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
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Heterotopic ossification is the formation of extraskeletal bone in soft connective tissues
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The bone tissue that forms during heterotopic ossification is qualitatively normal
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Two rare inherited forms of heterotopic ossification are fibrodysplasia ossificans progressiva (FOP) and progressive osseous heteroplasia (POH)
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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
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The genes and signaling pathways that are altered in these genetic disorders are key regulators of skeletal development and cell differentiation
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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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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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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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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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DOI: https://doi.org/10.1038/nrrheum.2010.122