Endoplasmic reticulum stress-unfolding protein response-apoptosis cascade causes chondrodysplasia in a col2a1 p.Gly1170Ser mutated mouse model.
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.
Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Guoyan
G
Liang
Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Chengjie
C
Lian
Department of Breast Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Di
D
Huang
Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Wenjie
W
Gao
Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Anjing
A
Liang
Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Yan
Y
Peng
Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Wei
W
Ye
Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Zizhao
Z
Wu
Department of Orthopedics, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Peiqiang
P
Su
Department of Orthopedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Dongsheng
D
Huang
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D024043:Collagen Type II / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D055879:Gene Knock-In Techniques; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008817:Mice, Mutant Strains; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D023421:Models, Animal; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000503:physiopathology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056811:Unfolded Protein Response / Q000502:physiology*
C447413:Col2a1 protein, mouse; D024043:Collagen Type II; D017931:DNA Primers