Bone Abstracts

Glycosphingolipids (GSL) are essential structural components of mammalian cell membranes and lipid rafts that exert pleiotropic effects on cell survival, proliferation, and differentiation. Cancer associated GSL have been shown to promote tumor growth, angiogenesis, and metastasis; however their role in osteoclast (OC) activation and the development of osteolytic bone diseases such as multiple myeloma are not known. We investigated the hypothesis that GSL contribute to OC activation and inhibitors of GSL biosynthesis would antagonise GSL-dependent osteoclastogenesis.

Exogenous addition of GM3, the prevailing GSL produced by myeloma plasma cells, synergistically enhanced the ability of the pro-osteoclastogenic factors RANKL and IGF1 to induce the maturation of OC in vitro. However, these effects were inhibited by the glycosphingolipid synthesis inhibitor N-butyl-deoxynojirimycin (NB-DNJ). In vivo administration of GM3 increased OC numbers and activity; this effect was reversed by treatment with the iminosugar agent NB-DNJ. NB-DNJ prevented OC development and activation by disrupting RANKL-induced localisation of TRAF6 and c-Src into lipid rafts thus attenuating MAPK signalling.

To prove the therapeutic potential of NB-DNJ, the 5TGM1 mouse model of multiple myeloma was used and we were able to demonstrate a significant improvement in bone parameters compared to the PBS treated mice. These data demonstrate a novel role for tumor-derived, as well as of de novo-synthesised GSL, in OC differentiation and activation and suggest that glycosphingolipid synthesis inhibitors, such as the clinically approved NB-DNJ, may be beneficial in reducing OC activation and bone destruction associated with multiple myeloma.