Endoplasmic reticulum stress-unfolding protein response-apoptosis cascade causes chondrodysplasia in a col2a1 p.Gly1170Ser mutated mouse model.
Endoplasmic reticulum stress-unfolding protein response-apoptosis cascade causes chondrodysplasia in a col2a1 p.Gly1170Ser mutated mouse model.
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内质网应激-解折叠蛋白反应-细胞凋亡级联导致 col2a1 p.Gly1170Ser 突变小鼠模型软骨发育不良
DOI：
10.1371/journal.pone.0086894
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Huang D
中科院分区：
文献类型：
--
作者：
Liang G;Lian C;Huang D;Gao W;Liang A;Peng Y;Ye W;Wu Z;Su P;Huang D
II 型胶原蛋白 α1 (COL2A1) 突变会导致严重的骨骼畸形，但其发病机制尚不清楚。为了了解这是如何发生的，构建了 col2a1 p.Gly1170Ser 突变小鼠模型，并在纯合子中观察到软骨发育不良表型。错误折叠的原胶原大部分合成并保留在扩张的内质网中，内质网应激（ERS）-未折叠蛋白反应（UPR）-凋亡级联被激活。细胞凋亡发生在肥大之前，阻止肥大区的形成，破坏正常的软骨形成信号通路，并最终引起软骨发育不良。杂合子表型正常，内质网应激强度有限，未检测到异常细胞凋亡。我们的结果表明，早期软骨细胞死亡与 ERS-UPR-凋亡级联有关，这是软骨发育不良的主要原因。 col2a1 p.Gly1170Ser 突变小鼠模型提供了错误折叠胶原蛋白与骨骼畸形之间的新联系。对这种小鼠突变模型的进一步研究可以帮助我们了解 II 型胶原病的机制。
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.
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影响因子：
7
作者：
Arita, M;Li, SW;Fertala, A
通讯作者：
Fertala, A
影响因子：
6.2
作者：
Donahue, LR;Chang, B;Davisson, MT
通讯作者：
Davisson, MT
影响因子：
4
作者：
Hoornaert, KP;Dewinter, C;Mortier, GR
通讯作者：
Mortier, GR
影响因子：
5.5
作者：
Barbieri, O;Astigiano, S;Garofalo, S
通讯作者：
Garofalo, S
DOI：
10.1073/pnas.88.21.9648
发表时间：
1991-11-01
影响因子：
11.1
作者：
GAROFALO, S;VUORIO, E;DECROMBRUGGHE, B
通讯作者：
DECROMBRUGGHE, B