Targeted induction of endoplasmic reticulum stress induces cartilage pathology.
Targeted induction of endoplasmic reticulum stress induces cartilage pathology.
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DOI：
10.1371/journal.pgen.1000691
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发表时间：
2009-10
期刊：
影响因子：
4.5
通讯作者：
Boot-Handford RP
中科院分区：
文献类型：
--
作者：
Rajpar MH;McDermott B;Kung L;Eardley R;Knowles L;Heeran M;Thornton DJ;Wilson R;Bateman JF;Poulsom R;Arvan P;Kadler KE;Briggs MD;Boot-Handford RP
由细胞外基质蛋白突变引起的病理通常被认为是由细胞外基质合成缺陷引起的。X型胶原蛋白突变导致干骺端软骨发育不良型施密德（MCDS），这是一种以侏儒症和生长板增厚带扩大为特征的疾病。我们建立了mcds致病突变（COL10A1 p.Asn617Lys）的敲入小鼠模型，以研究基因型和表型之间的致病机制。表达胶原X突变的小鼠四肢缩短，肥厚带扩大。肥大带的软骨细胞表现出内质网（ER）应激和由于细胞内突变蛋白的保留而产生的强大的未折叠蛋白反应（UPR）。增生性软骨细胞分化和破骨细胞募集明显减少，表明由于vegf介导的血管侵袭生长板的速率降低，增生性带扩大。为了直接测试内质网应激和UPR在产生MCDS表型中的作用，我们生产了转基因小鼠系，这些小鼠系使用胶原X启动子来驱动肥厚软骨细胞中内质网应激诱导蛋白（甲状腺球蛋白的cog突变体）的表达。该小鼠的增生性软骨细胞表现出内质网应激和典型的UPR反应。此外，肥厚带扩大，基因表达模式被破坏，破骨细胞向血管侵袭前沿募集减少，长骨生长下降。我们的数据表明，在增生性软骨细胞中触发内质网应激本身足以诱导与MCDS相关的软骨病理的基本特征，并证实内质网应激是该疾病机制中的核心致病因素。这些发现支持了内质网应激可能在许多与细胞外基质蛋白突变表达相关的结缔组织疾病的发病机制中起直接作用的观点。细胞外基质蛋白基因的突变通常被认为是由于细胞外基质的缺陷而发挥其致病作用。然而，越来越清楚的是，由于内质网应激的诱导，这种突变也可以在细胞内产生重大影响。X型胶原蛋白的突变导致一种叫做干骺端软骨发育不良型施密德的侏儒症。如前所述，表达突变型X胶原蛋白的基因靶向小鼠模型显示生长板增厚带扩大，细胞内质网应激显著增加。VEGF表达被破坏，导致血管侵袭率降低。为了直接评估内质网应激升高在疾病发病中的作用，我们制备了一种外源性内质网应激诱导蛋白（甲状腺球蛋白- tgcog突变体）靶向增生性软骨细胞的转基因小鼠系。表达Tgcog蛋白的小鼠表现出内质网应激升高、肥厚带扩大和骨生长减少，这表明内质网应激升高和由此产生的UPR是导致这种软骨病理的主要致病机制。有可能，旨在减轻内质网应激的治疗策略可能对这种和其他由细胞外基质基因突变引起的结缔组织疾病有益。
Pathologies caused by mutations in extracellular matrix proteins are generally considered to result from the synthesis of extracellular matrices that are defective. Mutations in type X collagen cause metaphyseal chondrodysplasia type Schmid (MCDS), a disorder characterised by dwarfism and an expanded growth plate hypertrophic zone. We generated a knock-in mouse model of an MCDS–causing mutation (COL10A1 p.Asn617Lys) to investigate pathogenic mechanisms linking genotype and phenotype. Mice expressing the collagen X mutation had shortened limbs and an expanded hypertrophic zone. Chondrocytes in the hypertrophic zone exhibited endoplasmic reticulum (ER) stress and a robust unfolded protein response (UPR) due to intracellular retention of mutant protein. Hypertrophic chondrocyte differentiation and osteoclast recruitment were significantly reduced indicating that the hypertrophic zone was expanded due to a decreased rate of VEGF–mediated vascular invasion of the growth plate. To test directly the role of ER stress and UPR in generating the MCDS phenotype, we produced transgenic mouse lines that used the collagen X promoter to drive expression of an ER stress–inducing protein (the cog mutant of thyroglobulin) in hypertrophic chondrocytes. The hypertrophic chondrocytes in this mouse exhibited ER stress with a characteristic UPR response. In addition, the hypertrophic zone was expanded, gene expression patterns were disrupted, osteoclast recruitment to the vascular invasion front was reduced, and long bone growth decreased. Our data demonstrate that triggering ER stress per se in hypertrophic chondrocytes is sufficient to induce the essential features of the cartilage pathology associated with MCDS and confirm that ER stress is a central pathogenic factor in the disease mechanism. These findings support the contention that ER stress may play a direct role in the pathogenesis of many connective tissue disorders associated with the expression of mutant extracellular matrix proteins. Mutations in genes for extracellular matrix proteins are generally thought to exert their pathogenic effects because of resulting defects in extracellular matrix. However, it is becoming increasingly clear that such mutations can also have significant effects inside the cell due to the induction of ER stress. Mutations in type X collagen cause a dwarfism called metaphyseal chondrodysplasia type Schmid. A gene targeted mouse model expressing mutant type X collagen exhibited an expanded hypertrophic zone of the growth plate and significant increases in cellular ER stress, as noted previously. VEGF expression was disrupted leading to decreases in the rate of vascular invasion. To directly assess the role of elevated ER stress in disease pathogenesis, transgenic mouse lines expressing an exogenous, ER stress–inducing protein (cog mutant of thyroglobulin—Tgcog) targeted to hypertrophic chondrocytes were generated. Mice expressing Tgcog protein showed elevated ER stress, an expanded hypertrophic zone, and reduced bone growth demonstrating that elevated ER stress and the resultant UPR is the principal pathogenic mechanism causing this cartilage pathology. It is possible that therapeutic strategies aimed at alleviating ER stress may be beneficial in this and other connective tissue diseases caused by mutant extracellular matrix genes.
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影响因子：
7.8
作者：
Kwan, KM;Pang, MKM;Zhou, S;Cowan, SK;Kong, RYC;Pfordte, T;Olsen, BR;Sillence, DO;Tam, PPL;Cheah, KSE
通讯作者：
Cheah, KSE
影响因子：
15.8
作者：
Heazlewood CK;Cook MC;Eri R;Price GR;Tauro SB;Taupin D;Thornton DJ;Png CW;Crockford TL;Cornall RJ;Adams R;Kato M;Nelms KA;Hong NA;Florin TH;Goodnow CC;McGuckin MA
通讯作者：
McGuckin MA
影响因子：
3.5
作者：
Gould, Douglas B.;Marchant, Jeffrey K.;John, Simon W. M.
通讯作者：
John, Simon W. M.
影响因子：
3.9
作者：
Bateman, JF;Wilson, R;Savarirayan, R
通讯作者：
Savarirayan, R
影响因子：
3.5
作者：
Ho, Matthew S. P.;Tsang, Kwok Yeung;Chan, Danny
通讯作者：
Chan, Danny