Regulation of Proton Production and Transport in Bone [microform]

Download or read book Regulation of Proton Production and Transport in Bone [microform] written by Anuradha Santhanagopal and published by National Library of Canada = Bibliothèque nationale du Canada. This book was released on 2001 with total page 215 pages. Available in PDF, EPUB and Kindle. Book excerpt: Bone remodeling occurs by the coupled processes of resorption and formation, disruption of which leads to diseases such as osteoporosis. Bone resorption by osteoblasts and formation by osteoblasts are regulated by small changes in extracellular pH (pHo). We hypothesized that proton efflux from osteoblastic cells regulates pHo in the bone microenvironment. Using cultured cells, we established a novel in vitro model simulating the bone microenvironment. This model enabled us to monitor proton efflux from osteoblastic cells and the resulting changes in pHo beneath the cell layer. The studies reported here characterized factors regulating these processes. Hyperglycemia and acidosis in diabetes are associated with impaired bone formation and increased osteoclastic resorption. We found that glucose enhanced efflux of protons and lactate from osteoblastic cells. Within minutes, glucose decreased pH. in the compartment immediately beneath the cell layer by 0.18 pH units, a change shown previously to be sufficient to activate osteoclastic resorption. Thus, alterations in glucose concentration may regulate proton efflux from bone, contributing to diabetic osteopenia. While a long-term effect of insulin-like growth factor-I (IGF-I) is increased bone formation, it stimulates resorption acutely through a primary effect on osteoblasts. We found that IGF-I enhanced proton efflux from osteoblasts leading to acidification, via a signaling pathway involving phosphatidylinositol 3-kinase. IGF-I-induced acidification of the compartment between the osteopenic layer and bone matrix may mediate the acute effects of IGF-I on bone resorption. The hormone calcitonin (CT) acts through G protein-coupled receptors in bone and kidney. Using cells transfected with different CT receptor isoforms, we found that CT acts through the commonly occurring C1a receptor isoform to enhance proton efflux. This response involved activation of Na+/H + exchange and enhanced glucose metabolism. These responses may contribute to the actions of CT on osteoclasts and renal tubular cells. Our studies demonstrate for the first time, the ability of osteoblasts to acidify a microcompartment beneath them. This process is regulated by glucose availability, growth factors and hormones. Changes in pHo in the microcompartment formed between the bone matrix and the osteogenic cell layer can regulate osteoclastic resorption and the formation and mineralization of bone.