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Immunological features of fibrodysplasia ossificans progressiva and the dysregulated BMP4 pathway

  • Fibrodysplasia Ossificans Progressiva
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Clinical Reviews in Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Dysregulation of the bone morphogenic protein (BMP)4-signaling pathway can explain many developmental and postnatal features of fibrodysplasia ossificans progressive (FOP). However, many puzzling clinical features of the disease strongly implicate an underlying immunological component to the disorder. In this article, we review features of the BMP4 signaling pathway that regulate the immune system, and suggest an integrated hypothesis for FOP that accounts for both BMP-related abnormalities and immunological features of the condition.

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References

  1. Kaplan FS, Shore EM, Connor JM. 2002 Fibrodysplasia ossificans progressiva (FOP). In: Royce PM, Steinmann B, eds. Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects, 2nd Ed. Wiley-Liss: John Wiley & Sons, New York, pp. 827–840.

    Google Scholar 

  2. Kaplan FS, Glaser, DL., hebela N, Shore EM. 2004 Heterotopic ossification. J Am Acad Orthop Surg 12:116–125.

    PubMed  Google Scholar 

  3. Shafritz AB, Shore EM, Gannon FH et al. 1996 Overexpression of an osteogenic morphogen in fibrodysplasia ossificans progressiva. N Engl J Med 335:555–561.

    Article  PubMed  CAS  Google Scholar 

  4. Ahn J, Serrano de la Peña L, Shore EM, Kaplan FS. 2003 Paresis of a bone morphogenetic protein-antagonist response in a genetic disorder of heterotopic skeletogenesis. J Bone Joint Surg Am 85:667–674.

    PubMed  Google Scholar 

  5. Olmsted EA, Kaplan FS, Shore EM. 2003 Bone morphogenetic protein 4 regulation in fibrodysplasia ossificans progressiva. Clin Orthop 408:331–343.

    Article  PubMed  Google Scholar 

  6. Gannon FH, Kaplan FS, Olmsted E, Finkel G, Zasloff MA, Shore EM. 1997 Bone morphogenetic protein 2/4 in early fibromatous lesions of fibrodysplasia ossificans progressiva. Hum Pathol 28:339–343.

    Article  PubMed  CAS  Google Scholar 

  7. Glaser DL, Economides AN, Wang L, et al. 2003 In vivo somatic cell gene transfer of an engineered noggin mutein prevents BMP4-induced heterotopic ossification. J Bone Joint Surg Am 85:2332–2342.

    PubMed  Google Scholar 

  8. Kan, L, Hu M, Gomes WA, Kessler JA. 2004 Transgenic mice overexpressing BMP4 develop a fibrodysplasia ossificans progressiva (FOP)-like phenotype. Am J Pathol 165:1107–1115.

    PubMed  CAS  Google Scholar 

  9. Serrano de la Peña L, Billings PC, Fiori JL, Ahn J, Kaplan FS, Shore EM. 2005 Fibrodysplasia ossificans progressiva (FOP), a disorder of ectopic osteogenesis, misregulates cell surface expression and trafficking of BMPRIA. J Bone Miner Res 20:1168–1176.

    Article  Google Scholar 

  10. Davidson A, Diamond B. 2001 Autoimmune diseases. N Engl J Med 345:340–350.

    Article  PubMed  CAS  Google Scholar 

  11. Marrack P, Kappler J, Kotzin BL. 2001 Autoimmune disease: why and where it occurs. Nat Med 7:899–905.

    Article  PubMed  CAS  Google Scholar 

  12. Rosen A, Casciola-Rosen L. 2001 Clearing the way to mechanisms of autoimmunity. Nat Med 7:664–665.

    Article  PubMed  CAS  Google Scholar 

  13. Shlomchik MJ, Craft JE, Mamula MJ. 2001 From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol 2:147–153.

    Article  Google Scholar 

  14. Cohen RB, Hahn GV, Tabas J, et al. 1993 The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 75:215–219.

    PubMed  CAS  Google Scholar 

  15. Lanchoney TF, Cohen RB, Rocke DM, Zasloff MA, Kaplan FS. 1995 Permanent heterotopic ossification at the injection site after diphtheria-tetanus-pertussis immunizations in children who have fibrodysplasia ossificans progressiva. J Pediatrics 126:762–764.

    Article  CAS  Google Scholar 

  16. Luchetti W, Cohen RB, Hahn GV, et al. 1996 Severe restriction in jaw movement after route injection of local anesthetic in patients who have fibrodysplasia ossificans progressiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81:21–25.

    Article  PubMed  CAS  Google Scholar 

  17. Scarlett RF, Rocke DM, Kantanie S, Patel JB, Shore EM, Kaplan FS. 2004 Influenza-like viral illnesses and flare-ups of fibrodysplasia ossificans progressiva (FOP). Clin Orthop 423:275–279.

    Article  PubMed  Google Scholar 

  18. Moriatis JM, Gannon FH, Shore EM, Bilker W, Zasloff MA, Kaplan FS, 1997. Limb swelling in patients who have fibrodysplasia ossificans progressiva. Clin Orthop 336:247–253.

    Article  PubMed  Google Scholar 

  19. Gannon FH, Valentine BA, Shore EM, Zasloff MA, Kaplan FS. 1998 Acute lymphocytic infiltration in an extremely early lesion of fibrodysplasia ossificans progressiva. Clin Orthop 346:19–25.

    PubMed  Google Scholar 

  20. Gannon FH, Glaser D, Caron R, Thompson LD, Shore EM, Kaplan FS. 2001 Mast cell involvement in fibrodysplasia ossificans progressiva. Hum Pathol 32:842–848.

    Article  PubMed  CAS  Google Scholar 

  21. Hafler DA. 2004 Multiple Sclerosis. J Clin Invest 113:788–794.

    Article  PubMed  CAS  Google Scholar 

  22. Ahn J, Feldman G, Terry L, Shore EM, Kaplan FS. 2003 Exoneration of NF-κB dysregulation in fibrodysplasia ossificans progressiva (FOP). Clin Orthop 406:205–213.

    Article  PubMed  Google Scholar 

  23. Godin I, Cumano A. 2002 The hare and the tortoise: an embryonic hematopoietic race. Nat Rev Immunol 2:593–604.

    PubMed  CAS  Google Scholar 

  24. Bhardwaj G, Murdoch B, Wu D, et al. 2001 Sonic hedgehog induces the proliferation of primary human hematopoietic cells via BMP regulation. Nat Immunol 2:172–180.

    Article  PubMed  CAS  Google Scholar 

  25. Zhang J, Niu C, Ye L, et al. 2003 Identification of the hematopoietic stem cell niche and control of the niche size. Nature 425:836–841.

    Article  PubMed  CAS  Google Scholar 

  26. Ohnemus S, Kanzler B, Jerome-Majewska LA, et al. 2002 Aortic arch and pharyngeal phenotype in the absence of BMP-dependent neural crest in the mouse. Mech Develop 119:127–135.

    Article  CAS  Google Scholar 

  27. Bachiller D, Klingensmith J, Shneyder N, et al. 2003 The role of chordin/BMP signals in mammalian pharyngeal development and DiGeorge syndrome. Development 130:3567–3578.

    Article  PubMed  CAS  Google Scholar 

  28. Tsai PT, Lee RA, Wu H, 2003 BMP4 acts upstream of FGF in modulating thymic stroma and regulating thymopoiesis. Blood 102:3947–3953.

    Article  PubMed  CAS  Google Scholar 

  29. Graf D, Nethisinghe S, Palmer DB, Fisher AG, Merkenschlager M. 2002 The developmentally regulated expression of twisted gastrulation reveals a role for bone morphogenetic proteins in the control of T cell development. J Exp Med 196:163–171.

    Article  PubMed  CAS  Google Scholar 

  30. Hager-Theodorides AL, Outram SV, Shah DK, et al. 2003 Bone morphogenetic protein 2/4 signaling regulates early thymocyte differentiation. J Immunol 169:5496–5504.

    Google Scholar 

  31. Nosaka T, Morita S, Kitamura H, et al. 2003 Mammalian twisted gastrulation is essential for skeleto-lymphogenesis. Mol Cell Biol 23:2969–2980.

    Article  PubMed  CAS  Google Scholar 

  32. Takagi T, Harada J, Ishii S. 2001 Murine Schnurri-2 is required for positive selection of thymocytes. Nat Immunol 2:1048–1053.

    Article  PubMed  CAS  Google Scholar 

  33. Kimura MY, Hosokawa H, Yamashita M, et al. 2005 Regulation of T helper type 2 cell differentiation by murine Schnurri-2. J Exp Med 201:397–408.

    Article  PubMed  CAS  Google Scholar 

  34. Detmer K, Steele TA, Shoop MA, Dannawi H, 1999 Lineage-restricted expression of bone morphogenetic protein genes in human hematopoietic cell lines. Blood Cells Mol Dis 25:310–323.

    Article  PubMed  CAS  Google Scholar 

  35. Ishisaki A, Yamato K, Hashimoto S, et al. 1999 Differential inhibition of Smad 6 and Smad 7 on bone morphogenetic protein- and activin-mediated growth arrest and apoptosis in B cells. J Biol Chem 274:13,637–13,642.

    Article  CAS  Google Scholar 

  36. Nakahara T, Tominaga K, Koseki T, et al. 2003 Growth/differentiation factor-5 induces growth arrest and apoptosis in mouse B lineage cells with modulation by Smad. Cell Signal 15:181–187.

    Article  PubMed  CAS  Google Scholar 

  37. Varas A, Hager-Theodorides AL, Sacedon R, Vicente A, Zapata AG, Crompton T. 2003 The role of morphogens in T-cell development. Trends Immunol 24:197–206.

    Article  PubMed  CAS  Google Scholar 

  38. Cunningham NS, Paralkar V, Reddi AH. 1992. Osteogenin and recombinant bone morphogenetic protein 2B are chemotactic for human monocytes and stimulate transforming growth factor B1 mRNA expression. Proc Natl Acad Sci USA 89:11,740–11,744.

    CAS  Google Scholar 

  39. Pignolo RJ, Billings PC, Suda K, et al. 2004 Circulating osteogenic cells in heterotopic bone formation. J Bone Miner Res 19:S35.

    Google Scholar 

  40. Banchereau J, Steinman RM. 1998 Dendritic cells and the control of immunity. Nature 392:245–252.

    Article  PubMed  CAS  Google Scholar 

  41. Ulloa L, Doody J, Massagué J. 1999 Inhibition of transforming growth factor-beta/SMAD signaling by the interferon-gamma/STAT pathway. Nature 397:710–713.

    Article  PubMed  CAS  Google Scholar 

  42. Dougall WC, Glaccum M, Charrier K, et al. 1999 RANK is essential for osteoclast and lymph node development. Genes Dev 13:2412–2424.

    Article  PubMed  CAS  Google Scholar 

  43. Bommireddy R, Saxena V, Ormsby I, et al. 2003 TGF-B 1 regulates lymphocyte homeostasis by preventing activation and subsequent apoptosis of peripheral lymphocytes. J Immunol 170:4612–4622.

    PubMed  CAS  Google Scholar 

  44. Kulkarni AB, Huh C-G, Becker D, et al. 1993 Transforming growth factor-B 1 null mutation in mice causes excesive inflammatory response and early death. Proc Natl Acad Sci USA 90:770–774.

    Article  PubMed  CAS  Google Scholar 

  45. Shull MM, Ormsby I, Kier AB, et al. 1992 Targeted disruption of the mouse transforming growth factor-B 1 gene results in multifocal inflammatory disease. Nature 359:693–699.

    Article  PubMed  CAS  Google Scholar 

  46. Yaswen L, Kulkarni AB, Fredrickson, T, et al. 1996 Autoimmune manifestations in the transforming growth factor-B 1 knockout mouse. Blood 87:1439–1445.

    PubMed  CAS  Google Scholar 

  47. Waldner H, Collins M, Kuchroo VK. 2004 Activation of antigen-presenting cells by microbial products breaks self-tolerance and induces autoimmune disease. J Clin Invest 113:990–997.

    Article  PubMed  CAS  Google Scholar 

  48. Leadbetter EA, Rifkin IR, Hohlbaum AM, et al. 2002 Chromatin-IgG complexes activate B cells by dual engagement of IgM and toll-like receptors. Nature 416:603–607.

    Article  PubMed  CAS  Google Scholar 

  49. Boule MW, Broughton C, MacKay F, Akira S, Marshak-Rothstein A, Rifkin IR. 2004 Toll-like receptor 9-dependent and independent dendritic cell activation by chromatin-immunoglobulin G complexes. J Exp Med 199:1631–1640.

    Article  PubMed  CAS  Google Scholar 

  50. Xiao C, Shim JH, Klüppel M, et al. 2003 Ecsit is required for BMP signaling and mesoderm formation during mouse embryogenesis. Genes Dev 17:2933–2949.

    Article  PubMed  CAS  Google Scholar 

  51. Moustakas A, Heldin CH. 2003 Ecsit-ement on the crossroads of toll and BMP signal transduction. Genes Dev 17:2855–2859.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department Medicine, The University of Pennsylvania School of Medicine, Philadelphia, PA

    Frederick S. Kaplan MD, Robert J. Pignolo MD, PhD & Malek Kamoun MD

  2. Department Genetics, The University of Pennsylvania School of Medicine, Philadelphia

    Eileen M. Shore PhD

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

    Frederick S. Kaplan MD, Eileen M. Shore PhD, Rishi Gupta MD, Paul C. Billings PhD, David L. Glaser, Robert J. Pignolo MD, PhD & Malek Kamoun MD

  4. The Institute of Immunology, Biomedical Sciences Research Center “Alexander Fleming”, Vari, Greece

    Daniel Graf PhD

  5. Department of Orthopaedic Surgery, The University of Pennsylvania School of Medicine, Silverstein Two, 3400 Spruce St., 19104, Philadelphia, PA

    Frederick S. Kaplan MD, Eileen M. Shore PhD, Rishi Gupta MD, Paul C. Billings PhD & David L. Glaser

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  1. Frederick S. Kaplan MD
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  2. Eileen M. Shore PhD
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  3. Rishi Gupta MD
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  6. Robert J. Pignolo MD, PhD
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Correspondence to Frederick S. Kaplan MD.

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Kaplan, F.S., Shore, E.M., Gupta, R. et al. Immunological features of fibrodysplasia ossificans progressiva and the dysregulated BMP4 pathway. Clinic Rev Bone Miner Metab 3, 189–193 (2005). https://doi.org/10.1385/BMM:3:3-4:189

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  • DOI: https://doi.org/10.1385/BMM:3:3-4:189

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