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 Sr(2+) 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 Ca(o)(2+) or Sr(2+) concentration-dependently activated the CaR in HEK-CaR but not in non-transfected cells, but the potency of Sr(2+) varied depending on the biological response tested. Sr(2+) was less potent than Ca(o)(2+) in stimulating inositol phosphate accumulation and in increasing Ca(i)(2+), but was comparable to Ca(o)(2+) in stimulating ERK phosphorylation and a non-selective cation channel, suggesting that Ca(2+) and Sr(2+) have differential effects on specific cellular processes. With physiological concentrations of Ca(o)(2+), Sr(2+)-induced further CaR activation. Neither Sr(2+) nor Ca(o)(2+) affected the four parameters just described in non-transfected cells. In POB, Sr(2+) stimulated cellular proliferation. This effect was CaR-mediated, as transfecting the cells with a dominant negative bovine CaR significantly attenuated Ca(o)(2+)-stimulated POB proliferation. Finally, Sr(2+) 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, Sr(2+) is a full CaR agonist in HEK-CaR and POB, and, therefore, the anabolic effect of Sr(2+) on bone in vivo could be mediated, in part, by the CaR.
Chattopadhyay
Naibedya
N
Division of Endocrinology, Diabetes and Hypertension and Membrane Biology Program, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, United States. Naibedya@cdriindia.org
Quinn
Stephen J
SJ
Kifor
Olga
O
Ye
Chianping
C
Brown
Edward M
EM
D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D017931:DNA Primers; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000502:physiology*; D013876:Thiophenes / Q000494:pharmacology*
D017931:DNA Primers; D009942:Organometallic Compounds; D044169:Receptors, Calcium-Sensing; D013876:Thiophenes; C081587:strontium ranelate; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium