Endoplasmic reticulum stress-unfolding protein response-apoptosis cascade causes chondrodysplasia in a col2a1 p.Gly1170Ser mutated mouse model

PLoS One. 2014 Jan 27;9(1):e86894. doi: 10.1371/journal.pone.0086894. eCollection 2014.

Abstract

The collagen type II alpha 1 (COL2A1) mutation causes severe skeletal malformations, but the pathogenic mechanisms of how this occurs are unclear. To understand how this may happen, a col2a1 p.Gly1170Ser mutated mouse model was constructed and in homozygotes, the chondrodysplasia phenotype was observed. Misfolded procollagen was largely synthesized and retained in dilated endoplasmic reticulum and the endoplasmic reticulum stress (ERS)-unfolded protein response (UPR)-apoptosis cascade was activated. Apoptosis occurred prior to hypertrophy, prevented the formation of a hypertrophic zone, disrupted normal chondrogenic signaling pathways, and eventually caused chondrodysplasia. Heterozygotes had normal phenotypes and endoplasmic reticulum stress intensity was limited with no abnormal apoptosis detected. Our results suggest that earlier chondrocyte death was related to the ERS-UPR-apoptosis cascade and that this was the chief cause of chondrodysplaia. The col2a1 p.Gly1170Ser mutated mouse model offered a novel connection between misfolded collagen and skeletal malformation. Further investigation of this mouse mutant model can help us understand mechanisms of type II collagenopathies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Apoptosis / physiology*
  • Collagen Type II / genetics*
  • DNA Primers / genetics
  • Endoplasmic Reticulum Stress / physiology*
  • Gene Knock-In Techniques
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Mice
  • Mice, Mutant Strains
  • Microscopy, Electron, Transmission
  • Microscopy, Fluorescence
  • Models, Animal*
  • Osteochondrodysplasias / genetics*
  • Osteochondrodysplasias / physiopathology
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Unfolded Protein Response / physiology*

Substances

  • Col2a1 protein, mouse
  • Collagen Type II
  • DNA Primers

Grants and funding

This work was supported by the National Natural Science Foundation of China (No. 81371907, No. 30971587 and No. 81071703), the Fundamental Research Funds for the Central Universities (No. 11ykzd10), and the Science Foundation of Guangdong Province (2010B031600224). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.