{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T07:22:28Z","timestamp":1775805748970,"version":"3.50.1"},"reference-count":83,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T00:00:00Z","timestamp":1713225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Radiant Hope Foundation"},{"name":"The Robert and Arlene Kogod Professorship in Geriatric Medician and Gerontology"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The formation of bone outside the normal skeleton, or heterotopic ossification (HO), occurs through genetic and acquired mechanisms. Fibrodysplasia ossificans progressiva (FOP), the most devastating genetic condition of HO, is due to mutations in the ACVR1\/ALK2 gene and is relentlessly progressive. Acquired HO is mostly precipitated by injury or orthopedic surgical procedures but can also be associated with certain conditions related to aging. Cellular senescence is a hallmark of aging and thought to be a tumor-suppressive mechanism with characteristic features such as irreversible growth arrest, apoptosis resistance, and an inflammatory senescence-associated secretory phenotype (SASP). Here, we review possible roles for cellular senescence in HO and how targeting senescent cells may provide new therapeutic approaches to both FOP and acquired forms of HO.<\/jats:p>","DOI":"10.3390\/biom14040485","type":"journal-article","created":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T09:16:33Z","timestamp":1713258993000},"page":"485","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Cell Senescence in Heterotopic Ossification"],"prefix":"10.3390","volume":"14","author":[{"given":"Robert J.","family":"Pignolo","sequence":"first","affiliation":[{"name":"Department of Medicine, Section of Geriatric Medicine & Gerontology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Divisions of Endocrinology and Hospital Internal Medicine, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frederick S.","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, The Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Medicine, The Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"The Center for Research in FOP and Related Disorders, The Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2340-0739","authenticated-orcid":false,"given":"Haitao","family":"Wang","sequence":"additional","affiliation":[{"name":"Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1016\/j.gim.2022.08.013","article-title":"The natural history of fibrodysplasia ossificans progressiva: A prospective, global 36-month study","volume":"24","author":"Pignolo","year":"2022","journal-title":"Genet. Med."},{"key":"ref_2","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."},{"key":"ref_3","first-page":"437","article-title":"Fibrodysplasia ossificans progressiva: Diagnosis, management, and therapeutic horizons","volume":"10","author":"Pignolo","year":"2013","journal-title":"Pediatr. Endocrinol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"908","DOI":"10.3389\/fendo.2019.00908","article-title":"Fibrodysplasia Ossificans Progressiva (FOP): A Segmental Progeroid Syndrome","volume":"10","author":"Pignolo","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1186\/s13023-017-0674-5","article-title":"Prevalence of fibrodysplasia ossificans progressiva (FOP) in France: An estimate based on a record linkage of two national databases","volume":"12","author":"Baujat","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1136\/jmg.19.1.35","article-title":"Genetic aspects of fibrodysplasia ossificans progressiva","volume":"19","author":"Connor","year":"1982","journal-title":"J. Med. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1186\/s13023-021-01983-2","article-title":"Prevalence of fibrodysplasia ossificans progressiva (FOP) in the United States: Estimate from three treatment centers and a patient organization","volume":"16","author":"Pignolo","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_8","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"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1002\/jbmr.4492","article-title":"Plasma-Soluble Biomarkers for Fibrodysplasia Ossificans Progressiva (FOP) Reflect Acute and Chronic Inflammatory States","volume":"37","author":"Pignolo","year":"2022","journal-title":"J. Bone Miner. Res."},{"key":"ref_10","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."},{"key":"ref_11","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."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1002\/humu.20868","article-title":"Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1","volume":"30","author":"Kaplan","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Lounev, V., Groppe, J.C., Brewer, N., Wentworth, K.L., Smith, V., Xu, M., Schomburg, L., Bhargava, P., Al Mukaddam, M., and Hsiao, E.C. (2024). MMP-9 deficiency confers resilience in Fibrodysplasia Ossificans Progressiva in a man and mice. J. Bone Miner. Res., zjae029.","DOI":"10.1093\/jbmr\/zjae029"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.2106\/00004623-198062070-00012","article-title":"Periarticular heterotopic ossification in head-injured adults. Incidence and location","volume":"62","author":"Garland","year":"1980","journal-title":"J. Bone Jt. Surg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1046\/j.1445-2197.2002.02549.x","article-title":"Incidence of heterotopic bone formation after major hip surgery","volume":"72","author":"Neal","year":"2002","journal-title":"ANZ J. Surg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1161\/01.CIR.103.11.1522","article-title":"Bone formation and inflammation in cardiac valves","volume":"103","author":"Mohler","year":"2001","journal-title":"Circulation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1164\/rccm.2108054","article-title":"Calcium deposition with or without bone formation in the lung","volume":"165","author":"Chan","year":"2002","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1097\/TA.0000000000000883","article-title":"Trauma-induced heterotopic bone formation and the role of the immune system: A review","volume":"80","author":"Kraft","year":"2016","journal-title":"J. Trauma Acute Care Surg."},{"key":"ref_19","first-page":"53","article-title":"Effect of a persistent inflammatory process on experimental heterotopic ossification. The influence of macrophages","volume":"26","author":"Moraes","year":"1993","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.bone.2017.08.023","article-title":"Mast cell inhibition as a therapeutic approach in fibrodysplasia ossificans progressiva (FOP)","volume":"109","author":"Brennan","year":"2018","journal-title":"Bone"},{"key":"ref_21","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."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.bone.2017.12.028","article-title":"Circulating osteogentic precursor cells in non-hereditary heterotopic ossification","volume":"109","author":"Egan","year":"2018","journal-title":"Bone"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2965","DOI":"10.1161\/ATVBAHA.111.234724","article-title":"Role for circulating osteogenic precursor cells in aortic valvular disease","volume":"31","author":"Egan","year":"2011","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.bone.2017.12.006","article-title":"Histopathology of periarticular non-hereditary heterotopic ossification","volume":"109","author":"Foley","year":"2018","journal-title":"Bone"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1053\/hupa.2001.26464","article-title":"Mast cell involvement in fibrodysplasia ossificans progressiva","volume":"32","author":"Gannon","year":"2001","journal-title":"Hum. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/S0046-8177(97)90133-7","article-title":"Bone morphogenetic protein 2\/4 in early fibromatous lesions of fibrodysplasia ossificans progressiva","volume":"28","author":"Gannon","year":"1997","journal-title":"Hum. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1097\/00003086-199801000-00005","article-title":"Acute lymphocytic infiltration in an extremely early lesion of fibrodysplasia ossificans progressiva","volume":"346","author":"Gannon","year":"1998","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_28","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 Jt. Surg."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1002\/jbmr.2848","article-title":"Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling","volume":"31","author":"Wang","year":"2016","journal-title":"J. Bone Miner. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1002\/jbmr.4458","article-title":"Clearance of Senescent Cells from Injured Muscle Abrogates Heterotopic Ossification in Mouse Models of Fibrodysplasia Ossificans Progressiva","volume":"37","author":"Wang","year":"2022","journal-title":"J. Bone Miner. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1016\/j.molmed.2020.03.005","article-title":"Reducing Senescent Cell Burden in Aging and Disease","volume":"26","author":"Pignolo","year":"2020","journal-title":"Trends Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.stem.2016.11.020","article-title":"Injury-Induced Senescence Enables In Vivo Reprogramming in Skeletal Muscle","volume":"20","author":"Chiche","year":"2017","journal-title":"Cell Stem Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"aaf4445","DOI":"10.1126\/science.aaf4445","article-title":"Tissue damage and senescence provide critical signals for cellular reprogramming in vivo","volume":"354","author":"Mosteiro","year":"2016","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.ebiom.2017.04.013","article-title":"Cellular Senescence: A Translational Perspective","volume":"21","author":"Kirkland","year":"2017","journal-title":"EBioMedicine"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"E6301","DOI":"10.1073\/pnas.1515386112","article-title":"JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age","volume":"112","author":"Xu","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.bone.2017.11.014","article-title":"Activin A amplifies dysregulated BMP signaling and induces chondro-osseous differentiation of primary connective tissue progenitor cells in patients with fibrodysplasia ossificans progressiva (FOP)","volume":"109","author":"Wang","year":"2018","journal-title":"Bone"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.bone.2017.08.009","article-title":"Acute unilateral hip pain in fibrodysplasia ossificans progressiva (FOP)","volume":"109","author":"Kaplan","year":"2018","journal-title":"Bone"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1126\/science.150.3698.893","article-title":"Bone: Formation by autoinduction","volume":"150","author":"Urist","year":"1965","journal-title":"Science"},{"key":"ref_39","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":"ref_40","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.molmed.2010.03.003","article-title":"Inflammatory networks during cellular senescence: Causes and consequences","volume":"16","author":"Freund","year":"2010","journal-title":"Trends Mol. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/nrm3823","article-title":"Cellular senescence: From physiology to pathology","volume":"15","author":"Serrano","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.bone.2017.06.011","article-title":"The obligatory role of Activin A in the formation of heterotopic bone in Fibrodysplasia Ossificans Progressiva","volume":"109","author":"Idone","year":"2018","journal-title":"Bone"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"303ra137","DOI":"10.1126\/scitranslmed.aac4358","article-title":"ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A","volume":"7","author":"Hatsell","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3339","DOI":"10.1172\/JCI93521","article-title":"Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva","volume":"127","author":"Hino","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"15438","DOI":"10.1073\/pnas.1510540112","article-title":"Neofunction of ACVR1 in fibrodysplasia ossificans progressiva","volume":"112","author":"Hino","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","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":"Yamamoto","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/s13287-016-0393-1","article-title":"Effects of matrix metalloproteinases on the fate of mesenchymal stem cells","volume":"7","author":"Almalki","year":"2016","journal-title":"Stem Cell Res. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1007\/s00418-008-0391-1","article-title":"Exposure to pro-inflammatory cytokines upregulates MMP-9 synthesis by mesenchymal stem cells-derived osteoprogenitors","volume":"129","author":"Reznick","year":"2008","journal-title":"Histochem. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"13057","DOI":"10.1073\/pnas.1603668113","article-title":"BMP-SMAD-ID promotes reprogramming to pluripotency by inhibiting p16\/INK4A-dependent senescence","volume":"113","author":"Hayashi","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"116129","DOI":"10.1016\/j.bone.2021.116129","article-title":"ACVR1(R206H) extends inflammatory responses in human induced pluripotent stem cell-derived macrophages","volume":"153","author":"Matsuo","year":"2021","journal-title":"Bone"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"799","DOI":"10.5966\/sctm.2015-0365","article-title":"Surgical Excision of Heterotopic Ossification Leads to Re-Emergence of Mesenchymal Stem Cell Populations Responsible for Recurrence","volume":"6","author":"Agarwal","year":"2017","journal-title":"Stem Cells Transl. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/nature20160","article-title":"Intronic polyadenylation of PDGFRalpha in resident stem cells attenuates muscle fibrosis","volume":"540","author":"Mueller","year":"2016","journal-title":"Nature"},{"key":"ref_53","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."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e355","DOI":"10.1002\/term.2320","article-title":"PDGF is a potent initiator of bone formation in a tissue engineered model of pathological ossification","volume":"12","author":"Davies","year":"2018","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1002\/jor.23216","article-title":"Location-dependent heterotopic ossification in the rat model: The role of activated matrix metalloproteinase 9","volume":"34","author":"Davis","year":"2016","journal-title":"J. Orthop. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.1089\/ten.tea.2011.0007","article-title":"Matrix metalloproteinase-9 is a diagnostic marker of heterotopic ossification in a murine model","volume":"17","author":"Rodenberg","year":"2011","journal-title":"Tissue Eng. Part A"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.3892\/mmr.2017.6275","article-title":"Dynamics of MMP-9, MMP-2 and TIMP-1 in a rat model of brain injury combined with traumatic heterotopic ossification","volume":"15","author":"Shi","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/S0092-8674(00)81169-1","article-title":"MMP-9\/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes","volume":"93","author":"Vu","year":"1998","journal-title":"Cell"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"eaaw0254","DOI":"10.1126\/sciadv.aaw0254","article-title":"The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype","volume":"5","author":"Hari","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.phrs.2016.05.015","article-title":"Perspective: Targeting the JAK\/STAT pathway to fight age-related dysfunction","volume":"111","author":"Xu","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Kasembeli, M.M., Bharadwaj, U., Robinson, P., and Tweardy, D.J. (2018). Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19082299"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/s41556-018-0151-y","article-title":"Denervation-activated STAT3-IL-6 signalling in fibro-adipogenic progenitors promotes myofibres atrophy and fibrosis","volume":"20","author":"Madaro","year":"2018","journal-title":"Nat. Cell Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1186\/s13046-021-02035-0","article-title":"Cellular senescence or stemness: Hypoxia flips the coin","volume":"40","author":"Carnero","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1016\/j.molcel.2021.03.018","article-title":"Physiological hypoxia restrains the senescence-associated secretory phenotype via AMPK-mediated mTOR suppression","volume":"81","author":"Wang","year":"2021","journal-title":"Mol. Cell"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Wang, H., Kaplan, F.S., and Pignolo, R.J. (2024). The HIF-1alpha and mTOR Pathways Amplify Heterotopic Ossification. Biomolecules, 14.","DOI":"10.3390\/biom14020147"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"47","DOI":"10.5483\/BMBRep.2019.52.1.293","article-title":"Senotherapeutics: Emerging strategy for healthy aging and age-related disease","volume":"52","author":"Kim","year":"2019","journal-title":"BMB Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1111\/joim.13141","article-title":"Senolytic drugs: From discovery to translation","volume":"288","author":"Kirkland","year":"2020","journal-title":"J. Intern. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1111\/jgs.14969","article-title":"The Clinical Potential of Senolytic Drugs","volume":"65","author":"Kirkland","year":"2017","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1111\/febs.16350","article-title":"Targeting cellular senescence with senotherapeutics: Senolytics and senomorphics","volume":"290","author":"Zhang","year":"2023","journal-title":"FEBS J."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1111\/acel.12344","article-title":"The Achilles\u2019 heel of senescent cells: From transcriptome to senolytic drugs","volume":"14","author":"Zhu","year":"2015","journal-title":"Aging Cell"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1001\/jama.2018.12440","article-title":"Aging, Cell Senescence, and Chronic Disease: Emerging Therapeutic Strategies","volume":"320","author":"Tchkonia","year":"2018","journal-title":"JAMA"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"456","DOI":"10.4062\/biomolther.2020.013","article-title":"Dasatinib Inhibits Lyn and Fyn Src-Family Kinases in Mast Cells to Suppress Type I Hypersensitivity in Mice","volume":"28","author":"Lee","year":"2020","journal-title":"Biomol. Ther."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1007\/s12272-001-1225-2","article-title":"Quercetin inhalation inhibits the asthmatic responses by exposure to aerosolized-ovalbumin in conscious guinea-pigs","volume":"31","author":"Moon","year":"2008","journal-title":"Arch. Pharmacal Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1111\/j.1476-5381.2009.00365.x","article-title":"The hydroxyflavone, fisetin, suppresses mast cell activation induced by interaction with activated T cell membranes","volume":"158","author":"Nagai","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_75","first-page":"27","article-title":"Quercetin effectively quells peanut-induced anaphylactic reactions in the peanut sensitized rats","volume":"9","author":"Shishehbor","year":"2010","journal-title":"Iran. J. Allergy Asthma Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"377","DOI":"10.3389\/fimmu.2019.00377","article-title":"Inhibition of JAK1\/2 Tyrosine Kinases Reduces Neurogenic Heterotopic Ossification After Spinal Cord Injury","volume":"10","author":"Alexander","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"14491","DOI":"10.1111\/jcmm.16076","article-title":"Metformin attenuates trauma-induced heterotopic ossification via inhibition of Bone Morphogenetic Protein signalling","volume":"24","author":"Lin","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Chen, X., Wang, S., Xu, W., Zhao, M., Zhang, Y., and Xiao, H. (2023). Metformin Directly Binds to MMP-9 to Improve Plaque Stability. J. Cardiovasc. Dev. Dis., 10.","DOI":"10.3390\/jcdd10020054"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"115473","DOI":"10.1016\/j.bone.2020.115473","article-title":"Activin A does not drive post-traumatic heterotopic ossification","volume":"138","author":"Hwang","year":"2020","journal-title":"Bone"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"649285","DOI":"10.3389\/fimmu.2021.649285","article-title":"Quercetin Attenuates Trauma-Induced Heterotopic Ossification by Tuning Immune Cell Infiltration and Related Inflammatory Insult","volume":"12","author":"Li","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1089\/scd.2014.0291","article-title":"Effects of aging on osteogenic response and heterotopic ossification following burn injury in mice","volume":"24","author":"Peterson","year":"2015","journal-title":"Stem Cells Dev."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Pignolo, R.J., Al Mukaddam, M., Baujat, G., Brown, M.A., De Cunto, C., Hsiao, E.C., Keen, R., Le Quan Sang, K.H., Grogan, D.R., and Marino, R. (2023). Study methodology and insights from the palovarotene clinical development program in fibrodysplasia ossificans progressiva. BMC Med. Res. Methodol., 23.","DOI":"10.1186\/s12874-023-02080-7"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1080\/21678707.2020.1751122","article-title":"Druggable targets, clinical trial design and proposed pharmacological management in fibrodysplasia ossificans progressiva","volume":"8","author":"Pignolo","year":"2020","journal-title":"Expert Opin. 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