Uncoupling of chondrocyte differentiation and perichondrial mineralization underlies the skeletal dysplasia in tricho-rhino-phalangeal syndrome
Uncoupling of chondrocyte differentiation and perichondrial mineralization underlies the skeletal dysplasia in tricho-rhino-phalangeal syndrome
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DOI：
10.1093/hmg/ddn125
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发表时间：
2008-07-15
影响因子：
3.5
通讯作者：
Lee, Brendan
中科院分区：
文献类型：
--
作者：
Napierala, Dobrawa;Sam, Kathy;Lee, Brendan
毛发-鼻-趾骨综合征（TRPS）是一种常染色体显性颅面和骨骼发育不良，由TRPS1基因突变引起。TRPS患者身材矮小，髋关节畸形，锥形骨骺和生长板过早闭合，反映了软骨内骨化的缺陷。TRPS1基因编码转录因子TRPS1，其已被证明在体外抑制转录。为了阐明TRPS骨骼异常的分子机制，我们分析了Trps1突变小鼠（Trps1 Delta GT小鼠）。生长板的分析表明，延迟软骨细胞分化和加速矿化的软骨膜Trps1突变小鼠。这些异常伴随着Runx2和Ihh表达的增加以及印度刺猬信号的增加。我们证明了Trps1与Runx2物理相互作用并抑制Runx2介导的反式激活。重要的是，Trps1（Delta GT/+）; Runx2（+/-）双杂合子小鼠的产生挽救了单突变体的相反生长板表型，证明了Trps1和Runx2转录因子之间的遗传相互作用。总的来说，这些数据表明，TRPS中的骨骼发育不良是由软骨细胞和软骨膜发育失调引起的，部分原因是由于Runx2的Trps1抑制的丧失。
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 (Trps1 Delta GT 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 Trps1(Delta GT/+);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.