The Calcium-sensing Receptor Is Involved in Strontium Ranelate-induced Osteoclast Apoptosis NEW INSIGHTS INTO THE ASSOCIATED SIGNALING PATHWAYS

Strontium ranelate exerts both an anti-catabolic and an anabolic effect on bone cells. To further investigate the molecular mechanism whereby strontium ranelate inhibits bone resorption, we focused our attention on the effects of strontium ranelate on osteoclast apoptosis and on the underlying mechanism(s). Using primary mature rabbit osteoclasts, we demonstrated that strontium (Sr-o(2+)) dose-dependently stimulates the apoptosis of mature osteoclasts. As shown previously for calcium (Ca-o(2+)), the Sr-o(2+)-induced effect on mature osteoclasts is mediated by the Ca-o(2+)-sensing receptor, CaR, which in turn stimulates a phospholipase C-dependent signaling pathway and nuclear translocation of NF-kappa B. Unlike Ca-o(2+), however, Sr-o(2+)-induced osteoclast apoptosis was shown to depend on PKC beta II activation and to be independent of inositol 1,4,5-trisphosphate action. As a consequence of these differences in their intracellular signaling pathways, Sr-o(2+) and Ca-o(2+) in combination were shown to exert a greater effect on mature osteoclast apoptosis than did either divalent cation by itself. Altogether, our results show that Sr-o(2+) acts through the CaR and induces osteoclast apoptosis through a signaling pathway similar to but different in certain respects from that of Ca-o(2+). This difference in the respective signaling cascades enables Sr-o(2+) to potentiate Ca-o(2)+ induced osteoclast apoptosis and vice versa. In this manner, it is conceivable that Sr-o(2+) and Ca-o(2+) act together to inhibit bone resorption in strontium ranelate-treated patients.