, et al. Nilotinib reduces muscle fibrosis in chronic muscle injury by promoting TNF-mediated apoptosis of fibro/adipogenic progenitors. Nat Med. 2015;21(7):786–94. https://doi.org/10.1038/nm.3869.

    Article  CAS  PubMed  Google Scholar 

  88. Zhao Y, Urganus AL, Spevak L, Shrestha S, Doty SB, Boskey AL, et al. Characterization of dystrophic calcification induced in mice by cardiotoxin. Calcif Tissue Int. 2009;85(3):267–75. https://doi.org/10.1007/s00223-009-9271-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. • Alexander KA, Tseng H-W, Fleming W, Jose B, Salga M, Kulina I et al. Inhibition of JAK1/2 tyrosine kinases reduces neurogenic heterotopic ossification after spinal cord injury. Front Immunol. 2019;10:377. https://doi.org/10.3389/fimmu.2019.00377. This study established that persistent STAT3 phosphorylation was present in muscles developing NHO using a mouse model of NHO after SCI and that treatment with ruxolitinib, a selective JAK1/2 tyrosine-kinase inhibitor, significantly reduced NHO formation in mice.

  90. Levesque J-P, Sims NA, Pettit AR, Alexander KA, Tseng H-W, Torossian F, et al. Macrophages driving heterotopic ossification: convergence of genetically-driven and trauma-driven mechanisms. J Bone Miner Res. 2018;33(2):365–6. https://doi.org/10.1002/jbmr.3346.

    Article  PubMed  Google Scholar 

  91. • Tseng H-W, Kulina I, Salga M, Fleming W, Vaquette C, Genêt F et al. Neurogenic heterotopic ossifications develop independently of granulocyte-colony stimulating factor and neutrophils. J Bone Miner Res. 2020;in press. https://doi.org/10.1002/jbmr.4118. This research establishes that neutrophils do not play an important role in the pathogenesis of NHO in a mouse model of NHO after SCI.

  92. Winkler IG, Sims NA, Pettit AR, Barbier V, Nowlan B, Helwani F, et al. Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood. 2010;116(23):4815–28. https://doi.org/10.1182/blood-2009-11-253534.

    Article  CAS  PubMed  Google Scholar 

  93. Christopher MJ, Rao M, Liu F, Woloszynek JR, Link DC. Expression of the G-CSF receptor in monocytic cells is sufficient to mediate hematopoietic progenitor mobilization by G-CSF in mice. J Exp Med. 2011;208(2):251–60. https://doi.org/10.1084/jem.20101700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. • Torossian F, Guerton B, Anginot A, Alexander KA, Desterke C, Soave S, et al. Macrophage-derived oncostatin M contributes to human and mouse neurogenic heterotopic ossifications. JCI Insight. 2017;2(21):e96034. https://doi.org/10.1172/jci.insight.96034This study established the role of oncostatin M in human NHO and a mouse model of NHO after SCI.

    Article  PubMed Central  Google Scholar 

  95. Bargellesi S, Cavasin L, Scarponi F, De Tanti A, Bonaiuti D, Bartolo M, et al. Occurrence and predictive factors of heterotopic ossification in severe acquired brain injured patients during rehabilitation stay: cross-sectional survey. Clin Rehabil. 2017;32(2):255–62. https://doi.org/10.1177/0269215517723161.

    Article  PubMed  Google Scholar 

  96. Wharton GW, Morgan TH. Ankylosis in the paralyzed patient. J Bone Joint Surg Am. 1970;52(1):105–12.

    Article  CAS  PubMed  Google Scholar 

  97. Salga M, Tseng H-W, Alexander KA, Jose B, Vaquette C, Debaud C, et al. Blocking neuromuscular junctions with botulinum toxin A injection enhances neurological heterotopic ossification development after spinal cord injury in mice. Ann Phys Rehabil Med. 2019 in press. https://doi.org/10.1016/j.rehab.2019.01.005.

  98. Leonard AV, Manavis J, Blumbergs PC, Vink R. Changes in substance P and NK1 receptor immunohistochemistry following human spinal cord injury. Spinal Cord. 2014;52(1):17–23. https://doi.org/10.1038/sc.2013.136.

    Article  CAS  PubMed  Google Scholar 

  99. Kim MS, Yan J, Wu W, Zhang G, Zhang Y, Cai D. Rapid linkage of innate immunological signals to adaptive immunity by the brain-fat axis. Nat Immunol. 2015;16(5):525–33. https://doi.org/10.1038/ni.3133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Debaud C, Salga M, Begot L, Holy X, Chedik M, de l’Escalopier N, et al. Peripheral denervation participates in heterotopic ossification in a spinal cord injury model. PLoS One. 2017;12(8):e0182454. https://doi.org/10.1371/journal.pone.0182454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Putz C, Helbig L, Gerner HJ, Zimmermann-Stenzel M, Akbar M. Autonomic dysreflexia: a possible trigger for the development of heterotopic ossifications after traumatic spinal cord injury? Eur J Trauma Emerg Surg. 2014;40(6):721–6. https://doi.org/10.1007/s00068-013-0353-8.

    Article  CAS  PubMed  Google Scholar 

  102. Weaver LC, Marsh DR, Gris D, Brown A, Dekaban GA. Autonomic dysreflexia after spinal cord injury: central mechanisms and strategies for prevention. Prog Brain Res. 2006;152:245–63. https://doi.org/10.1016/S0079-6123(05)52016-8.

  103. Sweis R, Biller J. Systemic complications of spinal cord injury. Curr Neurol Neurosci Rep. 2017;17(1):8. https://doi.org/10.1007/s11910-017-0715-4.

    Article  PubMed  Google Scholar 

  104. Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U. Central nervous system injury-induced immune deficiency syndrome. Nat Rev Neurosci. 2005;6(10):775–86. https://doi.org/10.1038/nrn1765.

    Article  CAS  PubMed  Google Scholar 

  105. Zhang Y, Guan Z, Reader B, Shawler T, Mandrekar-Colucci S, Huang K, et al. Autonomic dysreflexia causes chronic immune suppression after spinal cord injury. J Neurosci. 2013;33(32):12970–81. https://doi.org/10.1523/jneurosci.1974-13.2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. • Tuzmen C, Verdelis K, Weiss L, Campbell P. Crosstalk between substance P and calcitonin gene-related peptide during heterotopic ossification in murine Achilles tendon. J Orthop Res. 2018;36(5):1444–55. https://doi.org/10.1002/jor.23833In a mouse model of tenotomy-induced HO, this research established that substance P delivered to the injury site promoted HO development whereas when substance P was delivered along with calcitonin gene-related peptide HO development was no longer promoted.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. • Wang X, Li F, Xie L, Crane J, Zhen G, Mishina Y, et al. Inhibition of overactive TGF-β attenuates progression of heterotopic ossification in mice. Nat Commun. 2018;9(1):551. https://doi.org/10.1038/s41467-018-02988-5Using Acilles tendon puncture-induced and BMP-2-induced mouse models of HO, this research shows that TGF-β1 promotes HO formation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Janssens K, ten Dijke P, Janssens S, Van Hul W. Transforming growth factor-β1 to the bone. Endocr Rev. 2005;26(6):743–74. https://doi.org/10.1210/er.2004-0001.

    Article  CAS  PubMed  Google Scholar 

  109. Grenier G, Leblanc É, Faucheux N, Lauzier D, Kloen P, Hamdy RC. BMP-9 expression in human traumatic heterotopic ossification: a case report. Skelet Muscle. 2013;3(1):29. https://doi.org/10.1186/2044-5040-3-29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kang Q, Sun MH, Cheng H, Peng Y, Montag AG, Deyrup AT, et al. Characterization of the distinct orthotopic bone-forming activity of 14 BMPs using recombinant adenovirus-mediated gene delivery. Gene Ther. 2004;11(17):1312–20. https://doi.org/10.1038/sj.gt.3302298.

    Article  CAS  PubMed  Google Scholar 

  111. Dong L, Dong G, Cao J, Zhang J. Association of α2-HS glycoprotein with neurogenic heterotopic ossification in patients with spinal cord injury. Med Sci Monit. 2017;23:5382–8. https://doi.org/10.12659/msm.904626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Olmsted-Davis EA, Salisbury EA, Hoang D, Davis EL, Lazard Z, Sonnet C, et al. Progenitors in peripheral nerves launch heterotopic ossification. Stem Cells Transl Med. 2017;6(4):1109–19. https://doi.org/10.1002/sctm.16-0347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

JPL is supported by Research Fellowship 1136130 from the National Health and Medical Research Council of Australia (NHMRC). KAA, HWT, FG, and JPL research are supported by NHMRC Ideas Grant 1181053.

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Authors and Affiliations

  1. Mater Research Institute, The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, Queensland, 4102, Australia

    Kylie A. Alexander, Hsu-Wen Tseng & Jean-Pierre Levesque

  2. Department of Physical Medicine and Rehabilitation, CIC 1429, Raymond Poincaré Hospital, APHP, Garches, France

    Marjorie Salga & François Genêt

  3. END:ICAP U1179 INSERM, University of Versailles Saint Quentin en Yvelines, UFR Simone Veil-Santé, Montigny le Bretonneux, France

    Marjorie Salga & François Genêt

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  1. Kylie A. Alexander
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Alexander, K.A., Tseng, HW., Salga, M. et al. When the Nervous System Turns Skeletal Muscles into Bones: How to Solve the Conundrum of Neurogenic Heterotopic Ossification. Curr Osteoporos Rep 18, 666–676 (2020). https://doi.org/10.1007/s11914-020-00636-w

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