Figure 8 summarizes our current hypothesis of the sequence on molecular events that take place at the osteoblast cell membrane and lead to rapid 1,25D electrical effects coupled to exocytosis. Mechanical strain exerted on the cell surface is the initial natural primary stimulus that activates stretch-activated cation channels (SA-Cat) expressed in osteoblasts. Bones are subjected to mechanical load due to gravity force and muscle activity. This translates into movement of fluids within bone trabeculae and a shear force applied to the osteoblast surface. The influx of positive charges into the cytoplasm due to SA-Cat channel activation and potentiation by 1,25D causes an initial, local depolarization of the osteoblast membrane from -40 mV at rest, to around 0 mV. This depolarization opens L-Ca channels at low positive membrane potentials. As we showed in our research, calcium channel opening is potentiated at low depolarizing potentials by physiological concentrations of 1,25D. Hormone binding to a membrane-associated receptor (possibly VDR) appears to stimulate the production of cAMP via a Gq / adenylate cyclase pathway. This in turn may activate PKA, and ultimately the phosphorylation of L-Ca channels necessary for channel opening. A local elevation of cytoplasmic Ca2+ concentration near L-Ca channels promotes the fusion of secretory vesicles to the plasma membrane, and release of secretory contents into the extracellular medium. This local elevation of cytoplasmic Ca2+ causes a further depolarization of the plasma membrane to slightly positive values, which in turn promotes the opening of Cl– channels. These Cl– channels are also potentiated by 1,25D through similar VDR / Gq / PKA pathways. The influx of Cl– ions into the cytoplasm contributes to the repo- larization of the cell membrane to regenerate negative initial values.
Our work addresses molecular mechanisms of bone formation by investigating non-genomic effects of the steroid 1,25D in osteoblasts. The study of bone formation has traditionally focused on understanding the control of bone cell proliferation, differentiation and apoptosis by different metabolic agents with effects on bone. From this viewpoint, bone formation during the process of bone remodelling in the adult skeleton has been evaluated as the result of an increased osteoblast relative to osteoclast activity. Similar perspective has been applied to the study of the pathophysiology of bone mass loss, in which a disordered control of relative bone cell numbers – in osteoporosis, for example, too many osteoclasts relative to fewer osteoblasts – has been described. Therefore, the emphasis of these studies has typically been at the bone tissue level. By focusing at the single-cell level, our studies contribute to the understanding of the molecular basis of bone diseases characterized by decreased bone formation and mineralization, and therefore to their treatment. These include osteoporosis, rickets and osteomalacia. In particular, osteoporosis constitutes a major financial burden for the American society, which will increase in the near future owing to the extended life expectancy of the population. Every possible effort including a full understanding of the molecular basis of these diseases should be made to diminish the financial impact on society and to improve the quality of life of those who suffer from these diseases.
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Figure 8 – 1,25D non-genomic signaling pathways in osteoblasts. The scheme summarizes 1,25D membrane-initiated pathways overviewed in this paper. The explanation is given in the text.