Strontium ranelate decreases receptor activator of nuclear factor-ΚB ligand-induced osteoclastic differentiation in vitro: involvement of the calcium-sensing receptor.
Strontium ranelate exerts both an anticatabolic and an anabolic effect on bone cells. To further investigate the mechanism by which strontium ranelate inhibits bone resorption, the effects of varying concentrations of Sr(o)(2+) on osteoclastic differentiation were studied using RAW 264.7 cells and peripheral blood monocytic cells (PBMCs). We report that increasing concentrations of Sr(o)(2+) down-regulate osteoclastic differentiation and tartrate-resistant acid phosphatase activity, leading to inhibition of bone resorption (-48% when PBMCs were cultured for 14 days in the presence of 2 mM Sr(o)(2+)). Using a dominant-negative form of the calcium-sensing receptor (CaR) and a small interfering RNA approach, we provide evidences that the inhibition of osteoclast differentiation by Sr(o)(2+) is mediated by stimulation of the CaR. Moreover, our results suggest that the effects of Sr(o)(2+) on osteoclasts are, at least in part, mediated by inhibition of the receptor activator of nuclear factor-κB ligand (RANKL)-induced nuclear translocation of nuclear factor-κB and activator protein-1 in the early stages of osteoclastic differentiation. In conclusion, our data indicate that Sr(2+) directly inhibits the formation of mature osteoclasts through down-regulation of RANKL-induced osteoclast differentiation and decreases osteoclast differentiation through the activation of the CaR.
Caudrillier
Axelle
A
Institut National de la Santé et de la Recherche Médicale, Amiens, France.
Hurtel-Lemaire
Anne-Sophie
AS
Wattel
Alice
A
Cournarie
Fabienne
F
Godin
Corinne
C
Petit
Laurent
L
Petit
Jean-Pierre
JP
Terwilliger
Ernest
E
Kamel
Said
S
Brown
Edward Meigs
EM
Mentaverri
Romuald
R
Brazier
Michel
M
D000818:Animals; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009942:Organometallic Compounds / Q000494:pharmacology*; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000502:physiology*; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D013876:Thiophenes / Q000494:pharmacology*
D009942:Organometallic Compounds; D053245:RANK Ligand; D044169:Receptors, Calcium-Sensing; D013876:Thiophenes; C081587:strontium ranelate