For bone resorption, vacuolar-type H+-ATPases (V-ATPases) on the plasma membranes of osteoclasts acidifies the extracellular millieu adjacent to the bone surface. The V-ATPase a3 and d2 subunits are enriched in osteoclasts. B2 subunit is also expressed on the osteoclast plasma membrane. Disruption of genes encoding subunits a3 and d2 impairs bone resorption. In this study, we have shown an interaction between the a3-B2 and a3-d2 subunits. Luteolin and KM91104 were found to be effective inhibitors of the a3-d2 and a3-B2 interactions respectively. Secondary assays revealed luteolin and KM91104 were not toxic to cells, did not affect osteoclastogenesis yet inhibited bone resorption. Furthermore luteolin did not affect V-ATPase subunit formation or assembly. Inhibitors of osteoclast resorption that do not affect osteoclast viability, preserve osteoclast–osteoblast signalling are desirable than existing anti-resorptives. Therefore, V-ATPase a3–d2 and a3-B2 interactions are viable targets for anti-resorptive therapeutics for osteoporosis.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/32236 |
| Date | 21 March 2012 |
| Creators | Crasto, Gazelle Jean |
| Contributors | Manolson, Morris Frank |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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