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Posttraumatic elbow contractures: targeting neuroinflammatory fibrogenic mechanisms

  • Review Article
  • Published:
Journal of Orthopaedic Science

Abstract

Posttraumatic elbow stiffness remains a common and challenging clinical problem. In the setting of a congruent articular surface, the joint capsule is regarded as the major motion-limiting anatomic structure. The affected joint capsule is characterized by irreversible biomechanical and biochemical fibrogenic changes strikingly similar to those observed in many other fibroproliferative human conditions. Studies in humans and preclinical animal models are providing emergent evidence that neuroinflammatory mechanisms are critical upstream events in the pathogenesis of posttraumatic connective tissue fibrogenesis. Maladaptive recruitment and activation of mast cell infiltrates coupled with the aberrant expression of growth factors such as transforming growth factor-beta, nerve growth factor, and neuropeptides such as substance P are common observations in posttraumatic joint contractures and many other fibroproliferative disorders. Blockade of these factors is providing promising evidence that if treatment is timed correctly, the fibrogenic process can be interrupted or impeded. This review serves to highlight opportunities derived from these recent discoveries across many aberrant fibrogenic disorders as we strive to develop novel, targeted antifibrotic prevention and treatment strategies for posttraumatic elbow stiffness.

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References

  1. Cooney III, WP. Contractures of the elbow. In: Morrey BF, editor. The elbow and its disorders. Philadelphia: W.B. Saunders Company, 1993. p. 464.

  2. Myden C, Hildebrand K. Elbow joint contracture after traumatic injury. J Should Elbow Surg. 2011;20:39–44.

    Article  Google Scholar 

  3. Akeson WH, Amiel D, Abel MF, Garfin SR, Woo SL. Effects of immobilization on joints. Clin Orthop Rel Res 1987; 28–7.

  4. Charalambous CP, Morrey BF. Posttraumatic elbow stiffness. J Bone Joint Surg. American volume 2012; 94:1428–37.

    Google Scholar 

  5. Morrey BF. Surgical treatment of extraarticular elbow contracture. Clin Orthop Relat Res 2000;57–4.

  6. Hildebrand KA, Sutherland C, Zhang M. Rabbit knee model of post-traumatic joint contractures: the long-term natural history of motion loss and myofibroblasts. J Orthop Res. 2004;22:313–20.

    Article  Google Scholar 

  7. Nesterenko S, Morrey ME, Abdel MP, An KN, Steinmann SP, Morrey BF, Sanchez-Sotelo J. New rabbit knee model of posttraumatic joint contracture: indirect capsular damage induces a severe contracture. J Orthop Res. 2009;27:1028–32.

    Article  Google Scholar 

  8. Wada T, Ishii S, Usui M, Miyano S. The medial approach for operative release of post-traumatic contracture of the elbow. J Bone Joint Surg. British volume 2000;82:68–3.

    Google Scholar 

  9. Lindenhovius AL, Jupiter JB. The posttraumatic stiff elbow: a review of the literature. J Hand Surg [Am]. 2007;32:1605–23.

    Article  Google Scholar 

  10. Higgs ZC, Danks BA, Sibinski M, Rymaszewski LA. Outcomes of open arthrolysis of the elbow without post-operative passive stretching. J Bone Joint Surg. British volume 2012;94:348–52.

    Google Scholar 

  11. Cohen MS, Schimmel DR, Masuda K, Hastings H II, Muehleman C. Structural and biochemical evaluation of the elbow capsule after trauma. J Should Elbow Surg 2007;16:484–90.

    Google Scholar 

  12. Hildebrand KA, Zhang M, van Snellenberg W, King GJ, Hart DA. Myofibroblast numbers are elevated in human elbow capsules after trauma. Clin Orthop Relat Res 2004;189–97.

  13. Hildebrand KA, Zhang M, Hart DA. High rate of joint capsule matrix turnover in chronic human elbow contractures. Clin Orthop Relat Res. 2005;439:228–34.

    Article  Google Scholar 

  14. Germscheid NM, Hildebrand KA. Regional variation is present in elbow capsules after injury. Clin Orthop Relat Res. 2006;450:219–24.

    Article  Google Scholar 

  15. Hildebrand KA, Zhang M, Germscheid NM, Wang C, Hart DA. Cellular, matrix, and growth factor components of the joint capsule are modified early in the process of posttraumatic contracture formation in a rabbit model. Acta Orthop. 2008;79:116–25.

    Article  Google Scholar 

  16. Gabbiani G. The myofibroblast in wound healing and fibrocontractive diseases. J Pathol. 2003;200:500–3.

    Article  CAS  Google Scholar 

  17. Schollmeier G, Uhthoff HK, Sarkar K, Fukuhara K. Effects of immobilization on the capsule of the canine glenohumeral joint. A structural functional study. Clin Orthop Relat Res 1994;37–2.

  18. Finsterbush A, Friedman B. Reversibility of joint changes produced by immobilization in rabbits. Clin Orthop Relat Res 1975;290–98.

  19. Abdel MP, Morrey ME, Barlow JD, Kreofsky CR, An KN, Steinmann SP, Morrey BF, Sanchez-Sotelo J. Myofibroblast cells are preferentially expressed early in a rabbit model of joint contracture. J Orthop Res. 2012;30:713–9.

    Article  Google Scholar 

  20. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002;3:349–63.

    Article  CAS  Google Scholar 

  21. Vaughan MB, Howard EW, Tomasek JJ. Transforming growth factor-beta1 promotes the morphological and functional differentiation of the myofibroblast. Exp Cell Res. 2000;257:180–9.

    Article  CAS  Google Scholar 

  22. Zhang HY, Phan SH. Inhibition of myofibroblast apoptosis by transforming growth factor beta(1). Am J Respir Cell Mol Biol. 1999;21:658–65.

    Article  CAS  Google Scholar 

  23. Liu W, Wang DR, Cao YL. Tgf-beta: a fibrotic factor in wound scarring and a potential target for anti-scarring gene therapy. Curr Gene Ther. 2004;4:123–36.

    Article  CAS  Google Scholar 

  24. Singer AJ, Huang SS, Huang JS, McClain SA, Romanov A, Rooney J, Zimmerman T. A novel tgf-beta antagonist speeds reepithelialization and reduces scarring of partial thickness porcine burns. J Burn Care Res. 2009;30:329–34.

    Article  Google Scholar 

  25. Gruber BL. Mast cells: accessory cells which potentiate fibrosis. Int Rev Immunol. 1995;12:259–79.

    Article  CAS  Google Scholar 

  26. Skold CM, Ohkuni Y, Liu XD, Numerof R, Rennard SI. Co-cultured human mast cells stimulate fibroblast-mediated contraction of collagen gels. Inflammation. 2001;25:47–51.

    Article  CAS  Google Scholar 

  27. Akers IA, Parsons M, Hill MR, Hollenberg MD, Sanjar S, Laurent GJ, McAnulty RJ. Mast cell tryptase stimulates human lung fibroblast proliferation via protease-activated receptor-2. Am J Physiol Lung Cell Mol Physiol. 2000;278:L193–201.

    CAS  Google Scholar 

  28. Hildebrand KA, Zhang M, Hart DA. Joint capsule mast cells and neuropeptides are increased within four weeks of injury and remain elevated in chronic stages of posttraumatic contractures. J Orthop Res. 2008;26:1313–9.

    Article  Google Scholar 

  29. Craps LP, Ney UM. Ketotifen: current views on its mechanism of action and their therapeutic implications. Respiration. 1984;45:411–21.

    Article  CAS  Google Scholar 

  30. Norris AA. Pharmacology of sodium cromoglycate. Clin Exp Allergy. 1996;26(Suppl 4):5–7.

    Article  CAS  Google Scholar 

  31. Monument MJ, Hart DA, Befus AD, Salo PT, Zhang M, Hildebrand KA. The mast cell stabilizer ketotifen fumarate lessens contracture severity and myofibroblast hyperplasia: a study of a rabbit model of posttraumatic joint contractures. J Bone Joint Surg Am. 2010;92:1468–77.

    Article  Google Scholar 

  32. Monument MJ, Hart DA, Befus AD, Salo PT, Zhang M, Hildebrand KA. The mast cell stabilizer ketotifen reduces joint capsule fibrosis in a rabbit model of post-traumatic joint contractures. Inflamm Res. 2012;61:285–92.

    Article  CAS  Google Scholar 

  33. Gallant-Behm CL, Hildebrand KA, Hart DA. The mast cell stabilizer ketotifen prevents development of excessive skin wound contraction and fibrosis in red duroc pigs. Wound Repair Regen. 2008;16:226–33.

    Article  Google Scholar 

  34. Harunari N, Zhu KQ, Armendariz RT, Deubner H, Muangman P, Carrougher GJ, Isik FF, Gibran NS, Engrav LH. Histology of the thick scar on the female, red duroc pig: final similarities to human hypertrophic scar. Burns. 2006;32:669–77.

    Article  Google Scholar 

  35. Schaffer M, Beiter T, Becker HD, Hunt TK. Neuropeptides: mediators of inflammation and tissue repair? Arch Surg. 1998;133:1107–16.

    Article  CAS  Google Scholar 

  36. Foreman JC. Substance p and calcitonin gene-related peptide: effects on mast cells and in human skin. Int Arch Allergy Appl Immunol. 1987;82:366–71.

    Article  CAS  Google Scholar 

  37. Jing C, Jia-Han W, Hong-Xing Z. Double-edged effects of neuropeptide substance p on repair of cutaneous trauma. Wound Repair Regen 2010;18:319–24.

    Google Scholar 

  38. Franceschi F, Longo UG, Ruzzini L, Morini S, Battistoni F, Dicuonzo G, Maffulli N, Denaro V. Circulating substance p levels and shoulder joint contracture after arthroscopic repair of the rotator cuff. Br J Sports Med. 2008;42:742–5.

    Article  CAS  Google Scholar 

  39. Scott JR, Muangman P, Gibran NS. Making sense of hypertrophic scar: a role for nerves. Wound Repair Regen. 2007;15(Suppl 1):S27–31.

    Article  Google Scholar 

  40. Schubert TE, Weidler C, Borisch N, Schubert C, Hofstadter F, Straub RH. Dupuytren’s contracture is associated with sprouting of substance p positive nerve fibres and infiltration by mast cells. Ann Rheum Dis. 2006;65:414–5.

    Article  CAS  Google Scholar 

  41. Miller JS, Schwartz LB. Human mast cell proteases and mast cell heterogeneity. Curr Opin Immunol. 1989;1:637–42.

    Article  CAS  Google Scholar 

  42. Schwartz LB. Diagnostic value of tryptase in anaphylaxis and mastocytosis. Immunol Allergy Clin North Am. 2006;26:451–63.

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Rm #4260, Salt Lake City, UT, 84112, USA

    Michael J. Monument

  2. Division of Orthopaedic Surgery, Faculty of Medicine, McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, AB, Canada

    David A. Hart, Paul T. Salo & Kevin A. Hildebrand

  3. Pulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada

    A. Dean Befus

Authors
  1. Michael J. Monument
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  2. David A. Hart
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  3. Paul T. Salo
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  4. A. Dean Befus
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  5. Kevin A. Hildebrand
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Correspondence to Michael J. Monument.

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All listed authors contributed significantly to the conception and preparation of this manuscript.

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Monument, M.J., Hart, D.A., Salo, P.T. et al. Posttraumatic elbow contractures: targeting neuroinflammatory fibrogenic mechanisms. J Orthop Sci 18, 869–877 (2013). https://doi.org/10.1007/s00776-013-0447-5

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  • DOI: https://doi.org/10.1007/s00776-013-0447-5

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