Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Current Osteoporosis Reports
Published in: Current Osteoporosis Reports 2/2015

01-04-2015 | Skeletal Development (E Schanipani and E Zelzer, Section Editors)

The Immunological Contribution to Heterotopic Ossification Disorders

Authors: Michael R. Convente, Haitao Wang, Robert J. Pignolo, Frederick S. Kaplan, Eileen M. Shore

Published in: Current Osteoporosis Reports | Issue 2/2015

Login to get access

Abstract

The formation of bone outside the endogenous skeleton is a significant clinical event, rendering affected individuals with immobility and a diminished quality of life. This bone, termed heterotopic ossification (HO), can appear in patients following invasive surgeries and traumatic injuries, as well as progressively manifest in several congenital disorders. A unifying feature of both genetic and nongenetic episodes of HO is immune system involvement at the early stages of disease. Activation of the immune system sets the stage for the downstream anabolic events that eventually result in ectopic bone formation, rendering the immune system a particularly appealing site of early therapeutic intervention for optimal management of disease. In this review, we will discuss the immunological contributions to HO disorders, with specific focus on contributing cell types, signaling pathways, relevant in vivo animal models, and potential therapeutic targets.
Literature
1.
Alfieri KA, Forsberg JA, Potter BK. Blast injuries and heterotopic ossification. Bone Joint Res. 2012;1(8):192–7.CrossRefPubMed
2.
Bedi A, Zbeda RM, Bueno VF, et al. The incidence of heterotopic ossification after hip arthroscopy. Am J Sports Med. 2012;40(4):854–63.CrossRefPubMed
3.
Cohn RM, Schwarzkopf R, Jaffe F. Heterotopic ossification after total hip arthroplasty. Am J Orthop (Belle Mead NJ). 2011;40(11):E232–5.
4.
Adegbite NS, Xu M, Kaplan FS, et al. Diagnostic and mutational spectrum of progressive osseous heteroplasia (POH) and other forms of GNAS-based heterotopic ossification. Am J Med Genet A. 2008;146A(14):1788–96.CrossRefPubMedCentralPubMed
5.
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(3):379–90.CrossRefPubMedCentralPubMed
6.
Pignolo RJ, Foley KL. Nonhereditary heterotopic ossification: implications for injury, arthroplasty, and aging. Clin Rev Bone Miner Metab. 2005;3(3–4):261–6.CrossRef
7.
Mitchell EJ, Canter J, Norris P, et al. The genetics of heterotopic ossification: insight into the bone remodeling pathway. J Orthop Trauma. 2010;24(9):530–3.CrossRefPubMed
8.
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(5):1084–91.CrossRefPubMed
9.
Scarlett RF, Rocke DM, Kantanie S, et al. Influenza-like viral illnesses and flare-ups of fibrodysplasia ossificans progressiva. Clin Orthop Relat Res. 2004;423:275–9.CrossRefPubMed
10.
Salisbury E, Rodenberg E, Sonnet C, et al. Sensory nerve induced inflammation contributes to heterotopic ossification. J Cell Biochem. 2011;112(10):2748–58.CrossRefPubMedCentralPubMed
11.
12.
Hoff P, Rakow A, Gaber T, et al. Preoperative irradiation for the prevention of heterotopic ossification induces local inflammation in humans. Bone. 2013;55(1):93–101.CrossRefPubMed
13.
Evans KN, Forsberg JA, Potter BK, et al. Inflammatory cytokine and chemokine expression is associated with heterotopic ossification in high-energy penetrating war injuries. J Orthop Trauma. 2012;26(11):e204–13.CrossRefPubMed
14.
Kaplan FS, Shore EM, Gupta R, et al. Immunological features of fibrodysplasia ossificans progressiva and the dysregulated BMP4 pathway. Clin Rev Bone Miner Metab. 2005;3(3–4):189–93.CrossRef
15.
Forsberg JA, Potter BK, Polfer EM, et al. Do inflammatory markers portend heterotopic ossification and wound failure in combat wounds? Clin Orthop Relat Res. 2014;472(9):2845–54.CrossRefPubMed
16.
Lanchoney TF, Cohen RB, Rocke DM, et al. Permanent heterotopic ossification at the injection site after diphtheria-tetanus-pertussis immunizations in children who have fibrodysplasia ossificans progressiva. J Pediatr. 1995;126(5 Pt 1):762–4.CrossRefPubMed
17.
18.
Shore EM, Ahn J, Jan de Beur S, et al. Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N Engl J Med. 2002;346(2):99–106.
19.
Shore EM, Xu M, 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(5):525–7.CrossRefPubMed
20.
21.
Alexander KA, Chang MK, Maylin ER, et al. Osteal macrophages promote in vivo intramembranous bone healing in a mouse tibial injury model. J Bone Miner Res. 2011;26(7):1517–32.CrossRefPubMed
22.
23.
Huber-Lang M, Kovtun A, Ignatius A. The role of complement in trauma and fracture healing. Semin Immunol. 2013;25(1):73–8.CrossRefPubMed
24.
Wu AC, Raggatt LJ, Alexander KA, et al. Unraveling macrophage contributions to bone repair. Bonekey Rep. 2013;2:373.
25.
26.
De Benedetti F, Rucci N, Del Fattore A, et al. Impaired skeletal development in interleukin-6-transgenic mice: a model for the impact of chronic inflammation on the growing skeletal system. Arthritis Rheum. 2006;54(11):3551–63.CrossRefPubMed
27.
Bonar SL, Brydges SD, Mueller JL, et al. Constitutively activated NLRP3 inflammasome causes inflammation and abnormal skeletal development in mice. PLoS One. 2012;7(4):e35979.CrossRefPubMedCentralPubMed
28.
29.
30.
31.
32.
Ishida Y, Gao JL, Murphy PM. Chemokine receptor CX3CR1 mediates skin wound healing by promoting macrophage and fibroblast accumulation and function. J Immunol. 2007;180(1):569–79.CrossRef
33.
Tidball JG. Inflammatory processes in muscle injury and repair. Am J Physiol Regul Integr Comp Physiol. 2005;288(2):R345–53.CrossRefPubMed
34.••
Kan L, Lounev VY, Pignolo RJ, et al. Substance P signaling mediates BMP-dependent heterotopic ossification. J Cell Biochem. 2011;112(10):2759–72. This study is the first to show that chemical inhibition of mast cells and Substance P signaling significantly reduces HO formation in vivo and provides a link between elevated Substance P levels in FOP patients and HO development.
35.•
Kan L, Mutso AA, McGuire TL, et al. Opioid signaling in mast cells regulates injury responses associated with heterotopic ossification. Inflamm Res. 2014;63(3):207–15. This study further elucidated the role of mast cells and their signaling pathways in the development of HO.
36.
Kan L, Liu Y, McGuire TL, et al. Dysregulation of local stem/progenitor cells as a common cellular mechanism for heterotopic ossification. Stem Cells. 2009;27(1):150–6.CrossRefPubMedCentralPubMed
37.
Champagne CM, Takebe J, Offenbacher S, et al. Macrophage cell lines produce osteoinductive signals that include bone morphogenetic protein-2. Bone. 2002;30(1):26–31.CrossRefPubMed
38.
39.
Mohler ER, Gannon F, Reynolds C, et al. Bone formation and inflammation in cardiac valves. Circulation. 2001;103(11):1522–8.CrossRefPubMed
40.
Gannon FH, Glaser D, Caron R, et al. Mast cell involvement in fibrodysplasia ossificans progressiva. Hum Pathol. 2001;32(8):842–8.CrossRefPubMed
41.
Di Paolo N, Sacchi G, Lorenzoni P, et al. Ossification of the peritoneal membrane. Perit Dial Int. 2004;24(5):471–7.PubMed
42.
Smith RS, Smith TJ, Blieden TM, et al. Fibroblasts as sentinel cells. Synthesis of chemokines and regulation of inflammation. Am J Pathol. 1997;151(2):317–22.PubMedCentralPubMed
43.
44.
Ignatius A, Schoengraf P, Kreja L, et al. Complement C3a and C5a modulate osteoclast formation and inflammatory response of osteoblasts in synergism with IL-1beta. J Cell Biochem. 2011;112(9):2594–605.CrossRefPubMedCentralPubMed
45.
Tsuji T, Nakamura S, Komuro I, et al. A living case of pulmonary ossification associated with osteoclast formation from alveolar macrophage in the presence of T-cell cytokines. Intern Med. 2003;42(9):834–8.CrossRefPubMed
46.•
Chakkalakal SA, Zhang D, Culbert AL, et al. An Acvr1 R206H knock-in mouse has fibrodysplasia ossificans progressiva. J Bone Miner Res. 2012;27(8):1746–56. The first publication of an Alk2 (R206H) knock-in mouse model of HO, resulting in very strong recapitulation of the human disease.
47.
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(1):141–8.CrossRefPubMed
48.
Kan L, Hu M, Gomes WA, et al. Transgenic mice overexpressing BMP4 develop a fibrodysplasia ossificans progressiva (FOP)-like phenotype. Am J Pathol. 2004;165(4):1107–15.CrossRefPubMedCentralPubMed
49.
Mills CD. M1 and M2 macrophages: oracles of health and disease. Crit Rev Immunol. 2012;32(6):463–88.CrossRefPubMed
50.
Bischoff SC. Role of mast cells in allergic and non-allergic immune responses: comparison of human and murine data. Nat Rev Immunol. 2007;7(2):93–104.CrossRefPubMed
51.
Frieri M, Patel R, Celestin J. Mast cell activation syndrome: a review. Curr Allergy Asthma Rep. 2013;13(1):27–32.CrossRefPubMed
52.
Douaiher J, Succar J, Lancerotto L, et al. Development of mast cells and importance of their tryptase and chymase serine proteases in inflammation and wound healing. Adv Immunol. 2014;122:211–52.CrossRefPubMedCentralPubMed
53.
Ehrlich HP. A snapshot of direct cell-cell communications in wound healing and scarring. Adv Wound Care (New Rochelle). 2013;2(4):113–21.CrossRef
54.
Rodewald HR, Feyerabend TB. Widespread immunological functions of mast cells: fact or fiction? Immunity. 2012;37(1):13–24.CrossRefPubMed
55.
56.
Oldford SA, Marshall JS. Mast cells as targets for immunotherapy of solid tumors. Mol Immunol. 2014.
57.
58.
Farrugia BL, Whitelock JM, Jung M, et al. The localisation of inflammatory cells and expression of associated proteoglycans in response to implanted chitosan. Biomaterials. 2014;35(5):1462–77.CrossRefPubMed
59.
Thevenot PT, Baker DW, Weng H, et al. The pivotal role of fibrocytes and mast cells in mediating fibrotic reactions to biomaterials. Biomaterials. 2011;32(33):8394–403.CrossRefPubMedCentralPubMed
60.
Galli SJ, Grimbaldeston M, Tsai M. Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nat Rev Immunol. 2008;8(6):478–86.CrossRefPubMedCentralPubMed
61.
62.
63.
Bucelli RC, Gonsiorek EA, Kim WY, et al. Statins decrease expression of the proinflammatory neuropeptides calcitonin gene-related peptide and substance P in sensory neurons. J Pharmacol Exp Ther. 2008;324(3):1172–80.CrossRefPubMed
64.
Salisbury E, Sonnet C, Heggeness M, et al. Heterotopic ossification has some nerve. Crit Rev Eukaryot Gene Expr. 2010;20(4):313–24.CrossRefPubMed
65.
Overed-Sayer C, Rapley L, Mustelin T, et al. Are mast cells instrumental for fibrotic diseases? Front Pharmacol. 2013;4:174.PubMedCentralPubMed
66.
Monument MJ, Hart DA, Befus AD, et al. The mast cell stabilizer ketotifen reduces joint capsule fibrosis in a rabbit model of post-traumatic joint contractures. Inflamm Res. 2012;61(4):285–92.CrossRefPubMedCentralPubMed
67.
68.
Brocker C, Thompson D, Matsumoto A, et al. Evolutionary divergence and functions of the human interleukin (IL) gene family. Hum Genomics. 2010;5(1):30–55.CrossRefPubMedCentralPubMed
69.
70.
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.CrossRefPubMed
71.
Kaplan FS, Glaser DL, Shore EM, et al. Hematopoietic stem-cell contribution to ectopic skeletogenesis. J Bone Joint Surg Am. 2007;89(2):347–57.CrossRefPubMed
72.
Egan KP, Kim JH, Mohler 3rd ER, et al. Role for circulating osteogenic precursor cells in aortic valvular disease. Arterioscler Thromb Vasc Biol. 2011;31(12):2965–71.CrossRefPubMedCentralPubMed
73.
Rifas L. T-cell cytokine induction of BMP-2 regulates human mesenchymal stromal cell differentiation and mineralization. J Cell Biochem. 2006;98(4):706–14.CrossRefPubMed
74.
Carr MW, Roth SJ, Luther E, et al. Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci U S A. 1994;91(9):3652–6.CrossRefPubMedCentralPubMed
75.
76.
Karp JM, Leng Teo GS. Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell. 2009;4(3):206–16.CrossRefPubMed
77.
Chamberlain G, Wright K, Rot A, et al. Murine mesenchymal stem cells exhibit a restricted repertoire of functional chemokine receptors: comparison with human. PLoS One. 2008;3(8):e2934.CrossRefPubMedCentralPubMed
78.
Sordi V, Malosio ML, Marchesi F, et al. Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets. Blood. 2005;106(2):419–27.CrossRefPubMed
79.
80.
Kaviratne M, Hesse M, Leusink M, et al. IL-13 activates a mechanism of tissue fibrosis that is completely TGF-independent. J Immunol. 2004;173(6):4020–9.CrossRefPubMed
81.•
Culbert AL, Chakkalakal SA, Theosmy EG, et al. Alk2 regulates early chondrogenic fate in fibrodysplasia ossificans progressiva heterotopic endochondral ossification. Stem Cells. 2014;32(5):1289–300. This study utilized in vitro and in vivo approaches to demonstrate the molecular role of Alk2 in the chondrogenesis stage of HO in FOP.
82.
Akdis M, Burgler S, Crameri R, et al. Interleukins, from 1 to 37, and interferon-gamma: receptors, functions, and roles in diseases. J Allergy Clin Immunol. 2011;127(3):701–21. e1-70.
83.
Tsai PT, Lee RA, Wu H. BMP4 acts upstream of FGF in modulating thymic stroma and regulating thymopoiesis. Blood. 2003;102(12):3947–53.CrossRefPubMed
84.
Detmer K, Steele TA, Shoop MA, et al. Lineage-restricted expression of bone morphogenetic protein genes in human hematopoietic cell lines. Blood Cells Mol Dis. 1999;25(5–6):310–23.CrossRefPubMed
85.
Sivertsen EA, Huse K, Hystad ME, et al. Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells. Eur J Immunol. 2007;37(10):2937–48.CrossRefPubMed
86.
MacDonald KM, Swanstrom MM, McCarthy JJ, et al. Exaggerated inflammatory response after use of recombinant bone morphogenetic protein in recurrent unicameral bone cysts. J Pediatr Orthop. 2010;30(2):199–205.CrossRefPubMed
87.
Cunningham NS, Paralkar V, Reddi AH. Osteogenin and recombinant bone morphogenetic protein 2B are chemotactic for human monocytes and stimulate transforming growth factor beta 1 mRNA expression. Proc Natl Acad Sci U S A. 1992;89(24):11740–4.CrossRefPubMedCentralPubMed
88.
89.•
Shimono K, Tung WE, Macolino C, et al. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-gamma agonists. Nat Med. 2011;17(4):454–60. This study documents potent in vivo inhibition of HO by administration with retinoic acid receptor-gamma agonists, identifying a new potential therapeutic target for the treatment of HO disorders.
90.
Vavken P, Castellani L, Sculco TP. Prophylaxis of heterotopic ossification of the hip: systematic review and meta-analysis. Clin Orthop Relat Res. 2009;467(12):3283–9.CrossRefPubMedCentralPubMed
91.
92.
Grohs JG, Schmidt M, Wanivenhaus A. Selective COX-2 inhibitor versus indomethacin for the prevention of heterotopic ossification after hip replacement: a double-blind randomized trial of 100 patients with 1-year follow-up. Acta Orthop. 2007;78(1):95–8.CrossRefPubMed
93.
Van Rooijen N. The liposome-mediated macrophage ‘suicide’ technique. J Immunol Methods. 1989;124(1):1–6.CrossRefPubMed
94.
Ferenbach DA, Sheldrake TA, Dhaliwal K, et al. Macrophage/monocyte depletion by clodronate, but not diphtheria toxin, improves renal ischemia/reperfusion injury in mice. Kidney Int. 2012;82(8):928–33.CrossRefPubMed
95.
Summan M, Warren GL, Mercer RR, et al. Macrophages and skeletal muscle regeneration: a clodronate-containing liposome depletion study. Am J Physiol Regul Integr Comp Physiol. 2006;290(6):R1488–95.CrossRefPubMed
96.
Van Rooijen N, Sanders A. Kupffer cell depletion by liposome-delivered drugs: comparative activity of intracellular clodronate, propamidine, and ethylenediaminetetraacetic acid. Hepatology. 1996;23(5):1239–43.CrossRefPubMed
97.
Barrera P, Blom A, van Lent PL, et al. Synovial macrophage depletion with clodronate-containing liposomes in rheumatoid arthritis. Arthritis Rheum. 2000;43(9):1951–9.CrossRefPubMed
98.
O’Connor TM, O’Connell J, O’Brien DI, et al. The role of substance P in inflammatory disease. J Cell Physiol. 2004;201(2):167–80.CrossRefPubMed
99.
Manak MM, Moshkoff DA, Nguyen LT, et al. Anti-HIV-1 activity of the neurokinin-1 receptor antagonist aprepitant and synergistic interactions with other antiretrovirals. AIDS. 2010;24(18):2789–96.CrossRefPubMedCentralPubMed
100.
Juurikivi A, Sandler C, Lindstedt KA, et al. Inhibition of c-kit tyrosine kinase by imatinib mesylate induces apoptosis in mast cells in rheumatoid synovia: a potential approach to the treatment of arthritis. Ann Rheum Dis. 2005;64(8):1126–31.CrossRefPubMedCentralPubMed
101.•
Werner CM, Zimmermann SM, Wurgler-Hauri CC, et al. Use of imatinib in the prevention of heterotopic ossification. HSS J. 2013;9(2):166–70. Administration of imatinib, resulting in blockage of PDGF signaling, reduced HO volume by 85% in an Achilles tenotomy mouse model of HO, documenting an additional approach by which to therapeutically intervene in cases of HO.
102.
Sathish JG, Sethu S, Bielsky MC, et al. Challenges and approaches for the development of safer immunomodulatory biologics. Nat Rev Drug Discov. 2013;12(4):306–24.CrossRefPubMed
103.
Zalevsky J, Secher T, Ezhevsky SA, et al. Dominant-negative inhibitors of soluble TNF attenuate experimental arthritis without suppressing innate immunity to infection. J Immunol. 2007;179(3):1872–83.CrossRefPubMed
104.
Rau R. Adalimumab (a fully human anti-tumour necrosis factor alpha monoclonal antibody) in the treatment of active rheumatoid arthritis: the initial results of five trials. Ann Rheum Dis. 2002;61(2):ii70–3.CrossRefPubMedCentralPubMed
105.
Mohedas A, Wang Y, Sanvitale CE, et al. Structure-activity relationship of 3,5-diaryl-2-aminopyridine ALK2 inhibitors reveals unaltered binding affinity for fibrodysplasia ossificans progressiva causing mutants. J Med Chem. 2014.
Metadata
Title
The Immunological Contribution to Heterotopic Ossification Disorders
Authors
Michael R. Convente
Haitao Wang
Robert J. Pignolo
Frederick S. Kaplan
Eileen M. Shore
Publication date
01-04-2015
Publisher
Springer US
Published in
Current Osteoporosis Reports / Issue 2/2015
Print ISSN: 1544-1873
Electronic ISSN: 1544-2241
DOI
https://doi.org/10.1007/s11914-015-0258-z

Other articles of this Issue 2/2015

Current Osteoporosis Reports 2/2015 Go to the issue

Osteocytes (T Bellido and J Klein-Nulend, Section Editors)

Cx43 and Mechanotransduction in Bone

Rare Bone Disease (CB Langman and E Shore, Section Editors)

Hyperphosphatemic Familial Tumoral Calcinosis: Genetic Models of Deficient FGF23 Action

Rare Bone Disease (CB Langman and E Shore, Section Editors)

Hypophosphatemic Rickets: Lessons from Disrupted FGF23 Control of Phosphorus Homeostasis

Nutrition, Exercise, and Lifestyle in Osteoporosis (CM Weaver and R Daly, Section Editors)

Diet, Gut Microbiome, and Bone Health

Bone and Diabetes (AV Schwartz and P Vestergaard, Section Editors)

Diabetes, Diabetic Complications, and Fracture Risk

Osteocytes (T Bellido and J Klein-Nulend, Section Editors)

Osteocyte Shape and Mechanical Loading