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Targeted Induction of Endoplasmic Reticulum Stress Induces Cartilage Pathology
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 expande...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757901/ https://www.ncbi.nlm.nih.gov/pubmed/19834559 http://dx.doi.org/10.1371/journal.pgen.1000691 |
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author | Rajpar, M. Helen McDermott, Ben Kung, Louise Eardley, Rachel Knowles, Lynette Heeran, Mel Thornton, David J. Wilson, Richard Bateman, John F. Poulsom, Richard Arvan, Peter Kadler, Karl E. Briggs, Michael D. Boot-Handford, Raymond P. |
author_facet | Rajpar, M. Helen McDermott, Ben Kung, Louise Eardley, Rachel Knowles, Lynette Heeran, Mel Thornton, David J. Wilson, Richard Bateman, John F. Poulsom, Richard Arvan, Peter Kadler, Karl E. Briggs, Michael D. Boot-Handford, Raymond P. |
author_sort | Rajpar, M. Helen |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-2757901 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-27579012009-10-16 Targeted Induction of Endoplasmic Reticulum Stress Induces Cartilage Pathology Rajpar, M. Helen McDermott, Ben Kung, Louise Eardley, Rachel Knowles, Lynette Heeran, Mel Thornton, David J. Wilson, Richard Bateman, John F. Poulsom, Richard Arvan, Peter Kadler, Karl E. Briggs, Michael D. Boot-Handford, Raymond P. PLoS Genet Research Article 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. Public Library of Science 2009-10-16 /pmc/articles/PMC2757901/ /pubmed/19834559 http://dx.doi.org/10.1371/journal.pgen.1000691 Text en Rajpar et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Rajpar, M. Helen McDermott, Ben Kung, Louise Eardley, Rachel Knowles, Lynette Heeran, Mel Thornton, David J. Wilson, Richard Bateman, John F. Poulsom, Richard Arvan, Peter Kadler, Karl E. Briggs, Michael D. Boot-Handford, Raymond P. Targeted Induction of Endoplasmic Reticulum Stress Induces Cartilage Pathology |
title | Targeted Induction of Endoplasmic Reticulum Stress Induces Cartilage Pathology |
title_full | Targeted Induction of Endoplasmic Reticulum Stress Induces Cartilage Pathology |
title_fullStr | Targeted Induction of Endoplasmic Reticulum Stress Induces Cartilage Pathology |
title_full_unstemmed | Targeted Induction of Endoplasmic Reticulum Stress Induces Cartilage Pathology |
title_short | Targeted Induction of Endoplasmic Reticulum Stress Induces Cartilage Pathology |
title_sort | targeted induction of endoplasmic reticulum stress induces cartilage pathology |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757901/ https://www.ncbi.nlm.nih.gov/pubmed/19834559 http://dx.doi.org/10.1371/journal.pgen.1000691 |
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