Bone resorption requires the adhesion of osteoclasts to extracellular matrix (ECM) components, a process mediated by the alphavbeta 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. Mice with one inactivated ILK allele (ILK+/-) were mated with TRAP-Cre transgenic mice. Progeny from this cross (TRAP-Cre;ILK+/-) was bred to mice homozygous for a floxed ILK allele (ILKfl/fl) to yield mutant mice with ILK-deficient osteoclasts (TRAP-Cre;ILK+/fl ). The mutant animals thus had one ILK allele inactivated in all tissues, and both alleles disrupted in osteoclasts. Mutant mice appeared phenotypically normal, but histomorphometric analysis of the proximal tibia revealed an increase in bone volume and trabecular thickness. Osteoclastogenesis, assessed by TRAP staining of bone sections or in vitro cultures, was not affected. Indeed, osteoclast-specific ILK ablation was associated with an increase in osteoclast number both in vitro and in vivo. Primary cultures of osteoclasts were generated on synthetic calcium phosphate discs, as well as dentin, and the mutant cells displayed a decrease in resorption activity. We also measured decreased serum concentrations of the C-terminal telopeptide of collagen, a marker of osteoclastic activity, in mice with ILK-deficient osteoclasts. Our results show that ILK is important for the function, but not the differentiation, of osteoclasts. The characterization of the molecular mechanisms responsible for the observed phenotype will identify novel pathways regulating bone resorption.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.99336 |
| Date | January 2006 |
| Creators | Dossa, Tanya. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Master of Science (Department of Human Genetics.) |
| Rights | © Tanya Dossa, 2006 |
| Relation | alephsysno: 002566166, proquestno: AAIMR28481, Theses scanned by UMI/ProQuest. |
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