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Papers In Press, published online ahead of print October 9, 2001
Department of Pediatric Dentistry, Nagasaki University School of Dentistry, Nagasaki 852-8588
Corresponding Author: satoshi{at}dh.nagasaki-u.ac.jp
Glycoshingolipids (GSLs) and their metabolites play important roles in a variety of biological processes. Several signal molecules are localized in a glycolipid enriched microdomain (GEM) on the cell surface, and their signals are regulated by the glycolipid composition. However, the function of glycolipids in osteoclastogenesis has not been clearly understood. We found that D-threo-1-phenyle-2-decanoylamin-3-morpho-1-linopropanol (D-PDMP), a glucosylceramide synthase inhibitor, completely inhibits the osteoclast formation induced by macrophage colony stimulating factor (M-CSF) and receptor activator of NF-kB ligand (RANKL) in a dose dependent manner. Expression of RANK, the receptor of RANKL, induced by M-CSF was markedly reduced in D-PDMP treated cells. D-PDMP also inhibited the phosphorylation of IkB and ERK1/2 induced by RANKL. In several experiments with the addition of glycolipids to D-PDMP treated purified bone marrow cells, lactosylceramide (LacCer) strongly affected the differentiation into TRAP mononucleated cells, but not TRAP positive multinucleated cells. GM3 and GM1 also recovered, but less effectively compared to LacCer. Moreover, exogenous LacCer recovered the reduced expression of RANK and the phosphorylation of inhibitor of NF-kB (IkB) and extracellar signal-regulated kinase 1/2 (ERK1/2) after stimulation by RANKL at the same level of cells without D-PDMP treatment. Our data suggest that glycosphingolipids, especially LacCer, are necessary for the initiation step of RANKL induced osteoclastogenesis.
J. Biol. Chem, 10.1074/jbc.M104464200
Submitted on May 16, 2001
Revised on October 9, 2001
Accepted on October 9, 2001
Lactosylceramide is essential for the osteoclastogenesis mediated by the macrophage-colony stimulating factor and receptor activator of NF-kB ligand
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