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Rmrp Mutation Disrupts Chondrogenesis and Bone Ossification in Zebrafish Model of Cartilage-Hair Hypoplasia via Enhanced Wnt/β-Catenin Signaling.

Authors
  • Sun, Xianding1
  • Zhang, Ruobin1
  • Liu, Mi1
  • Chen, Hangang1
  • Chen, Liang1
  • Luo, Fengtao1
  • Zhang, Dali1
  • Huang, Junlan1
  • Li, Fangfang1
  • Ni, Zhenhong1
  • Qi, Huabing1
  • Su, Nan1
  • Jin, Min1
  • Yang, Jing1
  • Tan, Qiaoyan1
  • Du, Xiaolan1
  • Chen, Bo1
  • Huang, Haiyang1
  • Chen, Shuai1
  • Yin, Liangjun2
  • And 5 more
  • 1 Laboratory of Wound Repair and Rehabilitation, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China. , (China)
  • 2 Department of Orthopedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China. , (China)
  • 3 Faculty of Health Sciences, University of Macau, Macau SAR, China. , (China)
  • 4 Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Beibei, Chongqing, 400715, China. , (China)
Type
Published Article
Journal
Journal of Bone and Mineral Research
Publisher
Wiley (John Wiley & Sons)
Publication Date
Nov 01, 2019
Volume
34
Issue
11
Pages
2101–2116
Identifiers
DOI: 10.1002/jbmr.3820
PMID: 31237961
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. © 2019 American Society for Bone and Mineral Research.

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