Analysis of signaling pathways involved in polarization of osteoclasts.

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(1) We have previously established a culture system for examining osteoclast formation. In the present study, a new resorption assay system was also established using osteoclast-like cells formed in vitro. Therefore, it is now possible to examine the effect of various compounds on the recruitment of osteoclasts and pit formation by the same osteoclasts in a series of experiments.(2) Using op/op mouse-derived osteoblastic cells, we found that M-CSF is indispensable not only for proliferation of osteoclast precursors but also for their differentiation into osteoclasts.(3) When osteoclasts were placed on dentine slices or plastic dishes, they formed the ringed structure of podosomes (actin rings). The ringed structure is shown to correspond to clear zones of bone resorbing osteoclasts. The Formation and disruption of the actin ring were correlated well with pit forming activity of osteoclasts.(4) It was shown that signaling pathways meditated by p60^<c-src>, PI-3 kinase, focal adhesion kinase and small GTP binding protein, rho, are essentially involved in actin ring formation by osteoclasts. It has been proposed that calcitonin receptors are coupled to the pathways associated with both protein kinase A and protein kinase C.We examined the signaling pathway of calcitonin action in osteoclast-like cells. We found that calcitonin-induced dramatic alteration in the cytoskeleton is mainly mediated by the protein kinase A pathway.