title: Hypertrophic chondrocytes have a limited capacity to cope with increases in endoplasmic reticulum stress without triggering the unfolded protein response.
abstract: Mutations causing metaphyseal chondrodysplasia type Schmid (MCDS) (e.g., Col10a1p.N617K) induce the pathology by a mechanism involving increased endoplasmic reticulum (ER) stress triggering an unfolded protein response (UPR) in hypertrophic chondrocytes (Rajpar et al. 2009). Here we correlate the expression of mutant protein with the onset of the UPR and disease pathology (hypertrophic zone [HZ] expansion) in MCDS and ColXTg(cog) mouse lines from E14.5 to E17.5. Embryos homozygous for the Col10a1p.N617K mutation displayed a delayed secretion of mutant collagen X accompanied by a UPR at E14.5, delayed ossification of the primary center at E15.5, and an expanded HZ at E17.5. Heterozygote embryos expressed mutant collagen X from E14.5 but exhibited no evidence of a UPR or an HZ expansion until after E17.5. Embryos positive for the ER stress-inducing ColXTg(cog) allele expressed Tg(cog) at E14.5, but the onset of the UPR was not apparent until E15.5 in homozygous and E17.5 in hemizygous embryos. Only homozygous embryos exhibited an HZ expansion at E17.5. The differential onset of the UPR and pathology, dependent on mutation type and gene dosage, indicates that hypertrophic chondrocytes have a latent capacity to deal with ER stress, which must be exceeded to trigger the UPR and HZ expansion.
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom.
authors.forename: Louise H W
authors.initials: LH
authors.lastname: Kung
authors.forename: M Helen
authors.initials: MH
authors.lastname: Rajpar
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; D048429:Cell Size; D019902:Chondrocytes / Q000166:cytology / Q000502:physiology*; D024121:Collagen Type X / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D018628:Gene Dosage; D006132:Growth Plate / Q000196:embryology / Q000378:metabolism; D057898:Hemizygote; D006720:Homozygote; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000502:physiology; D010012:Osteogenesis; D019076:Transgenes; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: C570620:Col10a1 protein, mouse; D024121:Collagen Type X