{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T13:19:01Z","timestamp":1790255941896,"version":"4.1.0"},"reference-count":35,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2015,7,14]],"date-time":"2015-07-14T00:00:00Z","timestamp":1436832000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["AR049410"],"award-info":[{"award-number":["AR049410"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["AR057868"],"award-info":[{"award-number":["AR057868"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Merit Review grant","award":["BX001234"],"award-info":[{"award-number":["BX001234"]}]},{"DOI":"10.13039\/100000738","name":"US Department of Veterans Affairs","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal Orthopaedic Research"],"published-print":{"date-parts":[[2015,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:label\/><jats:p>Loeys\u2010Dietz syndrome (LDS) is a connective tissue disorder characterized by vascular and skeletal abnormalities resembling Marfan syndrome, including a predisposition for pathologic fracture. LDS is caused by heterozygous mutations in the genes encoding transforming growth factor\u2010\u03b2 (TGF\u2010\u03b2) type 1 and type 2 receptors. In this study, we characterized the skeletal phenotype of mice carrying a mutation in the TGF\u2010\u03b2 type 2 receptor associated with severe LDS in humans. Cortical bone in LDS mice showed significantly reduced tissue area, bone area, and cortical thickness with increased eccentricity. However, no significant differences in trabecular bone volume were observed. Dynamic histomorphometry performed in calcein\u2010labeled mice showed decreased mineral apposition rates in cortical and trabecular bone with normal numbers of osteoblasts and osteoclasts. Mechanical testing of femurs by three\u2010point bending revealed reduced femoral strength and fracture resistance. In vitro, osteoblasts from LDS mice demonstrated increased mineralization with enhanced expression of osteoblast differentiation markers compared with control cells. These changes were associated with impaired TGF\u2010\u03b21\u2013induced Smad2 and Erk1\/2 phosphorylation and upregulated TGF\u2010\u03b21 ligand mRNA expression, compatible with G357W as a loss\u2010of\u2010function mutation in the TGF\u2010\u03b2 type 2 receptor. Paradoxically, phosphorylated Smad2\/3 in cortical osteocytes measured by immunohistochemistry was increased relative to controls, possibly suggesting the cross\u2010activation of TGF\u2010\u03b2\u2013related receptors. The skeletal phenotype observed in the LDS mouse closely resembles the principal structural features of bone in humans with LDS and establishes this mouse as a valid in vivo model for further investigation of TGF\u2010\u03b2 receptor signaling in bone. \u00a9 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1447\u20131454, 2015.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jor.22920","type":"journal-article","created":{"date-parts":[[2015,7,15]],"date-time":"2015-07-15T00:28:33Z","timestamp":1436920113000},"page":"1447-1454","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Dysregulated TGF\u2010\u03b2 signaling alters bone microstructure in a mouse model of Loeys\u2010Dietz syndrome"],"prefix":"10.1002","volume":"33","author":[{"given":"Ashvin K.","family":"Dewan","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery The Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan E.","family":"Tomlinson","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery The Johns Hopkins University School of Medicine Baltimore 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