The role of osteoblast AMPA receptors in stimulation of bone formation

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The most intractable problem in skeletal pathology is stimulation of bone formation after loss. In pilot studies, we discovered that surprisingly, low but not high doses of antagonists of AMPA-type glutamate receptors stimulate expression of osteoblast phenotypic markers and bone formation in vitro and in vivo. We will test the hypothesis that low doses of antagonists that bind to the thiazide- sensitive anti-desensitisation site of AMPA receptors exert agonist effects, initiating osteogenic responses. We will determine subgroups of AMPA receptors expressed in bone, marrow and osteoblasts, and the characteristics of ligand and putative antagonist binding to osteoblasts. We will also measure effects of antagonists at different doses on intracellular calcium concentration, c-fos for expression and AP-1 activity, and in vivo, on bone mass in rats after ovariectomy and in response to mechanical loading.