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J. Biol. Chem., Vol. 276, Issue 49, 46031-46038, December 7, 2001

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Lactosylceramide Is Essential for the Osteoclastogenesis Mediated by Macrophage-Colony-stimulating Factor and Receptor Activator of Nuclear Factor-B Ligand^*

Tsutomu Iwamoto^**, Satoshi Fukumoto^§¶, Kazuhiro Kanaoka^**, Eiko Sakai^**, Mitsue Shibata^**, Emiko Fukumoto^**, Jin-ichi Inokuchi, Kogo Takamiya^§§, Keiko Furukawa^§§, Koichi Furukawa^§§, Yuzo Kato^**, and Akio Mizuno

From the  First Department of Oral and Maxillofacial Surgery and the Departments of ^§ Pediatric Dentistry,  Preventive Dentistry, and ^** Pharmacology, Nagasaki University School of Dentistry, Nagasaki 852-8588, the  Department of Biomembrane and Biofunctional Chemistry, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, and the ^§§ Department of Biochemistry II, Nagoya University School of Medicine, Nagoya 466-0065, Japan

Glycosphingolipids and their metabolites play important roles in a variety of biological processes. Several signal molecules are localized in a glycolipid-enriched microdomain 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-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), a glucosylceramide synthase inhibitor, completely inhibits the osteoclast formation induced by macrophage-colony-stimulating factor and receptor activator of nuclear factor-B ligand (RANKL) in a dose-dependent manner. Expression of RANK, the receptor of RANKL, induced by macrophage colony-stimulating factor, was reduced markedly in D-PDMP-treated cells. D-PDMP also inhibited the phosphorylation of the inhibitor of nuclear factor-B and extracellular signal-regulated kinase 1/2 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 tartrate-resistant acid phosphatase mononucleated cells, but not positive multinucleated cells. GM3 and GM1 also recovered, but less effectively compared with LacCer. Moreover, exogenous LacCer recovered the reduced expression of RANK and the phosphorylation of inhibitor of NF-B and extracellular signal-regulated kinase 1/2 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.

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