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Physiological levels of calcitonin regulate the mouse osteoclast calcitonin receptor by a protein kinase Alpha-mediated mechanism.

We have reported that calcitonin (CT) treatment induced downregulation of the CT receptor (CTR) in mouse osteoclast-like cells (OCLs). Here, we studied the features of homologous down-regulation of the CTR in mature mouse OCLs. Treatment with salmon CT (sCT) and human CT (hCT) reduced [125I]sCT specific binding. The decreased binding after 24 h of CT treatment was associated with a decrease in the cell surface receptor concentration. The extent of CT-induced down-regulation in 24 h was dose-dependent, and the ED50 value was 3.6 +/- 4.1 (mean +/- SD; n = 3) x 10(-13 M for sCT and 4.9 +/- 3.3 x 10(-11) M for hCT. These values were very similar to those for the CT inhibition of the bone-resorbing activity of OCLs. The data suggest that these two distinct actions of CT may be mediated by a common intracellular pathway. Treatment of OCLs with activators of protein kinase A (PKA) mimicked the effect of CT on CTR downregulation, whereas neither activation of protein kinase C nor elevation of intracellular Ca2+ did so. Attenuation of CT-induced CTR down-regulation by the competitive cAMP antagonist, RpcAMP, and high concentrations of H-7, but not by protein kinase C-specific inhibitors (sphingosine, staurosporine, and a lower concentration of H-7), suggested that the PKA pathway is primarily involved in homologous regulation of the CTR. The changes in CTR messenger RNA confirm the findings in binding studies and demonstrate that CT treatment of OCLs results in decreased CTR synthesis through the PKA pathway. The low concentrations of hCT that result in CTR regulation are very close to the physiological range, providing new insights into a dynamic relationship between circulating levels of CT and CTR expression in osteoclasts.