Targeted Induction of Endoplasmic Reticulum Stress Induces Cartilage Pathology

被引：128

作者：

Rajpar, M. Helen ^{[1
]}

McDermott, Ben ^{[1
]}

Kung, Louise ^{[1
]}

Eardley, Rachel ^{[1
]}

Knowles, Lynette ^{[1
]}

Heeran, Mel ^{[1
]}

Thornton, David J. ^{[1
]}

Wilson, Richard ^{[2
]}

Bateman, John F. ^{[2
]}

Poulsom, Richard ^{[3
]}

Arvan, Peter ^{[4
]}

Kadler, Karl E. ^{[1
]}

Briggs, Michael D. ^{[1
]}

Boot-Handford, Raymond P. ^{[1
]}

机构：

[1] Univ Manchester, Fac Life Sci, Wellcome Trust Ctr Cell Matrix Res, Manchester, Lancs, England

[2] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia

[3] London Res Inst, Canc Res UK, Histopathol Unit, London, England

[4] Univ Michigan, Sch Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI USA

来源：

PLOS GENETICS | 2009年 / 5卷 / 10期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

GROWTH-FACTOR VEGF; METAPHYSEAL CHONDRODYSPLASIA; ER STRESS; EPIPHYSEAL DYSPLASIA; TERMINAL DOMAIN; MURINE MODEL; MOUSE MODEL; MUTATIONS; EXPRESSION; BONE;

D O I：

10.1371/journal.pgen.1000691

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

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.

引用

页数：15

共 52 条

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