Intercellular communication is a crucial issue for understanding the pathogenesis of osteoporotic syndromes, which result from unbalanced bone remodeling, wherein the resorption phase prevails. Bone remodeling is coordinated by a network of signals, in most part converging onto the osteoblasts, which thus works as a signal transducer for hormones, and chemical and mechanical stimuli. This, deranged intercellular cross- talk between osteoblasts and other cell types residing on bone, may well result in unbalanced bone turnover. While a great effort has been expended on soluble factors, which convey messages in endocrine, paracrine or autocrine manner to bone cells, no data currently exists on the direct cell-cell communication through gap junctions. Studies described in this application will focus on the mechanisms whereby hormonal, chemical and mechanical stimuli are received, transduced, and transmitted throughout bone cell populations, with emphasis on the relationship between the expression, function and regulation of gap junctions and osteoblast differentiation. Transmission electron microscopy and video image analysis will be used to evidence gap junction structures and test their function in both rat and human bone cell networks. Experiments are also planned to analyze signal propagation between bone cell via gap junctions. Video image analysis will be employed to monitor and quantitate the changes in cytosolic calcium and cyclic AMP. In addition, the role of inositol triphosphate as a signal transmitter, the modulation of intercellular communication by other second messengers and protein kinase phosphorylation, and the transmission of mechanical signals between bone cells will be explored.
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