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Inherited human diseases of heterotopic bone formation

Nature Reviews Rheumatology volume 6, pages 518–527 (2010)Cite this article

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Abstract

Human disorders of hereditary and nonhereditary heterotopic ossification are conditions in which osteogenesis occurs outside of the skeleton, within soft tissues of the body. The resulting extraskeletal bone is normal. The aberration lies within the mechanisms that regulate cell-fate determination, directing the inappropriate formation of cartilage or bone, or both, in tissues such as skeletal muscle and adipose tissue. Specific gene mutations have been identified in two rare inherited disorders that are clinically characterized by extensive and progressive extraskeletal bone formation—fibrodysplasia ossificans progressiva and progressive osseous heteroplasia. In fibrodysplasia ossificans progressiva, activating mutations in activin receptor type-1, a bone morphogenetic protein type I receptor, induce heterotopic endochondral ossification, which results in the development of a functional bone organ system that includes skeletal-like bone and bone marrow. In progressive osseous heteroplasia, the heterotopic ossification leads to the formation of mainly intramembranous bone tissue in response to inactivating mutations in the GNAS gene. Patients with these diseases variably show malformation of normal skeletal elements, identifying the causative genes and their associated signaling pathways as key mediators of skeletal development in addition to regulating cell-fate decisions by adult stem cells.

Key Points

  • Heterotopic ossification is the formation of extraskeletal bone in soft connective tissues

  • The bone tissue that forms during heterotopic ossification is qualitatively normal

  • Two rare inherited forms of heterotopic ossification are fibrodysplasia ossificans progressiva (FOP) and progressive osseous heteroplasia (POH)

  • FOP is caused by a mutation in ACVR1, which encodes a bone morphogenetic protein type I receptor; POH is caused by a mutation in the GNAS locus

  • The genes and signaling pathways that are altered in these genetic disorders are key regulators of skeletal development and cell differentiation

  • Understanding the cellular mechanisms responsible for these rare disorders might lead to the development of therapeutic approaches relevant to common conditions of excessive and insufficient bone formation

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Figure 1: Characteristic clinical features of FOP.
Figure 2: Generalized schematic representation of the BMP signaling pathway.
Figure 3: Schematic histologic representation of the stages of endochondral heterotopic ossification in FOP.
Figure 4: A working model for altered BMP signaling in FOP.
Figure 5: Heterotopic ossification in POH.
Figure 6: Histopathology of a POH lesion.
Figure 7: The GNAS gene locus.

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References

  1. Yang, Y. In Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism (ed. Rosen, C. J.) 2–10 (American Society of Bone and Mineral Research, Washington, DC, 2008).

    Google Scholar 

  2. McCarthy, E. F. & Sundaram, M. Heterotopic ossification: a review. Skeletal Radiol. 34, 609–619 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Pignolo, R. J. & Foley, K. L. Nonhereditary heterotopic ossification. Implications for injury, arthropy, and aging. Clin. Rev. Bone Miner. Metab. 3, 261–266 (2005).

    Article  Google Scholar 

  4. Forsberg, J. A. et al. Heterotopic ossification in high-energy wartime extremity injuries: prevalence and risk factors. J. Bone Joint Surg. Am. 91, 1084–1091 (2009).

    Article  PubMed  Google Scholar 

  5. Neal, B., Gray, H., MacMahon, S. & Dunn, L. Incidence of heterotopic bone formation after major hip surgery. ANZ J. Surg. 72, 808–821 (2002).

    Article  PubMed  Google Scholar 

  6. Potter, B. K., Burns, T. C., Lacap, A. P., Granville, R. R. & Gajewski, D. Heterotopic ossification in the residual limbs of traumatic and combat-related amputees. J. Am. Acad. Orthop. Surg. 14 (10 Spec. No), S191–S197 (2006).

    Article  PubMed  Google Scholar 

  7. van Kuijk, A. A., Geurts, A. C. H. & van Kuppevelt, H. J. M. Neurogenic heterotopic ossification in spinal cord injury. Spinal Cord 40, 313–326 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Kaplan, F. S. & Shore, E. M. Progressive osseous heteroplasia. J. Bone Miner. Res. 15, 2084–2094 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Shore, E. M. & Kaplan, F. S. Insights from a rare genetic disorder of extra-skeletal bone formation, fibrodysplasia ossificans progressiva (FOP). Bone 43, 427–433 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. MIM #135100. National Center for Biotechnology Information [online], (2010).

  11. Kaplan, F. S. et al. The phenotype of fibrodysplasia ossificans progressiva. Clin. Rev. Bone Miner. Metab. 3, 183–188 (2005).

    Article  Google Scholar 

  12. Kaplan, F. S. et al. Fibrodysplasia ossificans progressiva. Best Pract. Res. Clin. Rheumatol. 22, 191–205 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kaplan, F. S. & Shore, E. M. In Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism (ed. Rosen, C. J.) 442–446 (American Society for Bone and Mineral Research, Washington, DC, 2008).

    Book  Google Scholar 

  14. Shore, E. M. & Kaplan, F. S. Fibrodysplasia ossificans progressiva and progressive osseous heteroplasia: two genetic disorders of heterotopic ossification. Clin. Rev. Bone Miner. Metab. 3, 257–259 (2005).

    Article  Google Scholar 

  15. Shore, E. M. et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat. Genet. 38, 525–527 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Derynck, R. & Akhurst, R. J. Differentiation plasticity regulated by TGF-β family proteins in development and disease. Nat. Cell Biol. 9, 1000–1004 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Eivers, E., Fuentealba, L. C. & De Robertis, E. M. Integrating positional information at the level of Smad1/5/8. Curr. Opin. Genet. Dev. 18, 304–310 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Heisenberg, C. P. & Solnica-Krezel, L. Back and forth between cell fate specification and movement during vertebrate gastrulation. Curr. Opin. Genet. Dev. 18, 311–316 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hogan, B. L. M. Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev. 10, 1580–1594 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Watabe, T. & Miyazono, K. Roles of TGF-β family signaling in stem cell renewal and differentiation. Cell Res. 19, 103–115 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. Wu, M. Y. & Hill, C. S. TGF-β superfamily signaling in embryonic development and homeostasis. Dev. Cell 16, 329–343 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Xu, J., Lamouille, S. & Derynck, R. TGF-β-induced epithelial to mesenchymal transition. Cell Res. 19, 156–172 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Urist, M. R. Bone: formation by autoinduction. Science 150, 893–899 (1965).

    Article  CAS  PubMed  Google Scholar 

  24. Derynck, R. & Zhang, Y. E. Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature 425, 577–584 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Huse, M. et al. The TGFβ receptor activation process: an inhibitor- to substrate-binding switch. Mol. Cell 8, 671–682 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Krause, C., de Gorter, D. J. J., Karperien, M. & ten Dijke, P. in Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism (ed. Rosen, C. J.) 10–16 (American Society of Bone and Mineral Research Washington, DC, (2008).

    Book  Google Scholar 

  27. Schmierer, B. & Hill, C. S. TGF-β–SMAD signal transduction: molecular specificity and functional flexibility. Nat. Rev. Mol. Cell Biol. 8, 970–982 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Shi, Y. & Massague, J. Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113, 685–700 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. ten Dijke, P. & Hill, C. S. New insights into TGF-β–Smad signalling. Trends Biochem. Sci. 29, 265–273 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Guo, X. & Wang, X.-F. Signaling cross-talk between TGF-β/BMP and other pathways. Cell Res. 19, 71–88 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Moustakas, A. & Heldin, C. H. Non-Smad TGF-β signals. J. Cell Sci. 118, 3573–3584 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Nohe, A. et al. The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways. J. Biol. Chem. 277, 5330–5338 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Chen, Y. G. et al. Determinants of specificity in TGF-β signal transduction. Genes Dev. 12, 2144–2152 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Little, S. C. & Mullins, M. C. Bone morphogenetic protein heterodimers assemble heteromeric type I receptor complexes that pattern the dorsoventral axis. Nat. Cell Biol. 11, 637–643 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Massague, J. How cells read TGF-β signals. Nat. Rev. Mol. Cell Biol. 1, 169–178 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Gazzerro, E. & Canalis, E. Bone morphogenetic proteins and their antagonists. Rev. Endocr. Metab. Disord. 7, 51–65 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Yu, P. B. et al. BMP type I receptor inhibition reduces heterotopic ossification. Nat. Med. 14, 1363–1369 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhang, D. et al. ALK2 functions as a BMP type I receptor and induces Indian hedgehog in chondrocytes during skeletal development. J. Bone Miner. Res. 18, 1593–1604 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Billings, P. C. 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. 23, 305–313 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Fiori, J. L., Billings, P. C., Serrano de la Pena, L. S., Kaplan, F. S. & Shore, E. M. Dysregulation of the BMP-p38 MAPK signaling pathway in cells from patients with fibrodysplasia ossificans progressiva (FOP). J. Bone Miner. Res. 21, 902–909 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Serrano de la Pena, L. S. et al. Fibrodysplasia ossificans progressiva (FOP), a disorder of ectopic osteogenesis, misregulates cell surface expression and trafficking of BMPRIA. J. Bone Miner. Res. 20, 1168–1176 (2005).

    Article  CAS  Google Scholar 

  42. Shafritz, A. B. et al. Overexpression of an osteogenic morphogen in fibrodysplasia ossificans progressiva. N. Engl. J. Med. 335, 555–561 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Fukuda, T. et al. Constitutively activated ALK2 and increased SMAD1/5 cooperatively induce bone morphogenetic protein signaling in fibrodysplasia ossificans progressiva. J. Biol. Chem. 284, 7149–7156 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Shen, Q. et al. The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization. J. Clin. Invest. 119, 3462–3472 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Gu, Z. et al. The type I serine/threonine kinase receptor ActRIA (ALK2) is required for gastrulation of the mouse embryo. Development 126, 2551–2561 (1999).

    CAS  PubMed  Google Scholar 

  46. Mishina, Y., Crombie, R., Bradley, A. & Behringer, R. R. Multiple roles for activin-like kinase-2 signaling during mouse embryogenesis. Dev. Biol. 213, 314–326 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Pignolo, R. J., Suda, R. K. & Kaplan, F. S. The fibrodysplasia ossificans progressiva lesion. Clin. Rev. Bone Miner. Metab. 3, 195–200 (2005).

    Article  Google Scholar 

  48. Cohen, R. B. et al. The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. A study of forty-four patients. J. Bone Joint Surg. Am. 75, 215–219 (1993).

    Article  CAS  PubMed  Google Scholar 

  49. Rocke, D. M., Zasloff, M., Peeper, J., Cohen, R. B. & Kaplan, F. S. Age- and joint-specific risk of initial heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. Clin. Orthop. Relat. Res. 301, 243–248 (1994).

    Google Scholar 

  50. Lanchoney, T. F., Cohen, R. B., Rocke, D. M., Zasloff, M. A. & Kaplan, F. S. Permanent heterotopic ossification at the injection site after diphtheria-tetanus-pertussis immunizations in children who have fibrodysplasia ossificans progressiva. J. Pediatr. 126, 762–764 (1995).

    Article  CAS  PubMed  Google Scholar 

  51. Scarlett, R. F. et al. Influenza-like viral illnesses and flare-ups of fibrodysplasia ossificans progressiva. Clin. Orthop. Rel. Res. 423, 275–279 (2004).

    Article  Google Scholar 

  52. Gannon, F. H., Valentine, B. A., Shore, E. M., Zasloff, M. A. & Kaplan, F. S. Acute lymphocytic infiltration in an extremely early lesion of fibrodysplasia ossificans progressiva. Clin. Orthop. Rel. Res. 346, 19–25 (1998).

    Article  Google Scholar 

  53. Glaser, D. L. et al. In vivo somatic cell gene transfer of an engineered noggin mutein prevents BMP4-induced heterotopic ossification. J. Bone Joint Surg. Am. 85A, 2332–2342 (2003).

    Article  Google Scholar 

  54. Hegyi, L. 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. 201, 141–148 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Kaplan, F. S. et al. Immunological features of fibrodysplasia ossificans progessiva and the dysregulated BMP4 pathway. Clin. Rev. Bone Miner. Metab. 3, 189–193 (2005).

    Article  Google Scholar 

  56. Kaplan, F. S. et al. The histopathology of fibrodysplasia ossificans progressiva. An endochondral process. J. Bone Joint Surg. Am. 75, 220–230 (1993).

    Article  CAS  PubMed  Google Scholar 

  57. Lounev, V. Y. et al. Identification of progenitor cells that contribute to heterotopic skeletogenesis. J. Bone Joint Surg. Am. 91, 652–663 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Kaplan, F. S. et al. Hematopoietic stem-cell contribution to ectopic skeletogenesis. J. Bone Joint Surg. Am. 89A, 347–357 (2007).

    Article  Google Scholar 

  59. Kaplan, F. S., Strear, C. M. & Zasloff, M. A. Radiographic and scintigraphic features of modeling and remodeling in the heterotopic skeleton of patients who have fibrodysplasia ossificans progressiva. Clin. Orthop. Rel. Res. 304, 238–247 (1994).

    Google Scholar 

  60. Kaplan, F. et al. Urinary basic fibroblast growth factor. A biochemical marker for preosseous fibroproliferative lesions in patients with fibrodysplasia ossificans progressiva. Clin. Orthop. Rel. Res. 346, 59–65 (1998).

    Google Scholar 

  61. Lutwak, L. Myositis ossificans progressiva. Mineral, metabolic and radioactive calcium studies of the effects of hormones. Am. J. Med. 37, 269–293 (1964).

    Article  CAS  PubMed  Google Scholar 

  62. Ferguson, C., Alpern, E., Miclau, T. & Helms, J. A. Does adult fracture repair recapitulate embryonic skeletal formation? Mech. Dev. 87, 57–66 (1999).

    Article  CAS  PubMed  Google Scholar 

  63. Vortkamp, A. et al. Recapitulation of signals regulating embryonic bone formation during postnatal growth and in fracture repair. Mech. Dev. 71, 65–76 (1998).

    Article  CAS  PubMed  Google Scholar 

  64. Dean, D. B., Watson, J. T., Moed, B. R. & Zhang, Z. Role of bone morphogenetic proteins and their antagonists in healing of bone fracture. Front. Biosci. 14, 2878–2888 (2009).

    Article  CAS  Google Scholar 

  65. Gerstenfeld, L. C., Cullinane, D. M., Barnes, G. L., Graves, D. T. & Einhorn, T. A. Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. J. Cell. Biochem. 88, 873–884 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Kloen, P. et al. BMP signaling components are expressed in human fracture callus. Bone 33, 362–371 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Tsuji, K. et al. BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat. Genet. 38, 1424–1429 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Einhorn, T. A. & Kaplan, F. S. Traumatic fractures of heterotopic bone in patients who have fibrodysplasia ossificans progressiva. A report of 2 cases. Clin. Orthop. Rel. Res. 308, 173–177 (1994).

    Google Scholar 

  69. Connor, J. M. & Evans, D. A. Fibrodysplasia ossificans progressiva. The clinical features and natural history of 34 patients. J. Bone Joint Surg. Br. 64, 76–83 (1982).

    Article  CAS  PubMed  Google Scholar 

  70. Deirmengian, G. K. et al. Proximal tibial osteochondromas in patients with fibrodysplasia ossificans progressiva. J. Bone Joint Surg. Am. 90, 366–374 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Schaffer, A. A. et al. Developmental anomalies of the cervical spine in patients with fibrodysplasia ossificans progressiva are distinctly different from those in patients with Klippel-Feil syndrome —Clues from the BMP signaling pathway. Spine 30, 1379–1385 (2005).

    Article  PubMed  Google Scholar 

  72. Seemann, P., Mundlos, S. & Lehmann, K. In Bone Morphogenetic Proteins: From Local to System Therapeutics (eds. Vukicevic, S. & Sampath, K. T.) 141–159 (Birkhäuser, Basel, 2008).

    Book  Google Scholar 

  73. Kaplan, F. S. et al. Classic and atypical FOP phenotypes are caused by mutations in the BMP type I receptor ACVR1. Hum. Mutat. 30, 379–390 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wozney, J. M. et al. Novel regulators of bone formation: molecular clones and activities. Science 242, 1528–1534 (1988).

    Article  CAS  PubMed  Google Scholar 

  75. Deng, Z. L. et al. Regulation of osteogenic differentiation during skeletal development. Front. Biosci. 13, 2001–2021 (2008).

    Article  CAS  PubMed  Google Scholar 

  76. Furuta, Y. & Hogan, B. L. BMP4 is essential for lens induction in the mouse embryo. Genes Dev. 12, 3764–3775 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Lawson, K. A. et al. Bmp4 is required for the generation of primordial germ cells in the mouse embryo. Genes Dev. 13, 424–436 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Mitu, G. M., Wang, S. & Hirschberg, R. BMP7 is a podocyte survival factor and rescues podocytes from diabetic injury. Am. J. Physiol. Renal Physiol. 293, F1641–F1648 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Morty, R. E. et al. Dysregulated bone morphogenetic protein signaling in monocrotaline-induced pulmonary arterial hypertension. Arterioscler. Thromb. Vasc. Biol. 27, 1072–1078 (2007).

    Article  CAS  PubMed  Google Scholar 

  80. Valdimarsdottir, G. et al. Stimulation of Id1 expression by bone morphogenetic protein is sufficient and necessary for bone morphogenetic protein-induced activation of endothelial cells. Circulation 106, 2263–2270 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. de Sousa Lopes, S. M. et al. BMP signaling mediated by ALK2 in the visceral endoderm is necessary for the generation of primordial germ cells in the mouse embryo. Genes Dev. 18, 1838–1849 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Dudas, M., Sridurongrit, S., Nagy, A., Okazaki, K. & Kaartinen, V. Craniofacial defects in mice lacking BMP type I receptor Alk2 in neural crest cells. Mech. Dev. 121, 173–182 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Kaartinen, V. et al. Cardiac outflow tract defects in mice lacking ALK2 in neural crest cells. Development 131, 3481–3490 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Kevenaar, M. E. et al. Variants in the ACVR1 gene are associated with AMH levels in women with polycystic ovary syndrome. Hum. Reprod. 24, 241–249 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. Komatsu, Y., Scott, G., Nagy, A., Kaartinen, V. & Mishina, Y. BMP type I receptor ALK2 is essential for proper patterning at late gastrulation during mouse embryogenesis. Dev. Dyn. 236, 512–517 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Rajagopal, R. et al. Functions of the type 1 BMP receptor Acvr1 (Alk2) in lens development: cell proliferation, terminal differentiation, and survival. Invest. Ophthal. Vis. Sci. 49, 4953–4960 (2008).

    Article  PubMed  Google Scholar 

  87. MIM #166350, National Center for Biotechnological Information. [online], (2010).

  88. Kaplan, F. S. et al. Progressive osseous heteroplasia: a distinct developmental disorder of heterotopic ossification. Two new case reports and follow-up of three previously reported cases. J. Bone Joint Surg. Am. 76, 425–436 (1994).

    Article  CAS  PubMed  Google Scholar 

  89. Shore, E. M., Feldman, G. J., Xu, M. & Kaplan, F. S. The genetics of fibrodysplasia ossificans progressiva. Clin. Rev. Bone Miner. Metab. 3, 201–204 (2005).

    Article  CAS  Google Scholar 

  90. Shore, E. M. et al. Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N. Engl. J. Med. 346, 99–106 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Adegbite, N. S., Xu, M., Kaplan, F. S., Shore, E. M. & Pignolo, R. J. Diagnostic and mutational spectrum of progressive osseous heteroplasia (POH) and other forms of GNAS-based heterotopic ossification. Am. J. Med. Genet. A 146A, 1788–1796 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Plagge, A., Kelsey, G. & Germain-Lee, E. L. Physiological functions of the imprinted Gnas locus and its protein variants Gαs and XLαs in human and mouse. J. Endocrinol. 196, 193–214 (2008).

    Article  CAS  PubMed  Google Scholar 

  93. Rubin, M. R. & Levine, M. A. in Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism (ed. Rosen, C. J.) 354–361 (American Society for Bone and Mineral Research, Washington, DC, 2008).

    Book  Google Scholar 

  94. Weinstein, L. S., Chen, M., Xie, T. & Liu, J. Genetic diseases associated with heterotrimeric G proteins. Trends Pharmacol. Sci. 27, 260–266 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Weinstein, L. S., Xie, T., Zhang, Q. H. & Chen, M. Studies of the regulation and function of the Gsα gene Gnas using gene targeting technology. Pharmacol. Ther. 115, 271–291 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Bastepe, M. & Jüppner, H. GNAS locus and pseudohypoparathyroidism. Horm. Res. 63, 65–74 (2005).

    CAS  PubMed  Google Scholar 

  97. Yeh, G. L. et al. GNAS1 mutation and Cbfa1 misexpression in a child with severe congenital platelike osteoma cutis. J. Bone Miner. Res. 15, 2063–2073 (2000).

    Article  CAS  PubMed  Google Scholar 

  98. Eddy, M. C. et al. Deficiency of the α-subunit of the stimulatory G protein and severe extraskeletal ossification. J. Bone Miner. Res. 15, 2074–2083 (2000).

    Article  CAS  PubMed  Google Scholar 

  99. Huso, D. L., McGuire, S. & Germaine-Lee, E. L. Heterotopic subcutaneous ossifications in a mouse model of Albright hereditary osteodystophy. Presented at The Endocrine Society 89th Annual Meeting, Toronto, Canada, (2007).

  100. Plagge, A. et al. The imprinted signaling protein XLαs is required for postnatal adaptation to feeding. Nat. Genet. 36, 818–826 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Bastepe, M. et al. A form of Jansen's metaphyseal chondrodysplasia with limited metabolic and skeletal abnormalities is caused by a novel activating parathyroid hormone (PTH)/PTH-related peptide receptor mutation. J. Clin. Endocrinol. Metab. 89, 3595–3600 (2004).

    Article  CAS  PubMed  Google Scholar 

  102. Sakamoto, A., Chen, M., Kobayashi, T., Kronenberg, H. M. & Weinstein, L. S. Chondrocyte-specific knockout of the G protein Gsα leads to epiphyseal and growth plate abnormalities and ectopic chondrocyte formation. J. Bone Miner. Res. 20, 663–671 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Sakamoto, A. et al. Deficiency of the G-protein α-subunit Gsα in osteoblasts leads to differential effects on trabecular and cortical bone. J. Biol. Chem. 289, 21369–21375 (2005).

    Article  CAS  Google Scholar 

  104. Wu, J. Y., Scadden, D. T. & Kronenberg, H. M. Role of the osteoblast lineage in the bone marrow hematopoietic niches. J. Bone Miner. Res. 24, 759–764 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Kaplan, F. S., Groppe, J. C. & Shore, E. M. When one skeleton is enough: approaches and strategies for the treatment of fibrodysplasia ossificans progressiva (FOP). Drug Discov. Today Ther. Strateg. 5, 255–262 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Aydin, C. et al. Extralarge XLαs (XXLαs), a variant of stimulatory G protein α-subunit (Gsα), is a distinct, membrane-anchored GNAS product that can mimic Gsα. Endocrinology 150, 3567–3575 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Bastepe, M. et al. Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo. Proc. Natl Acad. Sci. USA 101, 14794–14799 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Michienzi, S. et al. GNAS transcripts in skeletal progenitors: evidence for random asymmetric allelic expression of Gsα. Hum. Mol. Genet. 16, 1921–1930 (2007).

    Article  CAS  PubMed  Google Scholar 

  109. Yang, D. C. et al. cAMP/PKA regulates osteogenesis, adipogenesis and ratio of RANKL/OPG mRNA expression in mesenchymal stem cells by suppressing leptin. PLoS ONE 3, e1540 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Zhang, S., Xu, M., Kaplan, F. S., Pignolo, F. S. & Shore, E. M. G protein–cAMP pathway regulates early stage embryonic stem cell-derived osteoblast differentiation. J. Bone Miner. Res. 24, S115 (2009).

    Google Scholar 

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Acknowledgements

We thank the members of our research laboratories and our many collaborators and colleagues for their contributions, notably J. Haupt and R. Mauck who generously provided figures (Figure 2 and Figure 4, respectively) that were adapted for this manuscript. We also thank the NIH/NIAMS-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 Orthopedic Molecular Medicine, the Rita Allen Foundation, and by grants from the National Institutes of Health (R01- AR41916 and R01-AR046831).

Charles P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.

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  1. Department of Orthopedic Surgery, University of Pennsylvania School of Medicine, 424 Stemmler Hall, 3450 Hamilton Walk, Philadelphia, 19104-6081, PA, USA

    Eileen M. Shore & Frederick S. Kaplan

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  1. Eileen M. Shore
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  2. Frederick S. Kaplan
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E. M. Shore researched the data for the article and wrote the article. Both E. M. Shore and F. S. Kaplan contributed equally to discussion of content and to reviewing and editing the manuscript before submission.

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Correspondence to Eileen M. Shore.

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Shore, E., Kaplan, F. Inherited human diseases of heterotopic bone formation. Nat Rev Rheumatol 6, 518–527 (2010). https://doi.org/10.1038/nrrheum.2010.122

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