title: Loss of matrilin 1 does not exacerbate the skeletal phenotype in a mouse model of multiple epiphyseal dysplasia caused by a Matn3 V194D mutation.
abstract: OBJECTIVE
  Mutations in matrilin 3 can result in multiple epiphyseal dysplasia (MED), a disease characterized by delayed and irregular bone growth and early-onset osteoarthritis. Although intracellular retention of the majority of mutant matrilin 3 was previously observed in a murine model of MED caused by a Matn3 V194D mutation, some mutant protein was secreted into the extracellular matrix. Thus, it was proposed that secretion of mutant matrilin 3 may be dependent on the formation of hetero-oligomers with matrilin 1. The aim of this study was to investigate the hypothesis that deletion of matrilin 1 would abolish the formation of matrilin 1/matrilin 3 hetero-oligomers, eliminate the secretion of mutant matrilin 3, and influence disease severity.
  
  
  METHODS
  Mice with a Matn3 V194D mutation were crossed with Matn1-null mice, generating mice that were homozygous for V194D and null for matrilin 1. This novel mouse was used for in-depth phenotyping, while cartilage and chondrocytes were studied both histochemically and biochemically.
  
  
  RESULTS
  Endochondral ossification was not disrupted any further in mice with a double V194D mutation compared with mice with a single mutation. A similar proportion of mutant matrilin 3 was present in the extracellular matrix, and the amount of retained mutant matrilin 3 was not noticeably increased. Retained mutant matrilin 3 formed disulfide-bonded aggregates and caused the co-retention of matrilin 1.
  
  
  CONCLUSIONS
  We showed that secretion of matrilin 3 V194D mutant protein is not dependent on hetero-oligomerization with matrilin 1, and that the total ablation of matrilin 1 expression has no impact on disease severity in mice with MED. Mutant matrilin 3 oligomers form non-native disulfide-bonded aggregates through the misfolded A domain.
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Bell
authors.forename: Katarzyna A
authors.initials: KA
authors.lastname: Piróg
authors.forename: Maryline
authors.initials: M
authors.lastname: Fresquet
authors.forename: David J
authors.initials: DJ
authors.lastname: Thornton
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; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D002356:Cartilage / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D019281:Dimerization; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006023:Glycoproteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006132:Growth Plate / Q000378:metabolism / Q000473:pathology; D008297:Male; D064235:Matrilin Proteins; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D011859:Radiography
chemical_list: D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C577540:Matn1 protein, mouse; C577546:Matn3 protein, mouse; D064235:Matrilin Proteins
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