The Calcium-sensing Receptor (CaR) is involved in strontium ranelate-induced osteoblast differentiation and mineralization.
Strontium ranelate is known to reduce fracture risk in osteoporotic patients by stimulating bone formation and suppressing bone resorption. However, the mechanism by which strontium exerts this beneficial effect on bone is unclear. We examined whether or not the calcium-sensing receptor (CaR), which is activated by divalent cations including Sr (2+), is involved in this mechanism. Both strontium ranelate and strontium chloride dose-dependently stimulated phosphorylation of extracellular signal-regulated kinase (ERK) in Human Embryonic Kidney 293 cells transiently transfected with the human CaR. Strontium ranelate also dose- and time-dependently stimulated phosphorylation of ERK in mouse osteoblastic MC3T3-E1 cells expressing the CaR endogenously. Strontium ranelate increased mRNA expression of osteocalcin and bone morphogenetic protein-2 in MC3T3-E1 cells as well as mineralization and proliferation of the cells. Pretreatments of NPS2390, a CaR inhibitor, almost totally antagonized strontium ranelate-induced mineralization and proliferation of MC3T3-E1 cells. These findings indicate that strontium ranelate induces not only osteoblast proliferation but also its differentiation and mineralization by activating the CaR, and confirm that the therapeutic efficacy of strontium ranelate for osteoporosis may be partly mediated by the CaR.
Takaoka
S
S
Internal Medicine 1, Shimane University Faculty of Medicine, Shimane, Japan.
Yamaguchi
T
T
Yano
S
S
Yamauchi
M
M
Sugimoto
T
T
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D002113:Calcification, Physiologic / Q000187:drug effects*; D002118:Calcium / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D009942:Organometallic Compounds / Q000494:pharmacology*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044169:Receptors, Calcium-Sensing / Q000235:genetics / Q000378:metabolism*; D013876:Thiophenes / Q000494:pharmacology*; D014162:Transfection
D055396:Bone Morphogenetic Protein 2; D009942:Organometallic Compounds; D012333:RNA, Messenger; D044169:Receptors, Calcium-Sensing; D013876:Thiophenes; C081587:strontium ranelate; D015675:Osteocalcin; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium