{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T17:24:16Z","timestamp":1791566656770,"version":"4.3.4"},"reference-count":89,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T00:00:00Z","timestamp":1731974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008070","name":"Department of Medicine, University of California, San Francisco","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008070","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Robert L. Kroc Chair in Rheumatic and Connective Tissue Diseases III"},{"name":"Children's Hospital of Philadelphia research development fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,12,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Retinoids are metabolic derivatives of vitamin A and play crucial roles in the regulation of various tissues and organs during prenatal and postnatal development. Active retinoids, like all-trans-retinoic acid, are synthesized in the cytoplasm and subsequently interact with nuclear retinoic acid receptors (RAR\u03b1, RAR\u03b2, and RAR\u03b3) to enhance transcription of specific genes. In the absence of retinoids, RARs can still bind to response elements of target genes but repress their transcription. Chondrogenic cell differentiation and cartilage maturation in the growth plate require the absence of retinoid signaling and transcriptional repression by unliganded RARs. This led to the hypothesis that synthetic retinoid agonists may be pharmacological agents to inhibit those cellular processes and counter the excessive formation of cartilage and bone in conditions like heterotopic ossification (HO). HO can be instigated by diverse culprits including trauma, invasive surgeries, inflammatory disorders, or genetic conditions. One such genetic disease is fibrodysplasia ossificans progressiva (FOP), a rare disorder driven by activating mutations in the ACVR1 gene. Patients with FOP have severe and progressive HO formation in soft tissues, leading to extensive permanent loss of mobility and increased mortality. Synthetic retinoid agonists selective for RAR\u03b1 or RAR\u03b3 showed efficacy against injury-induced and genetic HO in mouse models. The RAR\u03b3 agonists showed the highest effectiveness, with palovarotene being selected for clinical trials in patients with FOP. Post hoc analyses of phase II and phase III clinical trials showed that palovarotene has significant disease-modifying effects for FOP, but with significant risks such as premature growth plate closure in some younger subjects. This review provides an overview of retinoid and RAR roles in skeletal development and discusses the identification of palovarotene as a potential FOP therapy, the clinical data supporting its regulatory approval in some countries, and the potential applications of this drug for other relevant disorders besides FOP.<\/jats:p>","DOI":"10.1093\/jbmrpl\/ziae147","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T18:16:16Z","timestamp":1732040176000},"source":"Crossref","is-referenced-by-count":13,"title":["Palovarotene (Sohonos), a synthetic retinoid for reducing new heterotopic ossification in fibrodysplasia ossificans progressiva: history, present, and future"],"prefix":"10.1093","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8924-106X","authenticated-orcid":false,"given":"Edward C","family":"Hsiao","sequence":"first","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Medicine; the Program in Craniofacial Biology; The Institute for Human Genetics; and The Ely and Edythe Broad Institute for Regeneration Medicine, University of California\u2014San Francisco , San Francisco, CA 94143 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Pacifici","sequence":"additional","affiliation":[{"name":"Translational Research Program in Pediatric Orthopedics, Division of Orthopaedic Surgery, Children's Hospital of Philadelphia , Philadelphia, PA 19104 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,11,19]]},"reference":[{"issue":"11","key":"2024121419373606100_ref1","first-page":"1243","article-title":"Palovarotene, a novel retinoic acid receptor gamma agonist for the treatment of emphysema","volume":"10","author":"Hind","year":"2009","journal-title":"Curr Opin Investig Drugs"},{"issue":"1","key":"2024121419373606100_ref2","doi-asserted-by":"publisher","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"},{"issue":"1","key":"2024121419373606100_ref3","doi-asserted-by":"publisher","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. 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