The discovery that extracellular calcium stimulates both chemotaxis and mitogenesis of osteoblasts in vitro has led to the exciting hypothesis that extracellular calcium couplers bone formation to bone resorption at importance of extracellular calcium as a bone remodeling coupling agent. The objective of my current research is to define the signal transduction mechanisms underlying the chemoattractant and mitogenic properties of extracellular calcium for osteoblasts. Preliminary studies suggest that calcium-induced chemotaxis and mitogenesis involves a G-protein- coupled seven-transmembrane-spanning calcium-sensing receptor. The signaling molecules adenylyl cyclase, protein kinase A, phospholipase C, intracellular calcium, protein kinase C, and Src appear to contribute to the signaling mechanisms responsible for both calcium-stimulated chemotaxis and DNA synthesis. Furthermore, mitogen-activated protein kinase may play a role in calcium-induced mitogenesis but not chemotaxis.
The specific aim of this pilot project is focused on determining whether Src tyrosine kinase activity is necessary for calcium receptor-mediated chemotaxis of osteoblasts. To address this specific aim, novel approaches using retroviral vectors to transfect dominant negative c-Src in osteoblasts will be employed. Ultimately, a molecular understanding of extracellular calcium-mediated osteoblast recruitment will lead to novel approaches to the prevention and treatment of disorders of bone metabolism.
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