Rmrp Mutation Disrupts Chondrogenesis and Bone Ossification in Zebrafish Model of Cartilage‐Hair Hypoplasia via Enhanced Wnt/β‐Catenin Signaling
Rmrp Mutation Disrupts Chondrogenesis and Bone Ossification in Zebrafish Model of Cartilage‐Hair Hypoplasia via Enhanced Wnt/β‐Catenin Signaling
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DOI：
10.1002/jbmr.3820
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发表时间：
2019-11
影响因子：
6.2
通讯作者：
Xianding Sun;Ruobin Zhang;Mi Liu;Hangang Chen;Liang Chen;F. Luo;Dali Zhang;Junlan Huang;Fangfang Li;Z. Ni;H. Qi;N. Su;M. Jin;Jing Yang;Q. Tan;Xiaolan Du;Bo Chen;Haiyang Huang;Shuai Chen;L. Yin;Xiaoling Xu;C. Deng;L. Luo;Yangli Xie;Lin Chen
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文献类型：
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作者：
Xianding Sun;Ruobin Zhang;Mi Liu;Hangang Chen;Liang Chen;F. Luo;Dali Zhang;Junlan Huang;Fangfang Li;Z. Ni;H. Qi;N. Su;M. Jin;Jing Yang;Q. Tan;Xiaolan Du;Bo Chen;Haiyang Huang;Shuai Chen;L. Yin;Xiaoling Xu;C. Deng;L. Luo;Yangli Xie;Lin Chen
腕毛发育不全（CHH）是一种常染色体隐性遗传的干骺端软骨发育不良，以骨发育不良和许多其他高度可变的特征为特征。负责CHH的基因是线粒体RNA加工核糖核酸内切酶（RMRP）基因的RNA组分。目前，CHH患者骨软骨发育不良和骨外表现的发病机制仍不完全清楚;此外，没有可行的CHH动物模型。我们建立了一个rmrp基因敲除的斑马鱼模型来研究CHH的发育机制。我们发现rmrp是咽弓形成和成形所必需的。Rmrp突变抑制颅骨膜内骨化，促进椎骨骨化。软骨内骨化的异常是可变的，取决于软骨发生失调的程度。此外，rmrp突变通过细胞周期和凋亡相关基因的表达失调抑制细胞增殖并促进凋亡。我们还证明，rmrp突变上调经典Wnt/β-catenin信号传导; Wnt/β-catenin的药理学抑制可以部分缓解rmrp突变体中的软骨发育不良和增加的椎骨矿化。本研究通过建立一种新的斑马鱼CHH模型，部分揭示了CHH的潜在机制，从而加深了我们对rmrp在骨骼发育中作用的理解。
Cartilage‐hair hypoplasia (CHH) is an autosomal recessive metaphyseal chondrodysplasia characterized by bone dysplasia and many other highly variable features. The gene responsible for CHH is the RNA component of the mitochondrial RNA‐processing endoribonuclease (RMRP) gene. Currently, the pathogenesis of osteochondrodysplasia and extraskeletal manifestations in CHH patients remains incompletely understood; in addition, there are no viable animal models for CHH. We generated an rmrp KO zebrafish model to study the developmental mechanisms of CHH. We found that rmrp is required for the patterning and shaping of pharyngeal arches. Rmrp mutation inhibits the intramembranous ossification of skull bones and promotes vertebrae ossification. The abnormalities of endochondral bone ossification are variable, depending on the degree of dysregulated chondrogenesis. Moreover, rmrp mutation inhibits cell proliferation and promotes apoptosis through dysregulating the expressions of cell‐cycle‐ and apoptosis‐related genes. We also demonstrate that rmrp mutation upregulates canonical Wnt/β‐catenin signaling; the pharmacological inhibition of Wnt/β‐catenin could partially alleviate the chondrodysplasia and increased vertebrae mineralization in rmrp mutants. Our study, by establishing a novel zebrafish model for CHH, partially reveals the underlying mechanism of CHH, hence deepening our understanding of the role of rmrp in skeleton development.