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Molecular Pharmacology

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Research ArticleArticle

Strontium Ranelate Decreases Receptor Activator of Nuclear Factor-κB Ligand-Induced Osteoclastic Differentiation In Vitro: Involvement of the Calcium-Sensing Receptor

Axelle Caudrillier, Anne-Sophie Hurtel-Lemaire, Alice Wattel, Fabienne Cournarie, Corinne Godin, Laurent Petit, Jean-Pierre Petit, Ernest Terwilliger, Said Kamel, Edward Meigs Brown, Romuald Mentaverri and Michel Brazier
Molecular Pharmacology October 2010, 78 (4) 569-576; DOI: https://doi.org/10.1124/mol.109.063347
Axelle Caudrillier
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Anne-Sophie Hurtel-Lemaire
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Alice Wattel
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Fabienne Cournarie
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Corinne Godin
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Laurent Petit
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Jean-Pierre Petit
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Ernest Terwilliger
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Said Kamel
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Edward Meigs Brown
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Romuald Mentaverri
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Abstract

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 Sro2+ on osteoclastic differentiation were studied using RAW 264.7 cells and peripheral blood monocytic cells (PBMCs). We report that increasing concentrations of Sro2+ 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 Sro2+). 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 Sro2+ is mediated by stimulation of the CaR. Moreover, our results suggest that the effects of Sro2+ 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 Sr2+ 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.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the Institut de Recherches Internationales Servier [Grant PHA-12911-141-FRA/001].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.063347.

  • ABBREVIATIONS:

    Sro2+
    extracellular concentration of Sr2+
    α-MEM
    α-modified minimum essential medium
    PBMC
    peripheral blood mononuclear cell
    TRAP
    tartrate-resistant acid phosphatase
    CaR
    calcium-sensing receptor
    RANKL
    receptor activator of nuclear factor-κB ligand
    HP
    hydroxylysylpyridinoline
    MTT
    3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide
    β-Gal
    β-galactosidase cDNA
    siRNA
    small interfering RNA
    FCS
    fetal calf serum
    PS
    penicillin/streptomycin
    PBS
    phosphate-buffered saline
    DN
    dominant-negative
    PE
    phosphatidylethanolamine
    NF-κB
    nuclear factor-κB
    AP-1
    activator protein-1
    ELISA
    enzyme-linked immunosorbent assay
    OCL
    osteoclast-like cell
    M-CSF
    macrophage colony-stimulating factor.

  • Received December 28, 2009.
  • Accepted June 28, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (4)
Molecular Pharmacology
Vol. 78, Issue 4
1 Oct 2010
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Research ArticleArticle

Strontium Ranelate Decreases Receptor Activator of Nuclear Factor-κB Ligand-Induced Osteoclastic Differentiation In Vitro: Involvement of the Calcium-Sensing Receptor

Axelle Caudrillier, Anne-Sophie Hurtel-Lemaire, Alice Wattel, Fabienne Cournarie, Corinne Godin, Laurent Petit, Jean-Pierre Petit, Ernest Terwilliger, Said Kamel, Edward Meigs Brown, Romuald Mentaverri and Michel Brazier
Molecular Pharmacology October 1, 2010, 78 (4) 569-576; DOI: https://doi.org/10.1124/mol.109.063347

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Research ArticleArticle

Strontium Ranelate Decreases Receptor Activator of Nuclear Factor-κB Ligand-Induced Osteoclastic Differentiation In Vitro: Involvement of the Calcium-Sensing Receptor

Axelle Caudrillier, Anne-Sophie Hurtel-Lemaire, Alice Wattel, Fabienne Cournarie, Corinne Godin, Laurent Petit, Jean-Pierre Petit, Ernest Terwilliger, Said Kamel, Edward Meigs Brown, Romuald Mentaverri and Michel Brazier
Molecular Pharmacology October 1, 2010, 78 (4) 569-576; DOI: https://doi.org/10.1124/mol.109.063347
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