Premium
High extracellular inorganic phosphate concentration inhibits RANK–RANKL signaling in osteoclast‐like cells
Author(s) -
Mozar Anaïs,
Haren Nathalie,
Chasseraud Maud,
Louvet Loïc,
Mazière Cécile,
Wattel Alice,
Mentaverri Romuald,
Morlière Patrice,
Kamel Saïd,
Brazier Michel,
Mazière Jean C.,
Massy Ziad A.
Publication year - 2008
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21283
Subject(s) - rankl , osteoclast , mapk/erk pathway , rank ligand , activator (genetics) , chemistry , macrophage colony stimulating factor , microbiology and biotechnology , p38 mitogen activated protein kinases , monocyte , extracellular , protein kinase b , kinase , medicine , endocrinology , signal transduction , receptor , biology , macrophage , biochemistry , in vitro
In this work, we investigated the effect of inorganic phosphate (Pi) on the differentiation of monocyte/macrophage precursors into an “osteoclastic” phenotype, and we delineated the molecular mechanisms which could be involved in this phenomenon. This was achieved by stimulating human peripheral blood monocytic cells and RAW 264.7 monocyte–macrophage precursor cells to differentiate into osteoclast‐like cells in the presence of receptor activator of NF‐κB ligand (RANKL) and macrophage colony‐stimulating factor (M‐CSF). RANKL has been previously reported to stimulate the signaling kinases ERK 1/2, p38, Akt, JNK, and the DNA‐binding activity of the transcription factors AP‐1 and NF‐κB. Increase in extracellular Pi concentration (1.5–4.5 mM) dose‐dependently inhibits both osteoclastic differentiation and bone resorption activity induced by RANKL and M‐CSF. Pi was found to specifically inhibit the RANKL‐induced JNK and Akt activation, while RANKL‐induced p38 and ERK 1/2 phosphorylation were not significantly affected. Moreover, we found that Pi significantly reduced the RANKL‐stimulated DNA‐binding activity of NF‐κB. The effects of Pi on osteoclast differentiation and DNA‐binding activity of NF‐κB were prevented by Foscarnet®, a sodium–phosphate cotransport inhibitor, suggesting that the effects of Pi occur subsequently to its intake. These results demonstrate that Pi downregulates the differentiation of osteoclasts via a negative feedback exerted on RANK–RANKL signaling. J. Cell. Physiol. 215: 47–54, 2008. © 2007 Wiley‐Liss, Inc.