title: Depletion of cartilage collagen fibrils in mice carrying a dominant negative Col2a1 transgene affects chondrocyte differentiation.
abstract: We have generated transgenic mice harboring the deletion of exon 48 in the mouse alpha1(II) procollagen gene (Col2a1). This was the first dominant negative mutation identified in the human alpha1(II) procollagen gene (COL2A1). Patients carrying a single allele with this mutation suffer from a severe skeletal disorder called spondyloepiphyseal dysplasia congenita (SED). Transgenic mice phenotype was neonatally lethal with severe respiratory failure, short bones, and cleft palate. Transgene mRNA was expressed at high levels. Growth plate cartilage of transgenic mice presented morphological abnormalities and reduced number of collagen type II fibrils. Chondrocytes carrying the mutation showed altered expression of several differentiation markers, like fibroblast growth factor receptor 3 (Fgfr3), Indian hedgehog (Ihh), runx2, cyclin-dependent kinase inhibitor P21CIP/WAF (Cdkn1a), and collagen type X (Col10a1), suggesting that a defective extracellular matrix (ECM) depleted of collagen fibrils affects chondrocytes differentiation and that this defect participates in the reduced endochondral bone growth observed in chondrodysplasias caused by mutations in COL2A1.
authors.affiliation: Università di Genova, Centro Biotecnologie Avanzate (Rm. C305 Largo Rosanna Benzi n.10, 16132 Genova, Italy.
authors.forename: Ottavia
authors.initials: O
authors.lastname: Barbieri
authors.forename: Simonetta
authors.initials: S
authors.lastname: Astigiano
authors.forename: Monica
authors.initials: M
authors.lastname: Morini
authors.forename: Sara
authors.initials: S
authors.lastname: Tavella
authors.forename: Anna
authors.initials: A
authors.lastname: Schito
authors.forename: Alessandro
authors.initials: A
authors.lastname: Corsi
authors.forename: Davide
authors.initials: D
authors.lastname: Di Martino
authors.forename: Paolo
authors.initials: P
authors.lastname: Bianco
authors.forename: Ranieri
authors.initials: R
authors.lastname: Cancedda
authors.forename: Silvio
authors.initials: S
authors.lastname: Garofalo
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000473:pathology / Q000648:ultrastructure; D002356:Cartilage / Q000737:chemistry / Q000254:growth & development / Q000473:pathology* / Q000648:ultrastructure; D002454:Cell Differentiation; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure*; D024043:Collagen Type II / Q000172:deficiency / Q000235:genetics*; D005109:Extracellular Matrix / Q000473:pathology* / Q000648:ultrastructure; D017353:Gene Deletion; D005799:Genes, Dominant; D006132:Growth Plate / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D010012:Osteogenesis / Q000502:physiology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D019076:Transgenes
chemical_list: C499177:COL2A1 protein, human; C447413:Col2a1 protein, mouse; D024043:Collagen Type II; D012333:RNA, Messenger