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One of the most remarkable but neglected aspects of osteoclast function is its unique adaptation that allows the cell to function despite its resorbing surface being exposed to extremely high levels of ambient Ca2+. Recently our studies have provided evidence of continuous transcellular Ca2+ disposal, suggesting that osteoclasts are able to prevent Ca2+ accumulation within the resorptive hemivacuole. It has also been shown that matrix protein degradation products that accumulate within the osteoclast resorptive vacuole are also undergoing transcellular transport by transcytosis. However, both experimental evidence and theoretical considerations suggest that transcellular transport of Ca2+ and matrix protein is likely to occur via distinct routes. In light of these considerations, we are able to provide convincing explanations for the apparent anomalies of osteoclast intracellular [Ca2+] responses to a variety of endocrine stimuli. The understanding of the mechanisms involved in Ca2+ handling by osteoclasts indicates the lack of a simple link between osteoclast function and changes in overall cytosolic [Ca2+].
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Calciotropic hormones such as parathyroid hormone (PTH) and calcitonin have been shown to have stimulatory and inhibitory effects respectively on superoxide anion (O2-) generation by osteoclasts, but the exact intracellular signalling mediating these pathways has not been investigated. In order to elucidate the intracellular pathways controlling O2- generation, we have carried out a systematic study of the effect of different agents on O2- production in osteoclasts cultured on bovine cortical bone. Dibutyryl cAMP and cholera toxin, while having no effect on the basal level of O2- production in bone-resorbing osteoclasts, were, however, found to completely block the stimulation of free radical production by PTH, pertussis toxin and ionomycin. The stimulation of O2- production was found to be independent of protein kinase C-dependent pathways since the presence of bisindolylmaleimide (GF109203X) (1 microM) did not block stimulation by PTH and pertussis toxin. Interestingly, while exposure to bisindolylmaleimide at this concentration did not have any effect on the basal level of O2- production, exposure to a higher concentration (10 microM), which is known to inhibit both protein kinase C and A, produced significant stimulation. These in vitro findings suggest that in the bone-resorbing cells, cAMP-dependent protein kinases prevent further stimulation of NADPH oxidase by agents such as PTH and pertussis toxin. The increase in cAMP has also been recently demonstrated to be associated with down-regulation of the oxidative burst in adherent neutrophils; and the findings reported here suggest a similar role for cAMP in O2- generation in osteoclasts cultured on bone.
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ABSTRACT
The propensity of ionic lithium to interfere with the coupling of receptors to guanine nucleotide binding proteins (G-proteins) has only recently been investigated using rat cortical membranes. In the present study we have used intact isolated osteoclasts to investigate lithium-induced uncoupling of the receptor-mediated actions of calcitonin. All actions of calcitonin on the osteoclast were abolished by ionic lithium. We believe that the cation prevents signal transduction by inhibiting G protein-receptor interaction, the first step in intracellular signalling.
