{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T08:38:20Z","timestamp":1792226300587,"version":"4.4.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2015,7,18]],"date-time":"2015-07-18T00:00:00Z","timestamp":1437177600000},"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":["AR064868"],"award-info":[{"award-number":["AR064868"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,1,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>A full understanding of the microenvironmental factors that control the activities of skeletal stem cells (also known as mesenchymal stem cells [MSCs]) in the adult bone marrow holds great promise for developing new therapeutic strategies to mitigate age-related diseases of bone and cartilage degeneration. Bone loss is an understudied manifestation of Marfan syndrome, a multisystem disease associated with mutations in the extracellular matrix protein and TGF\u03b2 modulator fibrillin-1. Here we demonstrate that progressive loss of cancellous bone in mice with limbs deficient for fibrillin-1 (Fbn1Prx1\u2013\/\u2013 mice) is accounted for by premature depletion of MSCs and osteoprogenitor cells combined with constitutively enhanced bone resorption. Longitudinal analyses of Fbn1Prx1\u2013\/\u2013 mice showed incremental bone loss and trabecular microarchitecture degeneration accompanied by a progressive decrease in the number and clonogenic potential of MSCs. Significant paucity of marrow fat cells in the long bones of Fbn1Prx1\u2013\/\u2013 mice, together with reduced adipogenic potential of marrow stromal cell cultures, indicated an additional defect in MSC differentiation. This postulate was corroborated by showing that an Fbn1-silenced osteoprogenitor cell line cultured in the presence of insulin yielded fewer than normal adipocytes and exhibited relatively lower PPAR\u03b3 levels. Consonant with fibrillin-1 modulation of TGF\u03b2 bioavailability, cultures of marrow stromal cells from Fbn1Prx1\u2013\/\u2013 limb bones showed improper overactivation of latent TGF\u03b2. In line with this finding, systemic TGF\u03b2 neutralization improved bone mass and trabecular microarchitecture along with normalizing the number of MSCs, osteoprogenitor cells, and marrow adipocytes. Collectively, our findings show that fibrillin-1 regulates MSC activity by modulating TGF\u03b2 bioavailability within the microenvironment of marrow niches. \u00a9 2015 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.2598","type":"journal-article","created":{"date-parts":[[2015,7,18]],"date-time":"2015-07-18T12:05:12Z","timestamp":1437221112000},"page":"86-97","source":"Crossref","is-referenced-by-count":44,"title":["Fibrillin-1 Regulates Skeletal Stem Cell Differentiation by Modulating TGF\u03b2 Activity Within the Marrow Niche"],"prefix":"10.1093","volume":"31","author":[{"given":"Silvia","family":"Smaldone","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Systems TherapeuticsIcahn School of Medicine at Mount SinaiNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas P","family":"Clayton","sequence":"additional","affiliation":[{"name":"Genzymea Sanofi CompanyFraminghamMAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"del Solar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Systems TherapeuticsIcahn School of Medicine at Mount SinaiNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma","family":"Pascual","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical SpecialtiesFaculty of Medicine and Health SciencesUniversity of Alcal\u00e1Biomedical Research Networking Centre on BioengineeringBiomaterials and Nanomedicine (CIBER-BBN)MadridSpain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seng H","family":"Cheng","sequence":"additional","affiliation":[{"name":"Genzymea Sanofi CompanyFraminghamMAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce M","family":"Wentworth","sequence":"additional","affiliation":[{"name":"Genzymea Sanofi CompanyFraminghamMAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell B","family":"Schaffler","sequence":"additional","affiliation":[{"name":"Department of Biomedical EngineeringCity College of New YorkNew YorkNYUSA"},{"name":"Department of Medicine and Medical SpecialtiesFaculty of Medicine and Health SciencesUniversity of Alcal\u00e1Biomedical Research Networking Centre on BioengineeringBiomaterials and Nanomedicine (CIBER-BBN)MadridSpain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Systems TherapeuticsIcahn School of Medicine at Mount SinaiNew YorkNYUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,7,18]]},"reference":[{"key":"2024021014185033700_jbmr2598-bib-0001","first-page":"9499","author":"Zhang","year":"2008"},{"key":"2024021014185033700_jbmr2598-bib-0002","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1138\/20110495","article-title":"Regulatory interactions in the bone marrow microenvironment","volume":"2","author":"Smith","year":"2011","journal-title":"IBMS Bonekey."},{"key":"2024021014185033700_jbmr2598-bib-0003","author":"Schipani","year":"2009"},{"key":"2024021014185033700_jbmr2598-bib-0004","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1002\/bdrc.20171","article-title":"Extracellular matrix provides an optimal niche for the maintenance and propagation of mesenchymal stem cells","volume":"90","author":"Chen","year":"2010","journal-title":"Birth Defects Res C Embryo Today."},{"key":"2024021014185033700_jbmr2598-bib-0005","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/j.ceb.2009.05.005","article-title":"Extracellular microfibrils: contextual platforms for TGFb and BMP signaling","volume":"21","author":"Ramirez","year":"2009","journal-title":"Curr Opin Cell Biol."},{"key":"2024021014185033700_jbmr2598-bib-0006","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s00441-009-0822-x","article-title":"Biogenesis and function of fibrillin assemblies","volume":"339","author":"Ramirez","year":"2010","journal-title":"Cell Tissue Res."},{"key":"2024021014185033700_jbmr2598-bib-0007","first-page":"1329","article-title":"Abnormal muscle mechanosignaling triggers cardiomyopathy in mice with Marfan syndrome","volume":"124","author":"Cook","year":"2014","journal-title":"J Clin Invest."},{"key":"2024021014185033700_jbmr2598-bib-0008","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1182\/blood-2007-07-075168","article-title":"Signaling pathways governing stem-cell fate","volume":"111","author":"Blank","year":"2008","journal-title":"Blood."},{"key":"2024021014185033700_jbmr2598-bib-0009","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/nm.1979","article-title":"TGF-\u03b21-induced migration of bone mesenchymal stem cells couples bone resorption with formation","volume":"15","author":"Tang","year":"2009","journal-title":"Nat Med."},{"key":"2024021014185033700_jbmr2598-bib-0010","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1146\/annurev.med.51.1.481","article-title":"The Marfan syndrome","volume":"51","author":"Pyeritz","year":"2000","journal-title":"Annu Rev Med."},{"key":"2024021014185033700_jbmr2598-bib-0011","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1007\/s00198-003-1433-0","article-title":"Assessment of bone mineral density in adults and children with Marfan syndrome","volume":"14","author":"Giampietro","year":"2003","journal-title":"Osteoporos Int."},{"key":"2024021014185033700_jbmr2598-bib-0012","doi-asserted-by":"crossref","first-page":"4790","DOI":"10.1093\/hmg\/ddq409","article-title":"Differential effects of alendronate and losartan therapy on osteopenia and aortic aneurysm in mice with severe Marfan syndrome","volume":"19","author":"Nistala","year":"2010","journal-title":"Hum Mol Genet."},{"key":"2024021014185033700_jbmr2598-bib-0013","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.matbio.2011.03.004","article-title":"Material and mechanical properties of bones deficient for fibrillin-1 or fibrillin-2 microfibrils","volume":"30","author":"Arteaga-Solis","year":"2011","journal-title":"Matrix Biol."},{"key":"2024021014185033700_jbmr2598-bib-0014","doi-asserted-by":"crossref","first-page":"34126","DOI":"10.1074\/jbc.M110.125328","article-title":"Extracellular microfibrils control osteoblast-supported osteoclastogenesis by restricting TGF\u03b2 stimulation of RANKL production","volume":"285","author":"Nistala","year":"2010","journal-title":"J Biol Chem."},{"key":"2024021014185033700_jbmr2598-bib-0015","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1083\/jcb.201003089","article-title":"Fibrillin-1 and -2 differentially modulate endogenous TGF-b and BMP bioavailability during bone formation","volume":"190","author":"Nistala","year":"2010","journal-title":"J Cell Biol."},{"key":"2024021014185033700_jbmr2598-bib-0016","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1002\/dvg.22022","article-title":"Generation of Fbn1 conditional null mice implicates the extracellular microfibrils in osteoprogenitor recruitment","volume":"50","author":"Cook","year":"2012","journal-title":"Genesis."},{"key":"2024021014185033700_jbmr2598-bib-0017","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1634\/stemcells.2005-0399","article-title":"Ablation of proliferating marrow with 5-fluorouracil allows partial purification of mesenchymal stem cells","volume":"24","author":"Wang","year":"2006","journal-title":"Stem Cells."},{"key":"2024021014185033700_jbmr2598-bib-0018","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1006\/abio.1994.1042","article-title":"An assay for transforming growth factor-\u03b2 using cells transfected with a plasminogen activator inhibitor-1 promoter-luciferase construct","volume":"216","author":"Abe","year":"1994","journal-title":"Anal Biochem."},{"key":"2024021014185033700_jbmr2598-bib-0019","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/1471-2121-8-41","article-title":"A rapid and sensitive bioassay to measure bone morphogenetic protein activity","volume":"8","author":"Zilberberg","year":"2007","journal-title":"BMC Cell Biol."},{"key":"2024021014185033700_jbmr2598-bib-0020","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1359\/jbmr.080304","article-title":"Age-related changes in the osteogenic differentiation potential of mouse bone marrow stromal cells","volume":"23","author":"Zhang","year":"2008","journal-title":"J Bone Miner Res."},{"key":"2024021014185033700_jbmr2598-bib-0021","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1006\/excr.1997.3858","article-title":"In vitro chondrogenesis of bone marrow-derived mesenchymal progenitor cells","volume":"238","author":"Johnstone","year":"1998","journal-title":"Exp Cell Res."},{"key":"2024021014185033700_jbmr2598-bib-0022","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1007\/s00441-011-1167-9","article-title":"Establishment of fibrillin-deficient osteoprogenitor cell lines identifies molecular abnormalities associated with extracellular matrix perturbation of osteogenic differentiation","volume":"344","author":"Smaldone","year":"2011","journal-title":"Cell Tissue Res."},{"key":"2024021014185033700_jbmr2598-bib-0023","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.stem.2014.06.008","article-title":"Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow","volume":"15","author":"Zhou","year":"2014","journal-title":"Cell Stem Cell."},{"key":"2024021014185033700_jbmr2598-bib-0024","doi-asserted-by":"crossref","first-page":"2649","DOI":"10.1016\/j.transproceed.2008.08.009","article-title":"Isolation and characterization of mouse mesenchymal stem cells","volume":"40","author":"Sung","year":"2008","journal-title":"Transplant Proc."},{"key":"2024021014185033700_jbmr2598-bib-0025","first-page":"990","author":"Schaedlich","year":"2010"},{"key":"2024021014185033700_jbmr2598-bib-0026","author":"Alliston","year":"2008"},{"key":"2024021014185033700_jbmr2598-bib-0027","doi-asserted-by":"crossref","first-page":"5087","DOI":"10.1074\/jbc.M110.188615","article-title":"Prodomains of transforming growth factor b (TGFb) superfamily members specify different functions: extracellular matrix interactions and growth factor bioavailability","volume":"286","author":"Sengle","year":"2011","journal-title":"J Biol Chem."},{"key":"2024021014185033700_jbmr2598-bib-0028","doi-asserted-by":"crossref","first-page":"30481","DOI":"10.1074\/jbc.M500573200","article-title":"Extracellular matrix proteoglycans control the fate of bone marrow stromal cells","volume":"280","author":"Bi","year":"2005","journal-title":"J Biol Chem."},{"key":"2024021014185033700_jbmr2598-bib-0029","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1210\/er.2010-0018","article-title":"Emerging roles for the transforming growth factor-\u03b2 superfamily in regulating adiposity and energy expenditure","volume":"32","author":"Zamani","year":"2011","journal-title":"Endocr Rev."},{"key":"2024021014185033700_jbmr2598-bib-0030","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1161\/CIRCULATIONAHA.108.841981","article-title":"Circulating transforming growth factor-\u03b2 in Marfan syndrome","volume":"120","author":"Matt","year":"2009","journal-title":"Circulation."},{"key":"2024021014185033700_jbmr2598-bib-0031","doi-asserted-by":"crossref","first-page":"2611","DOI":"10.1016\/j.ajpath.2011.02.024","article-title":"Inhibiting TGF-\u03b2 activity improves respiratory function in mdx mice","volume":"178","author":"Nelson","year":"2011","journal-title":"Am J Pathol."},{"key":"2024021014185033700_jbmr2598-bib-0032","first-page":"341","author":"Ramirez","year":"2009"},{"key":"2024021014185033700_jbmr2598-bib-0033","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1038\/nm.3544","article-title":"Excessive transforming growth factor-beta signaling is a common mechanism in osteogenesis imperfecta","volume":"20","author":"Grafe","year":"2014","journal-title":"Nat Med."},{"key":"2024021014185033700_jbmr2598-bib-0034","doi-asserted-by":"crossref","first-page":"5840","DOI":"10.1073\/pnas.1036475100","article-title":"Mesenchymal progenitor self-renewal deficiency leads to age-dependent osteoporosis in Sca-1\/Ly-6A null mice","volume":"100","author":"Bonyadi","year":"2003","journal-title":"Proc Natl Acad Sci U S.A."},{"key":"2024021014185033700_jbmr2598-bib-0035","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1084\/jem.20140643","article-title":"mTOR inhibition rescues osteopenia in mice with systemic sclerosis","volume":"212","author":"Chen","year":"2015","journal-title":"J Exp Med."},{"key":"2024021014185033700_jbmr2598-bib-0036","doi-asserted-by":"crossref","first-page":"3819","DOI":"10.1073\/pnas.96.7.3819","article-title":"Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1","volume":"96","author":"Pereira","year":"1999","journal-title":"Proc Natl Acad Sci U S.A."},{"key":"2024021014185033700_jbmr2598-bib-0037","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1172\/JCI200420641","article-title":"Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome","volume":"114","author":"Judge","year":"2004","journal-title":"J Clin Invest."},{"key":"2024021014185033700_jbmr2598-bib-0038","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1083\/jcb.150.3.667","article-title":"New insights into the assembly of extracellular microfibrils from the analysis of the fibrillin 1 mutation in the tight skin mouse","volume":"150","author":"Gayraud","year":"2000","journal-title":"J Cell Biol."},{"key":"2024021014185033700_jbmr2598-bib-0039","author":"Jensen","year":"2015"},{"key":"2024021014185033700_jbmr2598-bib-0040","first-page":"911","author":"Cook","year":"2015"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjbmr.2598","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjbmr.2598","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/31\/1\/86\/56650921\/jbmr2598.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/31\/1\/86\/56650921\/jbmr2598.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T14:54:41Z","timestamp":1710341681000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/31\/1\/86-97\/7605391"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,7,18]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,7,18]]},"published-print":{"date-parts":[[2016,1,1]]}},"URL":"https:\/\/doi.org\/10.1002\/jbmr.2598","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,1,1]]},"published":{"date-parts":[[2015,7,18]]}}}