Targeted Induction of Endoplasmic Reticulum Stress Induces Cartilage Pathology

DSpace/Manakin Repository

Targeted Induction of Endoplasmic Reticulum Stress Induces Cartilage Pathology

Show simple item record

dc.contributor.author Rajpar, M. Helen
dc.contributor.author McDermott, Ben
dc.contributor.author Kung, Louise
dc.contributor.author Eardley, Rachel
dc.contributor.author Knowles, Lynette
dc.contributor.author Heeran, Mel
dc.contributor.author Bateman, John F.
dc.contributor.author Poulsom, Richard
dc.contributor.author Arvan, Peter
dc.contributor.author Kadler, Karl E.
dc.contributor.author Briggs, Michael D.
dc.contributor.author Boot-Handford, Raymond P.
dc.contributor.author Thornton, David James
dc.contributor.author Wilson, Richard
dc.date.accessioned 2010-12-21T20:46:37Z
dc.date.issued 2009
dc.identifier.citation Rajpar, M. Helen, Ben McDermott, Louise Kung, Rachel Eardley, Lynette Knowles, Mel Heeran, David J. Thornton, et al. 2009. Targeted Induction of Endoplasmic Reticulum Stress Induces Cartilage Pathology. PLoS Genetics 5(10): e1000691. en_US
dc.identifier.issn 1553-7390 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:4632882
dc.description.abstract 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. en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi:10.1371/journal.pgen.1000691 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757901/pdf/ en_US
dash.license LAA
dc.subject biochemistry en_US
dc.subject genetics and genomics en_US
dc.subject disease models en_US
dc.subject rheumatology en_US
dc.subject cartilage biology and osteoarthritis en_US
dc.subject connective tissue disease en_US
dc.title Targeted Induction of Endoplasmic Reticulum Stress Induces Cartilage Pathology en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS Genetics en_US
dash.depositing.author Thornton, David James
dc.date.available 2010-12-21T20:46:37Z
dash.affiliation.other HMS^Medicine-Brigham and Women's Hospital en_US

Files in this item

Files Size Format View
2757901.pdf 2.513Mb PDF View/Open

This item appears in the following Collection(s)

Show simple item record

 
 

Search DASH


Advanced Search
 
 

Submitters