The calcium-sensing receptor (CaR) is involved in strontium ranelate-induced osteoblast proliferation

Strontium ranelate has several beneficial effects on bone and reduces the risk of vertebral and hip fractures in women with postmenopausal osteoporosis. We investigated whether Sr2+ acts via a cell surface calcium-sensing receptor (CaR) in HEK293 cells stably transfected with the bovine CaR (HEK-CaR) and rat primary osteoblasts (POBs) expressing the CaR endogenously. Elevating Cao2+ or Sr2+ concentration-dependently activated the CaR in HEK-CaR but not in non-transfected cells, but the potency of Sr2+ varied depending on the biological response tested. Sr2+ was less potent than Cao2+ in stimulating inositol phosphate accumulation and in increasing Cai2+, but was comparable to Cao2+ in stimulating ERK phosphorylation and a non-selective cation channel, suggesting that Ca2+ and Sr2+ have differential effects on specific cellular processes. With physiological concentrations of Cao2+, Sr2+-induced further CaR activation. Neither Sr2+ nor Cao2+ affected the four parameters just described in non-transfected cells. In POB, Sr2+ stimulated cellular proliferation. This effect was CaR-mediated, as transfecting the cells with a dominant negative bovine CaR significantly attenuated Cao2+-stimulated POB proliferation. Finally, Sr2+ significantly increased the mRNA levels of the immediate early genes, c-fos and egr-1, which are involved in POB proliferation, and this effect was attenuated by overexpressing the dominant negative CaR. In conclusion, Sr2+ is a full CaR agonist in HEK-CaR and POB, and, therefore, the anabolic effect of Sr2+ on bone in vivo could be mediated, in part, by the CaR.