Premium
Regulation of Osteoclast Differentiation by Fibroblast Growth Factor 2: Stimulation of Receptor Activator of Nuclear Factor κB Ligand/Osteoclast Differentiation Factor Expression in Osteoblasts and Inhibition of Macrophage Colony‐Stimulating Factor Function in Osteoclast Precursors
Author(s) -
Chikazu Daichi,
Katagiri Mika,
Ogasawara Toru,
Ogata Naoshi,
Shimoaka Takashi,
Takato Tsuyoshi,
Nakamura Kozo,
Kawaguchi Hiroshi
Publication year - 2001
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.2001.16.11.2074
Subject(s) - rankl , osteoclast , osteoprotegerin , macrophage colony stimulating factor , rank ligand , medicine , endocrinology , growth factor , fibroblast growth factor , chemistry , microbiology and biotechnology , receptor , biology , activator (genetics) , macrophage , biochemistry , in vitro
This study investigated the mechanism of direct and indirect actions of fibroblast growth factor 2 (FGF‐2) on osteoclast differentiation using two mouse cell culture systems. In the coculture system of osteoblasts and bone marrow cells, FGF‐2 stimulated osteoclast formation. This effect was decreased markedly by osteoprotegerin (OPG) or NS‐398, a selective cyclo‐oxygenase 2 (COX‐2) inhibitor. FGF‐2 (≥10 −9 M) stimulated receptor activator of nuclear factor κB ligand/osteoclast differentiation factor (RANKL/ODF) messenger RNA (mRNA) expression from 2 h to 7 days in cultured osteoblasts. NS‐398 did not affect the early induction but decreased the later one, indicating that the later effect is mediated by COX‐2 induction in osteoblasts. To study the direct action of FGF‐2 on osteoclast precursors, we used mouse macrophage‐like cell line C7 cells that can differentiate into osteoclasts in the presence of soluble RANKL/ODF (sRANKL/ODF) and macrophage colony‐stimulating factor (M‐CSF). Although osteoblasts expressed all FGF receptors (FGFR‐1 to −4), only FGFR‐1 was detected in C7 cells at various differentiation stages. FGF‐2 alone or in combination with sRANKL/ODF did not induce osteoclastogenesis from C7 cells; however, FGF‐2 from lower concentrations (≥10 −11 M) significantly decreased osteoclast formation induced by M‐CSF in the presence of sRANKL/ODF. FGF‐2 did not alter mRNA levels of M‐CSF receptor (Fms) or RANK in C7 cells. Immunoprecipitation/immunoblotting analyses revealed that tyrosine phosphorylation of several cellular proteins including Fms in C7 cells induced by M‐CSF was inhibited by FGF‐2 in the presence of sRANKL/ODF. We conclude that FGF‐2 regulates osteoclast differentiation through two different mechanisms: (1) an indirect stimulatory action via osteoblasts to induce RANKL/ODF partly through COX‐2 induction and prostaglandin production and (2) a direct inhibitory action on osteoclast precursors by counteracting M‐CSF signaling.