title: Decreased chondrocyte proliferation and dysregulated apoptosis in the cartilage growth plate are key features of a murine model of epiphyseal dysplasia caused by a matn3 mutation.
abstract: Disruption to endochondral ossification leads to delayed and irregular bone formation and can result in a heterogeneous group of genetic disorders known as the chondrodysplasias. One such disorder, multiple epiphyseal dysplasia (MED), is characterized by mild dwarfism and early-onset osteoarthritis and can result from mutations in the gene encoding matrilin-3 (MATN3). To determine the disease mechanisms that underpin the pathophysiology of MED we generated a murine model of epiphyseal dysplasia by knocking-in a matn3 mutation. Mice that are homozygous for the mutation develop a progressive dysplasia and have short-limbed dwarfism that is consistent in severity with the relevant human phenotype. Mutant matrilin-3 is retained within the rough endoplasmic reticulum of chondrocytes and is associated with an unfolded protein response. Eventually, there is reduced proliferation and spatially dysregulated apoptosis of chondrocytes in the cartilage growth plate, which is likely to be the cause of disrupted linear bone growth and the resulting short-limbed dwarfism in the mutant mice.
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Leighton
authors.forename: Seema
authors.initials: S
authors.lastname: Nundlall
authors.forename: Tobias
authors.initials: T
authors.lastname: Starborg
authors.forename: Roger S
authors.initials: RS
authors.lastname: Meadows
authors.forename: Farhana
authors.initials: F
authors.lastname: Suleman
authors.forename: Lynette
authors.initials: L
authors.lastname: Knowles
authors.forename: Raimund
authors.initials: R
authors.lastname: Wagener
authors.forename: David J
authors.initials: DJ
authors.lastname: Thornton
authors.forename: Karl E
authors.initials: KE
authors.lastname: Kadler
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Boot-Handford
authors.forename: Michael D
authors.initials: MD
authors.lastname: Briggs
mesh_terms: D000818:Animals; D017209:Apoptosis; D002356:Cartilage / Q000378:metabolism*; D049109:Cell Proliferation; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000502:physiology*; D064235:Matrilin Proteins; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D018832:Molecular Chaperones / Q000378:metabolism; D009154:Mutation; D010009:Osteochondrodysplasias / Q000378:metabolism*
chemical_list: D016326:Extracellular Matrix Proteins; C577546:Matn3 protein, mouse; D064235:Matrilin Proteins; D018832:Molecular Chaperones