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Published online 30 June 2003. doi:10.1083/jcb.200302066
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© The Rockefeller University Press, 0021-9525/2003/7/139 $5.00
The Journal of Cell Biology, Volume 162, Number 1, 139-148

Article

Reduced chondrocyte proliferation and chondrodysplasia in mice lacking the integrin-linked kinase in chondrocytes



Leonieke Terpstra1, Josée Prud'homme1, Alice Arabian1, Shu Takeda2, Gérard Karsenty2, Shoukat Dedhar3,4 and René St-Arnaud1,5

1 Genetics Unit, Shriners Hospital for Children, Montréal, Québec, Canada H3G 1A6
2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030
3 British Columbia Cancer Agency and Vancouver Hospital, Jack Bell Research Center, Vancouver, British Columbia, Canada V6H 3Z6
4 Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3
5 Department of Surgery and Department of Human Genetics, McGill University, Montréal, Québec, Canada H3A 2T5

Address correspondence to René St-Arnaud, Genetics Unit, Shriners Hospital for Children, 1529 Cedar Ave., Montréal, Québec, Canada H3G 1A6. Tel.: (514) 282-7155. Fax: (514) 842-5581. E-mail: rst-arnaud{at}shriners.mcgill.ca

Chondrocyte proliferation and differentiation requires their attachment to the collagen type II–rich matrix of developing bone. This interaction is mediated by integrins and their cytoplasmic effectors, such as the integrin-linked kinase (ILK). To elucidate the molecular mechanisms whereby integrins control these processes, we have specifically inactivated the ILK gene in growth plate chondrocytes using the Cre-lox methodology. Mice carrying an ILK allele flanked by loxP sites (ILK-fl) were crossed to transgenic mice expressing the Cre recombinase under the control of the collagen type II promoter. Inactivation of both copies of the ILK-fl allele lead to a chondrodysplasia characterized by a disorganized growth plate and to dwarfism. Expression of chondrocyte differentiation markers such as collagen type II, collagen type X, Indian hedgehog and the PTH-PTHrP receptor was normal in ILK-deficient growth plates. In contrast, chondrocyte proliferation, assessed by BrdU or proliferating cell nuclear antigen labeling, was markedly reduced in the mutant growth plates. Cell-based assays showed that integrin-mediated adhesion of primary cultures of chondrocytes from mutant animals to collagen type II was impaired. ILK inactivation in chondrocytes resulted in reduced cyclin D1 expression, and this most likely explains the defect in chondrocyte proliferation observed when ILK is inactivated in growth plate cells.

Key Words: integrin-linked kinase; chondrocytes; Cre-lox; cyclin D1; gene targeting

L. Terpstra's present address is Dept. of Pediatric Endocrinology, Vrije Universiteit University Hospital, 1007 MB Amsterdam, Netherlands.

* Abbreviations used in this paper: Col2-Cre, collagen type II gene promoter driving Cre recombinase transgene; CREB, cyclic AMP response element binding protein; DMEM, Dulbecco's Minimal Essential Medium; E, embryonic day; GSK, glycogen synthase kinase; Ihh, Indian hedgehog; ILK, integrin-linked kinase; ILK-fl, ILK allele flanked by loxP sites; PCNA, proliferating cell nuclear antigen; PKB, protein kinase B; PTHR1, PTH-PTHrP receptor.


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