Uncoupling of chondrocyte differentiation and perichondrial mineralization underlies the skeletal dysplasia in tricho-rhino-phalangeal syndrome
Open Access
- 17 April 2008
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 17 (14), 2244-2254
- https://doi.org/10.1093/hmg/ddn125
Abstract
Tricho-rhino-phalangeal syndrome (TRPS) is an autosomal dominant craniofacial and skeletal dysplasia that is caused by mutations involving the TRPS1 gene. Patients with TRPS have short stature, hip abnormalities, cone-shaped epiphyses and premature closure of growth plates reflecting defects in endochondral ossification. The TRPS1 gene encodes for the transcription factor TRPS1 that has been demonstrated to repress transcription in vitro. To elucidate the molecular mechanisms underlying skeletal abnormalities in TRPS, we analyzed Trps1 mutant mice (Trps1ΔGT mice). Analyses of growth plates demonstrated delayed chondrocyte differentiation and accelerated mineralization of perichondrium in Trps1 mutant mice. These abnormalities were accompanied by increased Runx2 and Ihh expression and increased Indian hedgehog signaling. We demonstrated that Trps1 physically interacts with Runx2 and represses Runx2-mediated trans-activation. Importantly, generation of Trps1ΔGT/+;Runx2+/− double heterozygous mice rescued the opposite growth plate phenotypes of single mutants, demonstrating the genetic interaction between Trps1 and Runx2 transcription factors. Collectively, these data suggest that skeletal dysplasia in TRPS is caused by dysregulation of chondrocyte and perichondrium development partially due to loss of Trps1 repression of Runx2.Keywords
This publication has 28 references indexed in Scilit:
- Trps1 regulates proliferation and apoptosis of chondrocytes through Stat3 signalingDevelopmental Biology, 2007
- Dominance of SOX9 function over RUNX2 during skeletogenesisProceedings of the National Academy of Sciences of the United States of America, 2006
- Runx2 inhibits chondrocyte proliferation and hypertrophy through its expression in the perichondriumGenes & Development, 2006
- Mutations and promoter SNPs in RUNX2, a transcriptional regulator of bone formationMolecular Genetics and Metabolism, 2005
- Dysregulation of Chondrogenesis in Human Cleidocranial DysplasiaAmerican Journal of Human Genetics, 2005
- Histone Deacetylase 4 Controls Chondrocyte Hypertrophy during SkeletogenesisCell, 2004
- Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehogGenes & Development, 2004
- Type X collagen gene regulation by Runx2 contributes directly to its hypertrophic chondrocyte–specific expression in vivoThe Journal of cell biology, 2003
- Developmental regulation of the growth plateNature, 2003
- Deletion of the GATA Domain of TRPS1 Causes an Absence of Facial Hair and Provides New Insights into the Bone Disorder in Inherited Tricho-Rhino-Phalangeal SyndromesMolecular and Cellular Biology, 2002