Reduced chondrocyte proliferation and chondrodysplasia in mice lacking the integrin-linked kinase in chondrocytes.
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.
Terpstra
Leonieke
L
Genetics Unit, Shriners Hospital for Children, 1529 Cedar Avenue, Montréal, Québec, Canada H3G 1A6.
Prud'homme
Josée
J
Arabian
Alice
A
Takeda
Shu
S
Karsenty
Gérard
G
Dedhar
Shoukat
S
St-Arnaud
René
R
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002356:Cartilage / Q000002:abnormalities* / Q000201:enzymology* / Q000503:physiopathology; D002448:Cell Adhesion / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D019902:Chondrocytes / Q000201:enzymology* / Q000473:pathology; D020219:Chondrogenesis / Q000235:genetics; D024043:Collagen Type II / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D004392:Dwarfism / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D005097:Exostoses, Multiple Hereditary / Q000201:enzymology* / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006132:Growth Plate / Q000002:abnormalities* / Q000201:enzymology / Q000473:pathology; D019426:Integrases / Q000235:genetics; D016023:Integrins / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010012:Osteogenesis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D019076:Transgenes / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics; D000099200:Scaffold Protein ILK
D024043:Collagen Type II; D019938:Cyclin D1; D019426:Integrases; D016023:Integrins; D017346:Protein Serine-Threonine Kinases; D014764:Viral Proteins; D000099200:Scaffold Protein ILK; C045073:Cre recombinase