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Role of Altered Signal Transduction in Heterotopic Ossification and Fibrodysplasia Ossificans Progressiva

Current Osteoporosis Reports volume 9, pages 83–88 (2011)Cite this article

Abstract

Heterotopic ossification is a pathologic condition in which bone tissue is formed outside of the skeleton, within soft tissues of the body. The extraskeletal bone that forms in these disorders is normal; the cellular mechanisms that direct cell fate decisions are dysregulated. Patients with fibrodysplasia ossificans progressiva (FOP), a rare human genetic disorder of extensive and progressive heterotopic ossification, have malformations of normal skeletal elements, identifying the causative gene mutation and its relevant signaling pathways as key regulators of skeletal development and of cell fate decisions by adult stem cells. The discovery that mildly activating mutations in ACVR1/ALK2, a bone morphogenetic protein (BMP) type I receptor, is the cause of FOP has provided opportunities to identify previously unknown functions for this receptor and for BMP signaling and to develop new diagnostic and therapeutic strategies for FOP and other more common forms of heterotopic ossification, as well as tissue engineering applications.

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References

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

  1. Yang Y. Skeletal morphogenesis and embryonic development. In: Rosen CJ, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism. Washington, DC: American Society of Bone and Mineral Research; 2008. p. 2–10.

    Google Scholar 

  2. McCarthy EF, Sundaram M. Heterotopic ossification: a review. Skeletal Radiol. 2005;34:609–19.

    PubMed  Article  CAS  Google Scholar 

  3. Pignolo RJ, Foley KL. Nonhereditary heterotopic ossification. Clin Rev Bone Miner Metab. 2005;3:261–6.

    Article  Google Scholar 

  4. Forsberg JA, Pepek JM, Wagner S, et al. Heterotopic ossification in high-energy wartime extremity injuries: prevalence and risk factors. J Bone Joint Surg Am. 2009;91:1084–91.

    PubMed  Article  Google Scholar 

  5. Neal B, Gray H, MacMahon S, Dunn L. Incidence of heterotopic bone formation after major hip surgery. ANZ J Surg. 2002;72:808–21.

    PubMed  Article  Google Scholar 

  6. van Kuijk AA, Geurts ACH, van Kuppevelt HJM. Neurogenic heterotopic ossification in spinal cord injury. Spinal Cord. 2002;40:313–26.

    PubMed  Article  Google Scholar 

  7. Mohler 3rd ER, Gannon F, Reynolds C, et al. Bone formation and inflammation in cardiac valves. Circulation. 2001;103:1522–8.

    PubMed  Google Scholar 

  8. Chalmers J, Gray DH, Rush J. Observations on induction of bone in soft-tissues. J Bone Jt Surg Br Vol B. 1975;57:36–45.

    CAS  Google Scholar 

  9. • Shore EM, Kaplan FS. Inherited human diseases of heterotopic bone formation. Nat Rev Rheumatol. 2010;6:518–27. This recent review provides an overview of POH and FOP, two human genetic disorders of HO.

    PubMed  Article  CAS  Google Scholar 

  10. Kaplan FS, Glaser DL, Shore EM, et al. The phenotype of fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab. 2005;3:183–8.

    Article  Google Scholar 

  11. Kaplan FS, Le Merrer M, Glaser DL, et al. Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol. 2008;22:191–205.

    PubMed  Article  CAS  Google Scholar 

  12. Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva and progressive osseous heteroplasia: two genetic disorders of heterotopic ossification. Clin Rev Bone Miner Metab. 2005;3:257–9.

    Article  Google Scholar 

  13. Kaplan FS, Groppe JC, Seeman P, et al. Fibrodysplasia ossificans progressiva: developmental implications of a novel metamorphogene. In: Bronner F, Farach-Carson MC, Roach HI, editors. Bone and development. London: Springer-Verlag; 2010. p. 233–49.

    Chapter  Google Scholar 

  14. • Kaplan FS, Xu M, Seemann P, 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;30:379–90. A series of atypical FOP clinical phenotypes and the identification of non-R206H ACVR1 mutations in these patients are reported.

    PubMed  Article  CAS  Google Scholar 

  15. •• Shore EM, Xu MQ, Feldman GJ, et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2006;38:525–7. This first report of ACVR1/ALK2 mutations in FOP identified the ACVR1 R206H mutation as recurrent in patients with a classic clinical presentation.

    PubMed  Article  CAS  Google Scholar 

  16. Urist MR. Bone: formation by autoinduction. Science. 1965;150:893–9.

    PubMed  Article  CAS  Google Scholar 

  17. Billings PC, Fiori JL, Bentwood JL, et al. Dysregulated BMP signaling and enhanced osteogenic differentiation of connective tissue progenitor cells from patients with fibrodysplasia ossificans progressiva (FOP). J Bone Miner Res. 2008;23:305–13.

    PubMed  Article  CAS  Google Scholar 

  18. Fiori JL, Billings PC, Serrano de la Pena LS, et al. Dysregulation of the BMP-p38 MAPK signaling pathway in cells from patients with fibrodysplasia ossificans progressiva (FOP). J Bone Miner Res. 2006;21:902–9.

    PubMed  Article  CAS  Google Scholar 

  19. Serrano de la Pena LS, Billings PC, Fiori JL, et al. Fibrodysplasia ossificans progressiva (FOP), a disorder of ectopic osteogenesis, misregulates cell surface expression and trafficking of BMPRIA. J Bone Miner Res. 2005;20:1168–76.

    Article  CAS  Google Scholar 

  20. Shafritz AB, Shore EM, Gannon FH, et al. Overexpression of an osteogenic morphogen in fibrodysplasia ossificans progressiva. N Engl J Med. 1996;335:555–61.

    PubMed  Article  CAS  Google Scholar 

  21. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003;425:577–84.

    PubMed  Article  CAS  Google Scholar 

  22. Schmierer B, Hill CS. TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol. 2007;8:970–82.

    PubMed  Article  CAS  Google Scholar 

  23. Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113:685–700.

    PubMed  Article  CAS  Google Scholar 

  24. Guo X, Wang X-F. Signaling cross-talk between TGF-beta/BMP and other pathways. Cell Res. 2009;19:71–88.

    PubMed  Article  CAS  Google Scholar 

  25. Derynck R, Akhurst RJ. Differentiation plasticity regulated by TGF-beta family proteins in development and disease. Nat Cell Biol. 2007;9:1000–4.

    PubMed  Article  CAS  Google Scholar 

  26. Eivers E, Fuentealba LC, De Robertis EM. Integrating positional information at the level of Smad1/5/8. Curr Opin Genet Dev. 2008;18:304–10.

    PubMed  Article  CAS  Google Scholar 

  27. Watabe T, Miyazono K. Roles of TGF-beta family signaling in stem cell renewal and differentiation. Cell Res. 2009;19:103–15.

    PubMed  Article  CAS  Google Scholar 

  28. Wu MY, Hill CS. Tgf-beta superfamily signaling in embryonic development and homeostasis. Dev Cell. 2009;16:329–43.

    PubMed  Article  CAS  Google Scholar 

  29. Xu J, Lamouille S, Derynck R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 2009;19:156–72.

    PubMed  Article  CAS  Google Scholar 

  30. Yu PB, Deng DY, Lai CS, et al. BMP type I receptor inhibition reduces heterotopic ossification. Nat Med. 2008;14:1363–9.

    PubMed  Article  CAS  Google Scholar 

  31. • Zhang D, Schwarz EM, Rosier RN, et al. ALK2 functions as a BMP type I receptor and induces Indian hedgehog in chondrocytes during skeletal development. J Bone Miner Res. 2003;18:1593–604.

    PubMed  Article  CAS  Google Scholar 

  32. Bocciardi R, Bordo D, Di Duca M, et al. Mutational analysis of the ACVR1 gene in Italian patients affected with fibrodysplasia ossificans progressiva: confirmations and advancements. Eur J Hum Genet. 2009;17:311–8.

    PubMed  Article  CAS  Google Scholar 

  33. Groppe JC, Shore EM, Kaplan FS. Functional modeling of the ACVR1 (R206H) mutation in FOP. Clin Orthop Relat Res. 2007;462:87–92.

    PubMed  Article  Google Scholar 

  34. Petrie KA, Lee WH, Bullock AN, et al.: Novel mutations in ACVR1 result in atypical features in two fibrodysplasia ossificans progressiva patients. Plos One. 2009:4.

  35. Fukuda T, Kohda M, Kanomata K, et al. Constitutively activated ALK2 and increased SMAD1/5 cooperatively induce bone morphogenetic protein signaling in fibrodysplasia ossificans progressiva. J Biol Chem. 2009;284:7149–56.

    PubMed  Article  CAS  Google Scholar 

  36. • Shen Q, Little SC, Xu M, et al. The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization. J Clin Invest. 2009;119:3462–72. In vitro and in vivo assays demonstrated ligand-independent and -responsive activation of the mutant ACVR1/ALK2 R206H receptor.

    PubMed  CAS  Google Scholar 

  37. Song GA, Kim HJ, Woo KM, et al. Molecular consequences of the ACVR1(R206H) mutation of fibrodysplasia ossificans progressiva. J Biol Chem. 2010;285:22542–53.

    PubMed  Article  CAS  Google Scholar 

  38. van Dinther M, Visser N, de Gorter DJJ, et al. ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the bmp type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation. J Bone Miner Res. 2010;25:1208–15.

    PubMed  Google Scholar 

  39. Huse M, Muir TW, Xu L, et al. The TGF beta receptor activation process: an inhibitor- to substrate-binding switch. Mol Cell. 2001;8:671–82.

    PubMed  Article  CAS  Google Scholar 

  40. Gannon FH, Valentine BA, Shore EM, et al. Acute lymphocytic infiltration in an extremely early lesion of fibrodysplasia ossificans progressiva. Clin Orthop Relat Res. 1998;346:19–25.

    PubMed  Article  Google Scholar 

  41. Glaser DL, Economides AN, Wang LL, et al. In vivo somatic cell gene transfer of an engineered noggin mutein prevents BMP4-induced heterotopic ossification. J Bone Joint Surg Am. 2003;85A:2332–42.

    Google Scholar 

  42. Hegyi L, Gannon FH, Glaser DL, et al. Stromal cells of fibrodysplasia ossificans progressiva lesions express smooth muscle lineage markers and the osteogenic transcription factor Runx2/Cbfa-1: clues to a vascular origin of heterotopic ossification? J Pathol. 2003;201:141–8.

    PubMed  Article  CAS  Google Scholar 

  43. Kaplan FS, Shore EM, Gupta R, et al. Immunological features of fibrodysplasia ossificans progessiva and the dysregulated BMP4 pathway. Clin Rev Bone Miner Metab. 2005;3:189–93.

    Article  Google Scholar 

  44. Kaplan FS, Tabas JA, Gannon FH, et al. The histopathology of fibrodysplasia ossificans progressiva An endochondral process. J Bone Joint Surg Am. 1993;75:220–30.

    PubMed  CAS  Google Scholar 

  45. Pignolo RJ, Suda RK, Kaplan FS. The fibrodysplasia ossificans progressiva lesion. Clin Rev Bone Miner Metab. 2005;3:195–200.

    Article  Google Scholar 

  46. Olmsted-Davis E, Gannon FH, Ozen M, et al. Hypoxic adipocytes pattern early heterotopic bone formation. Am J Pathol. 2007;170:620–32.

    PubMed  Article  CAS  Google Scholar 

  47. Wang H, Shore EM, Kaplan FS, et al. Hypoxia promotes ligand-independent activation of the ACVR1 (R206H) mutant receptor in C2C12 cells. J Bone Miner Res. 2008;23:S433–3.

    Google Scholar 

  48. Kaplan FS, Glaser DL, Shore EM, et al. Hematopoietic stem-cell contribution to ectopic skeletogenesis. J Bone Joint Surg Am. 2007;89A:347–57.

    Article  Google Scholar 

  49. Lounev VY, Ramachandran R, Wosczyna MN, et al. Identification of progenitor cells that contribute to heterotopic skeletogenesis. J Bone Joint Surg Am. 2009;91:652–63.

    PubMed  Article  Google Scholar 

  50. Medici D, Shore EM, Lounev VY, et al. Conversion of vascular endothelial cells into multipotent stem-like cells. Nat Med. 2010;16:1400–6.

    PubMed  Article  CAS  Google Scholar 

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Acknowledgments

We thank the members of our research laboratory and our many collaborators for their contributions. We also thank the National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases-supported Penn Center for Musculoskeletal Disorders (AR050950). This work was supported in part by the Center for Research in FOP and Related Disorders, the International FOP Association (IFOPA), the Ian Cali Endowment, the Weldon Family Endowment, the Isaac and Rose Nassau Professorship of Orthopaedic Molecular Medicine, the Rita Allen Foundation, and by grants from the NIH (R01-AR41916 and R01-AR046831).

Disclosure

Conflicts of interest: E.M. Shore: has received support for travel expenses for the 10th International Conference on the Chemistry and Biology of Mineralized Tissues meeting, Gordon Research Conference, NIH/National Institute of Dental and Craniofacial Research, and International Workshop on BMPs; F.S. Kaplan: none.

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Affiliations

  1. Department of Orthopaedic Surgery, University of Pennsylvania School of Medicine, 426 Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA, 19104-6081, USA

    Eileen M. Shore & Frederick S. Kaplan

  2. Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Eileen M. Shore

  3. Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Frederick S. Kaplan

  4. The Center for Research in FOP and Related Disorders, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Eileen M. Shore & Frederick S. Kaplan

  5. Department of Orthopaedic Surgery, Hospital of the University of Pennsylvania, Silverstein Pavilion - Second Floor, 3400 Spruce Street, Philadelphia, PA, 19104, USA

    Frederick S. Kaplan

Authors
  1. Eileen M. Shore
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  2. Frederick S. Kaplan
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Correspondence to Eileen M. Shore.

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Shore, E.M., Kaplan, F.S. Role of Altered Signal Transduction in Heterotopic Ossification and Fibrodysplasia Ossificans Progressiva. Curr Osteoporos Rep 9, 83–88 (2011). https://doi.org/10.1007/s11914-011-0046-3

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  • DOI: https://doi.org/10.1007/s11914-011-0046-3

Keywords

  • Activin A type I receptor
  • ACVR1
  • Activin-like kinase 2
  • ALK2
  • Bone morphogenetic proteins
  • BMP
  • BMP receptors
  • BMP signaling
  • Endochondral ossification
  • Fibrodysplasia ossificans progressiva
  • FOP
  • Heterotopic ossification
  • Extraskeletal bone formation