Dysregulated TGF-β signaling alters bone microstructure in a mouse model of Loeys-Dietz syndrome

Ashvin K. Dewan, Ryan E. Tomlinson, Stuart Mitchell, Brian C. Goh, Rachel M. Yung, Sarvesh Kumar, Eric W. Tan, Marie Claude Faugere, Harry C. Dietz, Thomas L. Clemens, Paul D. Sponseller

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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.

Original languageEnglish
Pages (from-to)1447-1454
Number of pages8
JournalJournal of Orthopaedic Research
Issue number10
StatePublished - Oct 1 2015

Bibliographical note

Publisher Copyright:
© 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.


  • Loeys-Dietz syndrome
  • TGF-β
  • bone

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine


Dive into the research topics of 'Dysregulated TGF-β signaling alters bone microstructure in a mouse model of Loeys-Dietz syndrome'. Together they form a unique fingerprint.

Cite this