title: Dysregulated TGF-β signaling alters bone microstructure in a mouse model of Loeys-Dietz syndrome.
abstract: Loeys-Dietz 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-β (TGF-β) type 1 and type 2 receptors. In this study, we characterized the skeletal phenotype of mice carrying a mutation in the TGF-β 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-labeled mice showed decreased mineral apposition rates in cortical and trabecular bone with normal numbers of osteoblasts and osteoclasts. Mechanical testing of femurs by three-point 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-β1-induced Smad2 and Erk1/2 phosphorylation and upregulated TGF-β1 ligand mRNA expression, compatible with G357W as a loss-of-function mutation in the TGF-β type 2 receptor. Paradoxically, phosphorylated Smad2/3 in cortical osteocytes measured by immunohistochemistry was increased relative to controls, possibly suggesting the cross-activation of TGF-β-related 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-β receptor signaling in bone.
authors.affiliation: Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Ashvin K
authors.initials: AK
authors.lastname: Dewan
authors.affiliation: Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Tomlinson
authors.affiliation: Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Stuart
authors.initials: S
authors.lastname: Mitchell
authors.affiliation: Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Goh
authors.affiliation: Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Yung
authors.affiliation: Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Sarvesh
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Tan
authors.affiliation: Division of Nephrology, University of Kentucky, Lexington, Kentucky.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Faugere
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
authors.affiliation: Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Baltimore Veterans Administration Medical Center, Baltimore, Maryland.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Clemens
authors.affiliation: Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Sponseller
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000473:pathology*; D002113:Calcification, Physiologic / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D055947:Loeys-Dietz Syndrome / Q000378:metabolism* / Q000473:pathology; D010006:Osteoblasts / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: Loeys-Dietz syndrome; TGF-β; bone