title: Targeted induction of endoplasmic reticulum stress induces cartilage pathology.
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.
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom.
authors.forename: M Helen
authors.initials: MH
authors.lastname: Rajpar
authors.forename: Ben
authors.initials: B
authors.lastname: McDermott
authors.forename: Louise
authors.initials: L
authors.lastname: Kung
authors.forename: Rachel
authors.initials: R
authors.lastname: Eardley
authors.forename: Lynette
authors.initials: L
authors.lastname: Knowles
authors.forename: Mel
authors.initials: M
authors.lastname: Heeran
authors.forename: David J
authors.initials: DJ
authors.lastname: Thornton
authors.forename: Richard
authors.initials: R
authors.lastname: Wilson
authors.forename: John F
authors.initials: JF
authors.lastname: Bateman
authors.forename: Richard
authors.initials: R
authors.lastname: Poulsom
authors.forename: Peter
authors.initials: P
authors.lastname: Arvan
authors.forename: Karl E
authors.initials: KE
authors.lastname: Kadler
authors.forename: Michael D
authors.initials: MD
authors.lastname: Briggs
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Boot-Handford
mesh_terms: D000818:Animals; D001483:Base Sequence; D002356:Cartilage / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D002806:Chondrodysplasia Punctata / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D024121:Collagen Type X / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D051379:Mice; D013312:Stress, Physiological; D056811:Unfolded Protein Response; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D024121:Collagen Type X; D042461:Vascular Endothelial Growth Factor A