Osteoclast-specific inactivation of the integrin-linked kinase (ILK) inhibits bone resorption.
Bone resorption requires the adhesion of osteoclasts to extracellular matrix (ECM) components, a process mediated by the alpha(v)beta(3) integrin. Following engagement with the ECM, integrin receptors signal via multiple downstream effectors, including the integrin-linked kinase (ILK). In order to characterize the physiological role of ILK in bone resorption, we generated mice with an osteoclast-specific Ilk gene ablation by mating mice with a floxed Ilk allele with TRAP-Cre transgenic mice. The TRAP-Cre mice specifically excised floxed alleles in osteoclasts, as revealed by crossing them with the ROSA26R reporter strain. Osteoclast-specific Ilk mutant mice appeared phenotypically normal, but histomorphometric analysis of the proximal tibia revealed an increase in bone volume and trabecular thickness. Osteoclast-specific Ilk ablation was associated with an increase in osteoclastogenesis both in vitro and in vivo. However, the mutant osteoclasts displayed a decrease in resorption activity as assessed by reduced pit formation on dentin slices in vitro and decreased serum concentrations of the C-terminal telopeptide of collagen in vivo. Interestingly, compound heterozygous mice in which one allele of Ilk and one allele of the beta(3) integrin gene were inactivated (ILK(+/-); beta(3) (+/-)) also had increased trabecular thickness, confirming that beta(3) integrin and Ilk form part of the same genetic cascade. Our results show that ILK is important for the function, but not the differentiation, of osteoclasts.
Dossa
Tanya
T
Genetics Unit, Shriners Hospital for Children, Montreal, Quebec, Canada H3G 1A6.
Arabian
Alice
A
Windle
Jolene J
JJ
Dedhar
Shoukat
S
Teitelbaum
Steven L
SL
Ross
F Patrick
FP
Roodman
G David
GD
St-Arnaud
René
R
D000135:Acid Phosphatase / Q000235:genetics; D000818:Animals; D001862:Bone Resorption; D007527:Isoenzymes / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071681:Tartrate-Resistant Acid Phosphatase; D014054:Tomography; D000099200:Scaffold Protein ILK
D000135:Acid Phosphatase; D007527:Isoenzymes; D017346:Protein Serine-Threonine Kinases; D000071681:Tartrate-Resistant Acid Phosphatase; D000099200:Scaffold Protein ILK; C000605511:Acp5 protein, mouse