Heterotopic Ossification Following Musculoskeletal Trauma: Modeling Stem and Progenitor Cells in Their Microenvironment

  • Youngmi Ji
  • Gregory T. Christopherson
  • Matthew W. Kluk
  • Orna Amrani
  • Wesley M. Jackson
  • Leon J. Nesti
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 720)

Abstract

Heterotopic ossification (HO), characterized by the formation of mature bone in the soft tissues, is a complication that can accompany musculoskeletal injury, and it is a frequent occurrence within the military population that has experienced orthopaedic combat trauma. The etiology of this disease is largely unknown. Our laboratory has developed strategies to investigate the cellular and molecular events leading to HO using clinical specimens that were obtained during irrigation and debridement of musculoskeletal injuries. Our approach enables to study (1) the cell types that are responsible for pathological transformation and ossification, (2) the cell- and tissue-level signaling that induces the pathologic transformation, and (3) the effect of extracellular matrix topography and force transduction on HO progression. In this review, we will report on our findings in each of these aspects of HO etiology and describe our efforts to recapitulate our findings in an animal model for traumatic HO.

Keywords

Migration Attenuation Immobilization Coumadin Polystyrene 

Notes

Acknowledgements

This work was supported acknowledged as part of the NIH Intramural Research Program. (Z01 AR41131 and 1ZIAAR041191), grants from the Department of Defense Military Amputee Research Program at WRAMC (PO5-A011), Comprehensive Neurosci­ences Program (CNP-2008-CR01) and Peer-Reviewed Orthopaedic Research Program (W81XWH-10-2-0084).

References

  1. 1.
    Potter BK et al (2007) Heterotopic ossification following traumatic and combat-related amputations. Prevalence, risk factors, and preliminary results of excision. J Bone Joint Surg Am 89(3):476–86PubMedCrossRefGoogle Scholar
  2. 2.
    Potter BK et al (2006) Heterotopic ossification in the residual limbs of traumatic and combat-related amputees. J Am Acad Orthop Surg 14(10 Spec No.):S191–7PubMedGoogle Scholar
  3. 3.
    Pape HC et al (2004) Current concepts in the development of heterotopic ossification. J Bone Joint Surg Br 86(6):783–7PubMedCrossRefGoogle Scholar
  4. 4.
    Stover SL, Hataway CJ, Zeiger HE (1975) Heterotopic ossification in spinal cord-injured patients. Arch Phys Med Rehabil 56(5):199–204PubMedGoogle Scholar
  5. 5.
    Peterson SL et al (1989) Postburn heterotopic ossification: insights for management decision making. J Trauma 29(3):365–9PubMedCrossRefGoogle Scholar
  6. 6.
    Vanden Bossche L et al (2008) Free radical scavengers have a preventive effect on heterotopic bone formation following manipulation of immobilized rabbit legs. Eur J Phys Rehabil Med 44(4):423–8PubMedGoogle Scholar
  7. 7.
    Shore EM et al (2006) A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet 38(5):525–7PubMedCrossRefGoogle Scholar
  8. 8.
    Shafritz AB et al (1996) Overexpression of an osteogenic morphogen in fibrodysplasia ossificans progressiva. N Engl J Med 335(8):555–61PubMedCrossRefGoogle Scholar
  9. 9.
    Ahn J et al (2003) Paresis of a bone morphogenetic protein-antagonist response in a genetic disorder of heterotopic skeletogenesis. J Bone Joint Surg Am 85-A(4):667–74PubMedGoogle Scholar
  10. 10.
    Shore EM, Kaplan FS (2008) Insights from a rare genetic disorder of extra-skeletal bone formation, fibrodysplasia ossificans progressiva (FOP). Bone 43(3):427–33PubMedCrossRefGoogle Scholar
  11. 11.
    Nesti LJ et al (2008) Differentiation potential of multipotent progenitor cells derived from war-­traumatized muscle tissue. J Bone Joint Surg Am 90(11):2390–8PubMedCrossRefGoogle Scholar
  12. 12.
    Chamberlain G et al (2007) Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 25(11):2739–2749PubMedCrossRefGoogle Scholar
  13. 13.
    Owen ME, Cave J, Joyner CJ (1987) Clonal analysis in vitro of osteogenic differentiation of marrow CFU-F. J Cell Sci 87(5):731–738PubMedGoogle Scholar
  14. 14.
    Grefte S et al (2007) Skeletal muscle development and regeneration. Stem Cells Dev 16(5):857–68PubMedCrossRefGoogle Scholar
  15. 15.
    Zheng B et al (2007) Prospective identification of myogenic endothelial cells in human skeletal muscle. Nat Biotechnol 25(9):1025–34PubMedCrossRefGoogle Scholar
  16. 16.
    Lumelsky NL (2007) Commentary: engineering of tissue healing and regeneration. Tissue Eng 13(7):1393PubMedCrossRefGoogle Scholar
  17. 17.
    Caplan AI, Dennis JE (2006) Mesenchymal stem cells as trophic mediators. J Cell Biochem 98(5):1076–84PubMedCrossRefGoogle Scholar
  18. 18.
    Jackson WM et al (2010) Differentiation and regeneration potential of mesenchymal progenitor cells derived from traumatized muscle tissue. J Cell Mol Med 2010 Dec 3. doi: 10.1111/j.1582-4934.2010.01225.x. [Epub ahead of print]Google Scholar
  19. 19.
    Sivakumar P, Das A (2008) Fibrosis, chronic inflammation and new pathways for drug discovery. Inflamm Res 57(9):410–418PubMedCrossRefGoogle Scholar
  20. 20.
    Jackson WM et al (2009) Mesenchymal progenitor cells derived from traumatized human muscle. J Tissue Eng Regen Med 3(2):129–38PubMedCrossRefGoogle Scholar
  21. 21.
    Jackson WM et al (2009) Putative heterotopic ossification progenitor cells derived from traumatized muscle. J Orthop Res 27(12):1645–51PubMedCrossRefGoogle Scholar
  22. 22.
    Velnar T, Bailey T, Smrkolj V (2009) The wound healing process: an overview of the cellular and molecular mechanisms. J Int Med Res 37(5):1528–42PubMedCrossRefGoogle Scholar
  23. 23.
    Singer AJ, Clark RA (1999) Cutaneous wound healing. N Engl J Med 341(10):738–46PubMedCrossRefGoogle Scholar
  24. 24.
    Quintero AJ et al (2009) Stem cells for the treatment of skeletal muscle injury. Clin Sports Med 28(1):1–11PubMedCrossRefGoogle Scholar
  25. 25.
    Jackson WM et al (2011) Cytoke expression in ­muscle following traumatic injury. J Orthop Res 2011 Mar 30. doi: 10.1002/jor.21354. [Epub ahead of print]Google Scholar
  26. 26.
    Cowin AJ et al (2001) Expression of TGF-beta and its receptors in murine fetal and adult dermal wounds. Eur J Dermatol 11(5):424–31PubMedGoogle Scholar
  27. 27.
    Lu L et al (2005) The temporal effects of anti-TGF-beta1, 2, and 3 monoclonal antibody on wound healing and hypertrophic scar formation. J Am Coll Surg 201(3):391–7PubMedCrossRefGoogle Scholar
  28. 28.
    Schofield R (1978) The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4(1–2):7–25PubMedGoogle Scholar
  29. 29.
    Jones DL, Wagers AJ (2008) No place like home: anatomy and function of the stem cell niche. Nat Rev Mol Cell Biol 9(1):11–21PubMedCrossRefGoogle Scholar
  30. 30.
    Lutolf MP, Hubbell JA (2005) Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nat Biotechnol 23(1):47–55PubMedCrossRefGoogle Scholar
  31. 31.
    Discher DE, Mooney DJ, Zandstra PW (2009) Growth factors, matrices, and forces combine and control stem cells. Science 324(5935):1673–7PubMedCrossRefGoogle Scholar
  32. 32.
    Place ES, Evans ND, Stevens MM (2009) Complexity in biomaterials for tissue engineering. Nat Mater 8(6):457–70PubMedCrossRefGoogle Scholar
  33. 33.
    Guilak F et al (2009) Control of stem cell fate by physical interactions with the extracellular matrix. Cell Stem Cell 5(1):17–26PubMedCrossRefGoogle Scholar
  34. 34.
    Lutton C, Goss B (2008) Caring about microenvironments. Nat Biotechnol 26(6):613–4PubMedCrossRefGoogle Scholar
  35. 35.
    Lim SH, Mao HQ (2009) Electrospun scaffolds for stem cell engineering. Adv Drug Deliv Rev 61(12):1084–96PubMedCrossRefGoogle Scholar
  36. 36.
    Li WJ et al (2005) Multilineage differentiation of human mesenchymal stem cells in a three-dimensional nanofibrous scaffold. Biomaterials 26(25):5158–66PubMedCrossRefGoogle Scholar
  37. 37.
    Yim EK, Pang SW, Leong KW (2007) Synthetic nanostructures inducing differentiation of human mesenchymal stem cells into neuronal lineage. Exp Cell Res 313(9):1820–9PubMedCrossRefGoogle Scholar
  38. 38.
    Baker BM, Mauck RL (2007) The effect of nanofiber alignment on the maturation of engineered meniscus constructs. Biomaterials 28(11):1967–77PubMedCrossRefGoogle Scholar
  39. 39.
    Sefcik LS et al (2008) Collagen nanofibres are a ­biomimetic substrate for the serum-free osteogenic differentiation of human adipose stem cells. J Tissue Eng Regen Med 2(4):210–20PubMedCrossRefGoogle Scholar
  40. 40.
    Nie H et al (2008) Three-dimensional fibrous PLGA/HAp composite scaffold for BMP-2 delivery. Biotechnol Bioeng 99(1):223–34PubMedCrossRefGoogle Scholar
  41. 41.
    Engler AJ et al (2006) Matrix elasticity directs stem cell lineage specification. Cell 126(4):677–89PubMedCrossRefGoogle Scholar
  42. 42.
    Shih YR et al (2006) Growth of mesenchymal stem cells on electrospun type I collagen nanofibers. Stem Cells 24(11):2391–7PubMedCrossRefGoogle Scholar
  43. 43.
    Michelsson JE, Granroth G, Andersson LC (1980) Myositis ossificans following forcible manipulation of the leg. A rabbit model for the study of heterotopic bone formation. J Bone Joint Surg Am 62(5):811–5PubMedGoogle Scholar
  44. 44.
    Lin L et al (2006) Adenovirus-mediated transfer of siRNA against Runx2/Cbfa1 inhibits the formation of heterotopic ossification in animal model. Biochem Biophys Res Commun 349(2):564–72PubMedCrossRefGoogle Scholar
  45. 45.
    O’Connor JP (1998) Animal models of heterotopic ossification. Clin Orthop Relat Res 346:71–80PubMedCrossRefGoogle Scholar
  46. 46.
    Kaplan FS et al (2004) Heterotopic ossification. J Am Acad Orthop Surg 12(2):116–25PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Youngmi Ji
    • 1
  • Gregory T. Christopherson
    • 1
  • Matthew W. Kluk
    • 1
    • 2
  • Orna Amrani
    • 1
  • Wesley M. Jackson
    • 3
  • Leon J. Nesti
    • 4
    • 2
  1. 1.Clinical and Experimental Orthopaedics Group, National Institutes of Arthritis and Musculoskeletal and Skin DiseasesNational Institutes of HealthBethesdaUSA
  2. 2.Integrated Department of Orthopaedics and RehabilitationWalter Reed Army Medical and National Naval Medical CenterBethesdaUSA
  3. 3.Clinical and Experimental Orthopaedics Laboratory, Department of SurgeryThe Uniformed Services UniversityBethesdaUSA
  4. 4.Clinical and Experimental Orthopaedics Group, National Institutes of Arthritis and Musculoskeletal and Skin DiseasesNational Institutes of HealthBethesdaUSA

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