{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T13:43:43Z","timestamp":1790516623775,"version":"4.1.0"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"19","license":[{"start":{"date-parts":[[2022,5,14]],"date-time":"2022-05-14T00:00:00Z","timestamp":1652486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AR068579"],"award-info":[{"award-number":["R01 AR068579"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Elster Family Research Endowment"},{"DOI":"10.13039\/100010258","name":"Marfan Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010258","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Canadian Marfan Association"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,9,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>A disproportionate tall stature is the most evident manifestation in Marfan syndrome (MFS), a multisystem condition caused by mutations in the extracellular protein and TGF\u03b2 modulator, fibrillin-1. Unlike cardiovascular manifestations, there has been little effort devoted to unravel the molecular mechanism responsible for long bone overgrowth in MFS. By combining the Cre-LoxP recombination system with metatarsal bone cultures, here we identify the outer layer of the perichondrium as the tissue responsible for long bone overgrowth in MFS mice. Analyses of differentially expressed genes in the fibrillin-1-deficient perichondrium predicted that loss of TGF\u03b2 signaling may influence chondrogenesis in the neighboring epiphyseal growth plate (GP). Immunohistochemistry revealed that fibrillin-1 deficiency in the outer perichondrium is associated with decreased accumulation of latent TGF\u03b2-binding proteins (LTBPs)-3 and\u00a0-4, and reduced levels of phosphorylated (activated) Smad2. Consistent with these findings, mutant metatarsal bones grown in vitro were longer and released less TGF\u03b2 than the wild-type counterparts. Moreover, addition of recombinant TGF\u03b21 normalized linear growth of mutant metatarsal bones. We conclude that longitudinal bone overgrowth in MFS is accounted for by diminished sequestration of LTBP-3 and LTBP-4 into the fibrillin-1-deficient matrix of the outer perichondrium, which results in less TGF\u03b2 signaling locally and improper GP differentiation distally.<\/jats:p>","DOI":"10.1093\/hmg\/ddac107","type":"journal-article","created":{"date-parts":[[2022,5,14]],"date-time":"2022-05-14T13:36:08Z","timestamp":1652535368000},"page":"3281-3289","source":"Crossref","is-referenced-by-count":11,"title":["Fibrillin-1 deficiency in the outer perichondrium causes longitudinal bone overgrowth in mice with Marfan syndrome"],"prefix":"10.1093","volume":"31","author":[{"given":"Lauriane","family":"Sedes","sequence":"first","affiliation":[{"name":"Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai , New York, NY 10021 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Wondimu","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai , New York, NY 10021 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany","family":"Crockett","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai , New York, NY 10021 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai , New York, NY 10021 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Cantalupo","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai , New York, NY 10021 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiichi","family":"Asano","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai , New York, NY 10021 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi","family":"Iyengar","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai , New York, NY 10021 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel B","family":"Rifkin","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, New York University School of Medicine , New York, NY 10016 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Smaldone","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai , New York, NY 10021 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2668-8785","authenticated-orcid":false,"given":"Francesco","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai , New York, NY 10021 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,5,14]]},"reference":[{"key":"2022093009391517900_ref1","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.matbio.2017.07.004","article-title":"Marfan syndrome: a connective tissue disease at the crossroads of mechanotransduction, TGF\u03b2 signaling and cell stemness","volume":"71-72","author":"Ramirez","year":"2018","journal-title":"Matrix Biol."},{"key":"2022093009391517900_ref2","first-page":"450","volume-title":"Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism","author":"Ramirez","year":"2013","edition":"7th"},{"key":"2022093009391517900_ref3","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1210\/er.2002-0033","article-title":"Systemic and local regulation of the growth plate","volume":"24","author":"Van Der Eerden","year":"2003","journal-title":"Endocr. 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Cell Biol."},{"key":"2022093009391517900_ref7","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/dvdy.1141","article-title":"The perichondrium plays an important role in mediating the effects of TGF\u03b21 on endochondral bone formation","volume":"221","author":"Alvarez","year":"2001","journal-title":"Dev. Dyn."},{"key":"2022093009391517900_ref8","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1387\/ijdb.072322mc","article-title":"Pericohondrial-mediated TGF-beta regulation of cartilage growth in avian long bone development","volume":"52","author":"Crochiere","year":"2008","journal-title":"Int. J. Dev. Biol."},{"key":"2022093009391517900_ref9","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a021907","article-title":"B, regulation of the bioavailability of TGF-\u03b2 and TGF-\u03b2-related proteins","volume":"8","author":"Robertson","year":"2016","journal-title":"Cold Spring Harb. Perspect. 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Cytochem."},{"key":"2022093009391517900_ref13","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/S0945-053X(02)00100-2","article-title":"Fibrillin-1 and fibrillin-1 in human embryonic and early fetal development","volume":"21","author":"Quondamatteo","year":"2002","journal-title":"Matrix Biol."},{"key":"2022093009391517900_ref14","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1002\/jbmr.2598","article-title":"Fibrillin-1 regulates skeletal stem cell differentiation by modulating TGF\u03b2 activity within the marrow niche","volume":"31","author":"Smaldone","year":"2016","journal-title":"J. Bone Miner. Res."},{"key":"2022093009391517900_ref15","doi-asserted-by":"crossref","first-page":"3828","DOI":"10.1002\/jcp.24094","article-title":"Specificity of latent TGF-\u03b2 binding protein (LTBP) incorporation into matrix: role of fibrillin and fibronectin","volume":"227","author":"Zilberberg","year":"2012","journal-title":"J. Cell. 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