title: An unfolded protein response is the initial cellular response to the expression of mutant matrilin-3 in a mouse model of multiple epiphyseal dysplasia.
abstract: Multiple epiphyseal dysplasia (MED) can result from mutations in matrilin-3, a structural protein of the cartilage extracellular matrix. We have previously shown that in a mouse model of MED the tibia growth plates were normal at birth but developed a progressive dysplasia characterised by the intracellular retention of mutant matrilin-3 and abnormal chondrocyte morphology. By 3 weeks of age, mutant mice displayed a significant decrease in chondrocyte proliferation and dysregulated apoptosis. The aim of this current study was to identify the initial post-natal stages of the disease. We confirmed that the disease phenotype is seen in rib and xiphoid cartilage and, like tibia growth plate cartilage is characterised by the intracellular retention of mutant matrilin-3. Gene expression profiling showed a significant activation of classical unfolded protein response (UPR) genes in mutant chondrocytes at 5 days of age, which was still maintained by 21 days of age. Interestingly, we also noted the upregulation of arginine-rich, mutated in early stage of tumours (ARMET) and cysteine-rich with EGF-like domain protein 2 (CRELD2) are two genes that have only recently been implicated in the UPR. This endoplasmic reticulum (ER) stress and UPR did not lead to increased chondrocyte apoptosis in mutant cartilage by 5 days of age. In an attempt to alleviate ER stress, mutant mice were fed with a chemical chaperone, 4-sodium phenylbutyrate (SPB). SPB at the dosage used had no effect on chaperone expression at 5 days of age but modestly decreased levels of chaperone proteins at 3 weeks. However, this did not lead to increased secretion of mutant matrilin-3 and in the long term did not improve the disease phenotype. We performed similar studies with a mouse model of Schmid metaphyseal chondrodysplasia, but again this treatment did not improve the phenotype.
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: Seema
authors.initials: S
authors.lastname: Nundlall
authors.forename: M Helen
authors.initials: MH
authors.lastname: Rajpar
authors.forename: Peter A
authors.initials: PA
authors.lastname: Bell
authors.forename: Christopher
authors.initials: C
authors.lastname: Clowes
authors.forename: Leo A H
authors.initials: LA
authors.lastname: Zeeff
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gardner
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; D002356:Cartilage / Q000473:pathology / Q000648:ultrastructure; D019902:Chondrocytes / Q000378:metabolism; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D064235:Matrilin Proteins; D051379:Mice; D009154:Mutation; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D010009:Osteochondrodysplasias / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D010654:Phenylbutyrates / Q000494:pharmacology; D012272:Ribs / Q000166:cytology; D013997:Time Factors; D056811:Unfolded Protein Response; D015854:Up-Regulation
chemical_list: D016326:Extracellular Matrix Proteins; C577546:Matn3 protein, mouse; D064235:Matrilin Proteins; D009414:Nerve Growth Factors; D010654:Phenylbutyrates; C522218:cdnf protein, mouse