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This Article Full Text Full Text (PDF) All Versions of this Article: 285/6/C1504    most recent 00579.2002v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Barbieri, O. Articles by Garofalo, S. Search for Related Content PubMed PubMed Citation Articles by Barbieri, O. Articles by Garofalo, S.

GROWTH, DIFFERENTIATION, AND APOPTOSIS

Depletion of cartilage collagen fibrils in mice carrying a dominant negative Col2a1 transgene affects chondrocyte differentiation

¹Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa; ²Dipartimento di Oncologia, Biologia e Genetica, Università di Genova, 16132 Genoa; ³Dipartimento di Medicina Sperimentale, Università dell'Aquila, 67010 Cappito di L'Aquila; ⁴Dipartimento di Medicina Sperimentale e Patologia, Università di Roma La Sapienza, and Parco Scientifico Biomedico San Raffaele, 00161 Rome, Italy

Submitted 12 December 2002 ; accepted in final form 8 August 2003

We have generated transgenic mice harboring the deletion of exon 48 in the mouse 1(II) procollagen gene (Col2a1). This was the first dominant negative mutation identified in the human 1(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 P21^CIP/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.

skeletal dyplasias; growth plate; cartilage extracellular matrix; spondyloepiphyseal dysplasia congenita

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