{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T22:57:53Z","timestamp":1776293873812,"version":"3.50.1"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2020,12,1]],"date-time":"2020-12-01T00:00:00Z","timestamp":1606780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"},{"start":{"date-parts":[[2022,1,24]],"date-time":"2022-01-24T00:00:00Z","timestamp":1642982400000},"content-version":"vor","delay-in-days":419,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100006396","name":"Alexion Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006396","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Radiant Hope Foundation"},{"DOI":"10.13039\/100006396","name":"Alexion Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006396","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["asbmr.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,12,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Fibrodysplasia ossificans progressiva (FOP) is a progressive, debilitating genetic disease in which skeletal muscle and connective tissue is episodically replaced by heterotopic bone. Discovery of surrogate biomarkers of disease (genotype)-related and flare-up-associated activity of FOP in a readily accessible matrix, such as plasma, would facilitate an understanding of the complex pathophysiology of FOP, aid patient care, and provide a valuable tool for the development and monitoring of potential therapeutics. In a case\u2013control study, using a carefully collected and curated set of plasma samples from 40 FOP patients with the classic ACVR1R206H mutation and 40 age- and sex-matched controls, we report the identification of disease-related and flare-up-associated biomarkers of FOP using a multiplex analysis of 113 plasma-soluble analytes. Adiponectin (implicated in hypoxia, inflammation, and heterotopic ossification) as well as tenascin-C (an endogenous activator of innate immune signaling through the TLR4 pathway and a substrate for kallikrein-7) were highly correlated with FOP genotype, while kallikrein-7 was highly correlated with acute flare-up status. Plasma-soluble biomarkers for FOP support a flare-up-related acute inflammatory phase of disease activity superimposed on a genotypic background of chronic inflammation. \u00a9 2021 American Society for Bone and Mineral Research (ASBMR).<\/jats:p>","DOI":"10.1002\/jbmr.4492","type":"journal-article","created":{"date-parts":[[2021,12,26]],"date-time":"2021-12-26T10:23:25Z","timestamp":1640514205000},"page":"475-483","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Plasma-Soluble Biomarkers for Fibrodysplasia Ossificans Progressiva (FOP) Reflect Acute and Chronic Inflammatory States"],"prefix":"10.1093","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8533-9438","authenticated-orcid":false,"given":"Robert J","family":"Pignolo","sequence":"first","affiliation":[{"name":"Departments of Medicine and Physiology\/Biomedical Engineering Mayo Clinic Alix School of Medicine, Mayo Clinic Rochester MN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruth","family":"McCarrick-Walmsley","sequence":"additional","affiliation":[{"name":"The Center for Research in FOP and Related Disorders Perelman School of Medicine, University of Pennsylvania Philadelphia PA USA"},{"name":"Department of Orthopaedic Surgery Perelman School of Medicine, University of Pennsylvania Philadelphia PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haitao","family":"Wang","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Physiology\/Biomedical Engineering Mayo Clinic Alix School of Medicine, Mayo Clinic Rochester MN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shirley","family":"Qiu","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Cambridge MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey","family":"Hunter","sequence":"additional","affiliation":[{"name":"Alexion Pharmaceuticals New Haven CT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharon","family":"Barr","sequence":"additional","affiliation":[{"name":"Alexion Pharmaceuticals New Haven CT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"He","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Cambridge MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Blueprint Medicines Cambridge MA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frederick S","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Department of Medicine Perelman School of Medicine, University of Pennsylvania Philadelphia PA USA"},{"name":"The Center for Research in FOP and Related Disorders Perelman School of Medicine, University of Pennsylvania Philadelphia PA USA"},{"name":"Department of Orthopaedic Surgery Perelman School of Medicine, University of Pennsylvania Philadelphia PA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,12,26]]},"reference":[{"key":"2024012714033323600_jbmr4492-bib-0001","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/1750-1172-6-80","article-title":"Fibrodysplasia ossificans progressiva: clinical and genetic aspects","volume":"6","author":"Pignolo","year":"2011","journal-title":"Orphanet J Rare Dis"},{"issue":"Suppl 2","key":"2024012714033323600_jbmr4492-bib-0002","first-page":"437","article-title":"Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons","volume":"10","author":"Pignolo","year":"2013","journal-title":"Pediatr Endocrinol Rev."},{"issue":"3","key":"2024012714033323600_jbmr4492-bib-0003","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1002\/jbmr.2728","article-title":"The natural history of flare-ups in fibrodysplasia ossificans progressiva (FOP): a comprehensive global assessment","volume":"31","author":"Pignolo","year":"2016","journal-title":"J Bone Miner Res."},{"issue":"5","key":"2024012714033323600_jbmr4492-bib-0004","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/ng1783","article-title":"A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva","volume":"38","author":"Shore","year":"2006","journal-title":"Nat Genet."},{"issue":"22","key":"2024012714033323600_jbmr4492-bib-0005","doi-asserted-by":"crossref","first-page":"e122958","DOI":"10.1172\/jci.insight.122958","article-title":"NF-kappaB\/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification","volume":"3","author":"Barruet","year":"2018","journal-title":"JCI Insight"},{"issue":"8","key":"2024012714033323600_jbmr4492-bib-0006","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1002\/jbmr.1637","article-title":"An Acvr1 R206H knock-in mouse has fibrodysplasia ossificans progressiva","volume":"27","author":"Chakkalakal","year":"2012","journal-title":"J Bone Miner Res."},{"issue":"2","key":"2024012714033323600_jbmr4492-bib-0007","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1002\/jbmr.3304","article-title":"Depletion of mast cells and macrophages impairs heterotopic ossification in an Acvr1(R206H) mouse model of fibrodysplasia ossificans progressiva","volume":"33","author":"Convente","year":"2018","journal-title":"J Bone Miner Res."},{"issue":"2","key":"2024012714033323600_jbmr4492-bib-0008","doi-asserted-by":"crossref","first-page":"347","DOI":"10.2106\/00004623-200702000-00017","article-title":"Hematopoietic stem-cell contribution to ectopic skeletogenesis","volume":"89","author":"Kaplan","year":"2007","journal-title":"J Bone Joint Surg Am."},{"issue":"12","key":"2024012714033323600_jbmr4492-bib-0009","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.1002\/jbmr.3235","article-title":"The expansion of heterotopic bone in fibrodysplasia ossificans progressiva is activin A-dependent","volume":"32","author":"Upadhyay","year":"2017","journal-title":"J Bone Miner Res."},{"key":"2024012714033323600_jbmr4492-bib-0010","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.bone.2017.12.024","article-title":"ECSIT links TLR and BMP signaling in FOP connective tissue progenitor cells","volume":"109","author":"Wang","year":"2018","journal-title":"Bone."},{"key":"2024012714033323600_jbmr4492-bib-0011","first-page":"59","article-title":"Urinary basic fibroblast growth factor. A biochemical marker for preosseous fibroproliferative lesions in patients with fibrodysplasia ossificans progressiva","volume":"346","author":"Kaplan","year":"1998","journal-title":"Clin Orthop Relat Res."},{"key":"2024012714033323600_jbmr4492-bib-0012","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.bone.2017.09.016","article-title":"Cartilage-derived retinoic acid-sensitive protein (CD-RAP): a stage-specific biomarker of heterotopic endochondral ossification (HEO) in fibrodysplasia ossificans progressiva (FOP)","volume":"109","author":"Lindborg","year":"2018","journal-title":"Bone."},{"issue":"4","key":"2024012714033323600_jbmr4492-bib-0013","doi-asserted-by":"crossref","first-page":"e0214619","DOI":"10.1371\/journal.pone.0214619","article-title":"Identification of pharmacodynamic biomarker hypotheses through literature analysis with IBM Watson","volume":"14","author":"Hatz","year":"2019","journal-title":"PLoS One."},{"issue":"1","key":"2024012714033323600_jbmr4492-bib-0014","doi-asserted-by":"crossref","first-page":"16705","DOI":"10.1038\/s41598-017-16996-w","article-title":"The uniform pattern of growth and skeletal maturation during the human adolescent growth spurt","volume":"7","author":"Sanders","year":"2017","journal-title":"Sci Rep"},{"issue":"1","key":"2024012714033323600_jbmr4492-bib-0015","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1002\/jcb.20890","article-title":"Regulation of bone formation by adiponectin through autocrine\/paracrine and endocrine pathways","volume":"99","author":"Shinoda","year":"2006","journal-title":"J Cell Biochem."},{"issue":"10","key":"2024012714033323600_jbmr4492-bib-0016","doi-asserted-by":"crossref","first-page":"2839","DOI":"10.1007\/s10067-018-4258-0","article-title":"Serum adiponectin levels in patients with diffuse idiopathic skeletal hyperostosis (DISH)","volume":"37","author":"Mader","year":"2018","journal-title":"Clin Rheumatol."},{"issue":"1","key":"2024012714033323600_jbmr4492-bib-0017","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/s41467-018-02872-2","article-title":"Activin-dependent signaling in fibro\/adipogenic progenitors causes fibrodysplasia ossificans progressiva","volume":"9","author":"Lees-Shepard","year":"2018","journal-title":"Nat Commun"},{"issue":"5","key":"2024012714033323600_jbmr4492-bib-0018","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1002\/jbmr.1562","article-title":"Multipotent progenitors resident in the skeletal muscle interstitium exhibit robust BMP-dependent osteogenic activity and mediate heterotopic ossification","volume":"27","author":"Wosczyna","year":"2012","journal-title":"J Bone Miner Res."},{"issue":"2","key":"2024012714033323600_jbmr4492-bib-0019","doi-asserted-by":"crossref","first-page":"620","DOI":"10.2353\/ajpath.2007.060692","article-title":"Hypoxic adipocytes pattern early heterotopic bone formation","volume":"170","author":"Olmsted-Davis","year":"2007","journal-title":"Am J Pathol."},{"issue":"3","key":"2024012714033323600_jbmr4492-bib-0020","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1007\/s00424-007-0301-8","article-title":"Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes","volume":"455","author":"Wang","year":"2007","journal-title":"Pflugers Arch."},{"issue":"4","key":"2024012714033323600_jbmr4492-bib-0021","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1369\/0022155418757443","article-title":"Internal affairs: tenascin-C as a clinically relevant, endogenous driver of innate immunity","volume":"66","author":"Marzeda","year":"2018","journal-title":"J Histochem Cytochem."},{"issue":"2","key":"2024012714033323600_jbmr4492-bib-0022","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1615\/CritRevImmunol.v31.i2.30","article-title":"Expression and immune function of tenascin-C","volume":"31","author":"Udalova","year":"2011","journal-title":"Crit Rev Immunol."},{"issue":"4","key":"2024012714033323600_jbmr4492-bib-0023","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/S8756-3282(97)00297-4","article-title":"Regulation of tenascin-C expression in bone cells by transforming growth factor-beta","volume":"22","author":"Mackie","year":"1998","journal-title":"Bone."},{"issue":"Pt 3","key":"2024012714033323600_jbmr4492-bib-0024","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1242\/jcs.103.3.765","article-title":"Tenascin in bone morphogenesis: expression by osteoblasts and cell type-specific expression of splice variants","volume":"103","author":"Mackie","year":"1992","journal-title":"J Cell Sci."},{"issue":"6 Pt 1","key":"2024012714033323600_jbmr4492-bib-0025","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.1083\/jcb.105.6.2569","article-title":"Tenascin is associated with chondrogenic and osteogenic differentiation in vivo and promotes chondrogenesis in vitro","volume":"105","author":"Mackie","year":"1987","journal-title":"J Cell Biol."},{"issue":"11","key":"2024012714033323600_jbmr4492-bib-0026","doi-asserted-by":"crossref","first-page":"3354","DOI":"10.1002\/jcb.23265","article-title":"Regulation of tenascin expression in bone","volume":"112","author":"Morgan","year":"2011","journal-title":"J Cell Biochem."},{"issue":"5","key":"2024012714033323600_jbmr4492-bib-0027","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1007\/s10067-017-3938-5","article-title":"Tenascin-C, a biomarker of disease activity in early ankylosing spondylitis","volume":"37","author":"Gupta","year":"2018","journal-title":"Clin Rheumatol."},{"issue":"7","key":"2024012714033323600_jbmr4492-bib-0028","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1038\/nm.1987","article-title":"Tenascin-C is an endogenous activator of toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease","volume":"15","author":"Midwood","year":"2009","journal-title":"Nat Med."},{"issue":"1","key":"2024012714033323600_jbmr4492-bib-0029","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1038\/s41467-017-01718-7","article-title":"Mapping tenascin-C interaction with toll-like receptor 4 reveals a new subset of endogenous inflammatory triggers","volume":"8","author":"Zuliani-Alvarez","year":"2017","journal-title":"Nat Commun"},{"issue":"29","key":"2024012714033323600_jbmr4492-bib-0030","doi-asserted-by":"crossref","first-page":"17762","DOI":"10.1074\/jbc.M115.643551","article-title":"Novel biological substrates of human kallikrein 7 identified through degradomics","volume":"290","author":"Yu","year":"2015","journal-title":"J Biol Chem."},{"issue":"4","key":"2024012714033323600_jbmr4492-bib-0031","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/0030-4220(94)90043-4","article-title":"Regulation of bone metabolism by the kallikrein-kinin system, the coagulation cascade, and the acute-phase reactants","volume":"78","author":"Lerner","year":"1994","journal-title":"Oral Surg Oral Med Oral Pathol."},{"issue":"7","key":"2024012714033323600_jbmr4492-bib-0032","doi-asserted-by":"crossref","first-page":"E381","DOI":"10.1097\/BRS.0000000000002364","article-title":"Adiponectin downregulates TNF-alpha expression in degenerated intervertebral discs","volume":"43","author":"Yuan","year":"2018","journal-title":"Spine (Phila Pa 1976)"},{"issue":"12","key":"2024012714033323600_jbmr4492-bib-0033","doi-asserted-by":"crossref","first-page":"2269","DOI":"10.1016\/j.joca.2015.06.005","article-title":"Leptin protects rat articular chondrocytes from cytotoxicity induced by TNF-alpha in the presence of cyclohexamide","volume":"23","author":"Lee","year":"2015","journal-title":"Osteoarthr Cartil."},{"issue":"3","key":"2024012714033323600_jbmr4492-bib-0034","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1006\/bbrc.1998.8680","article-title":"Leptin regulation of peroxisome proliferator-activated receptor-gamma, tumor necrosis factor, and uncoupling protein-2 expression in adipose tissues","volume":"246","author":"Qian","year":"1998","journal-title":"Biochem Biophys Res Commun"},{"issue":"6","key":"2024012714033323600_jbmr4492-bib-0035","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1089\/jop.2010.0079","article-title":"Effect of infliximab on tumor necrosis factor-alpha-induced alterations in retinal microvascular endothelial cells and retinal pigment epithelial cells","volume":"26","author":"Li","year":"2010","journal-title":"J Ocul Pharmacol Ther."},{"issue":"12","key":"2024012714033323600_jbmr4492-bib-0036","doi-asserted-by":"crossref","first-page":"4512","DOI":"10.1167\/iovs.04-1494","article-title":"The implications of the upregulation of ICAM-1\/VCAM-1 expression of corneal fibroblasts on the pathogenesis of allergic keratopathy","volume":"46","author":"Okada","year":"2005","journal-title":"Invest Ophthalmol Vis Sci."},{"issue":"6","key":"2024012714033323600_jbmr4492-bib-0037","doi-asserted-by":"crossref","first-page":"e0198969","DOI":"10.1371\/journal.pone.0198969","article-title":"Associations between lean mass and leptin in men with chronic spinal cord injury: results from the FRASCI-muscle study","volume":"13","author":"Park","year":"2018","journal-title":"PLoS One."},{"issue":"2","key":"2024012714033323600_jbmr4492-bib-0038","doi-asserted-by":"crossref","first-page":"220","DOI":"10.2106\/00004623-199302000-00009","article-title":"The histopathology of fibrodysplasia ossificans progressiva. An endochondral process","volume":"75","author":"Kaplan","year":"1993","journal-title":"J Bone Joint Surg Am."},{"key":"2024012714033323600_jbmr4492-bib-0039","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.bone.2017.09.014","article-title":"Clinical staging of fibrodysplasia ossificans progressiva (FOP)","volume":"109","author":"Pignolo","year":"2018","journal-title":"Bone."}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbmr.4492","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jbmr.4492","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/37\/3\/475\/55459281\/jbmr4492.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/37\/3\/475\/55459281\/jbmr4492.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T15:08:23Z","timestamp":1710342503000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/37\/3\/475-483\/7516803"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,1]]},"references-count":39,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,12,26]]},"published-print":{"date-parts":[[2020,12,1]]}},"URL":"https:\/\/doi.org\/10.1002\/jbmr.4492","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,12,1]]},"published":{"date-parts":[[2020,12,1]]},"assertion":[{"value":"2021-10-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-12-21","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-01-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}