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Am J Physiol Cell Physiol (August 13, 2003). doi:10.1152/ajpcell.00579.2002
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Submitted on December 12, 2002
Accepted on August 8, 2003

Depletion of Cartilage Collagen Fibrils In Mice Carrying A Dominant-Negative Col2a1 Transgene Affects Chondrocyte Differentiation

Ottavia Barbieri1, Simonetta Astigiano2, Monica Morini3, Sara Tavella3, Anna Schito3, Alessandro Corsi4, Davide Di Martino3, Paolo Bianco5, Ranieri Cancedda1, and Silvio Garofalo1*

1 Department of Oncology, Biology and Genetics, University of Genoa Medical School, Genoa, Italy; Regenerative Medicine, National Cancer Research Institute, Genoa, Italy
2 Regenerative Medicine, National Cancer Research Institute, Genoa, Italy
3 Department of Oncology, Biology and Genetics, University of Genoa Medical School, Genoa, Italy
4 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy; Parco Scientifico Biomedico San Raffaele, University of Rome "La Sapienza", Rome, Italy
5 ; Parco Scientifico Biomedico San Raffaele, University of Rome "La Sapienza", Rome, Italy

* To whom correspondence should be addressed. E-mail: garofalo{at}cba.unige.it.

We have generated transgenic mice harboring the deletion of exon 48 in the mouse alpha 1(II) procollagen gene (Col2a1). This was the first dominant-negative mutation identified in the human alpha 1(II) procollagen gene (COL2A1). Patients carrying a single allele with this mutation suffer of a severe skeletal disorder named Spondylo-Epiphyseal Dysplasia (SED) Congenita. 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 show 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 this defect partecipates to the reduced endochondral bone growth observed in chondrodysplasias caused by mutations in COL2A1.




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