| Theme |
Calcitonin -- update |
| Title |
Mechanism of calcitonin actions and their relation to calcitonin desensitization |
| Author |
Seiki Wada |
The Fourth Department of Internal Medicine, Saitama Medical School |
| Author |
Satoru Suda |
The Fourth Department of Internal Medicine, Saitama Medical School |
| Author |
Shigemitsu Yasuda |
The Fourth Department of Internal Medicine, Saitama Medical School |
| Author |
Tsutomu Nagai |
The Fourth Department of Internal Medicine, Saitama Medical School |
| [ Summary ] |
Since Calcitonin (CT) inhibits osteoclastic bone resorption, it has been widely used to treat metabolic bone disorders, such as Paget's disease of bone, malignancy-associated hypercalcemia, and osteoporosis. It is recognized, however, that continuous treatment with CT causes a loss of its inhibitory effects on bone resorption. We and other investigators have studied the mechanism and the results indicated that desensitization to CT was closely associated with the down regulation of the CT receptor (CTR). This down regulation was due not only to internalization of the receptor but also to reduced cell surface receptor concentration through inhibition of de novo CTR synthesis. An essential signal for osteoclast differentiation from its precursor cells, which was termed as ODF, was also found identical to tumor necrosis factor (TNF) related activation induced cytokine (TRANCE) and receptor activator of nuclear factor-kB ligand (RANKL). Using soluble (s) RANKL and macrophage colony stimulating factor (M-CSF), we recently studied the mechanisms of the biological responses to CT in cells of human osteoclast lineage. The signaling pathway responsible for CTR down regulation in human osteoclasts is different from that observed in mouse osteoclasts: the activation of protein kinase A pathway is primarily responsible for CTR regulation in mouse osteoclasts, while the activation of protein kinase C was predominant in humans. Treatment with glucocorticoids enhanced concentration of cellularsurface CTR and CTR mRNA expression in both species. These results would explain the beneficial interaction of glucocorticoids and CTs through modulation of CTR expression in human osteoclasts with somewhat limited values. |