title: Abnormal chondrocyte apoptosis in the cartilage growth plate is influenced by genetic background and deletion of CHOP in a targeted mouse model of pseudoachondroplasia.
abstract: Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia caused by mutations in cartilage oligomeric matrix protein (COMP) and characterised by short limbed dwarfism and early onset osteoarthritis. Mouse models of PSACH show variable retention of mutant COMP in the ER of chondrocytes, however, in each case a different stress pathway is activated and the underlying disease mechanisms remain largely unknown. T585M COMP mutant mice are a model of moderate PSACH and demonstrate a mild ER stress response. Although mutant COMP is not retained in significant quantities within the ER of chondrocytes, both BiP and the pro-apoptotic ER stress-related transcription factor CHOP are mildly elevated, whilst bcl-2 levels are decreased, resulting in increased and spatially dysregulated chondrocyte apoptosis. To determine whether the abnormal chondrocyte apoptosis observed in the growth plate of mutant mice is CHOP-mediated, we bred T585M COMP mutant mice with CHOP-null mice to homozygosity, and analysed the resulting phenotype. Although abnormal apoptosis was alleviated in the resting zone following CHOP deletion, the mutant growth plates were generally more disorganised. Furthermore, the bone lengths of COMP mutant CHOP null mice were significantly shorter at 9 weeks of age when compared to the COMP mutant mice, including a significant difference in the skull length. Overall, these data demonstrate that CHOP-mediated apoptosis is an early event in the pathobiology of PSACH and suggest that the lack of CHOP, in conjunction with a COMP mutation, may lead to aggravation of the skeletal phenotype via a potentially synergistic effect on endochondral ossification.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom.
authors.forename: Katarzyna A
authors.initials: KA
authors.lastname: Piróg
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, United Kingdom.
authors.forename: Andreja
authors.initials: A
authors.lastname: Irman
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, United Kingdom.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Young
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, United Kingdom.
authors.forename: Poonam
authors.initials: P
authors.lastname: Halai
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Bell
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, United Kingdom.
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Boot-Handford
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Briggs
mesh_terms: D000130:Achondroplasia / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D001842:Bone and Bones / Q000473:pathology; D002356:Cartilage / Q000473:pathology*; D049109:Cell Proliferation; D019902:Chondrocytes / Q000166:cytology*; D004195:Disease Models, Animal; D006132:Growth Plate / Q000378:metabolism; D006720:Homozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009154:Mutation; D010641:Phenotype; D051742:Transcription Factor CHOP / Q000235:genetics*; D014989:Xiphoid Bone / Q000473:pathology
chemical_list: C497250:Ddit3 protein, mouse; D051742:Transcription Factor CHOP