Deficiency of GD3 Synthase in Mice Resulting in the Attenuation of Bone Loss with Aging

Abstract

Gangliosides are widely expressed in almost all tissues and cells and are also considered to be essential in the development and maintenance of various organs and tissues. However, little is known about their roles in bone metabolism. In this study, we investigated the effects of genetic deletion of ganglioside D3 (GD3) synthase, which is responsible for the generation of all b-series gangliosides, on bone metabolism. Although b-series gangliosides were not expressed in osteoblasts, these gangliosides were expressed in pre-osteoclasts. However, the expression of these gangliosides was decreased after induction of osteoclastogenesis by receptor activator of nuclear factor kappa-B ligand (RANKL). Three-dimensional micro-computed tomography (3D-μCT) analysis revealed that femoral cancellous bone mass in GD3 synthase-knockout (GD3S KO) mice was higher than that in wild type (WT) mice at the age of 40 weeks, although there were no differences in that between GD3S KO and WT mice at 15 weeks old. Whereas bone formation parameters (osteoblast numbers/bone surface and osteoblast surface/bone surface) in GD3S KO mice did not differ from WT mice, bone resorption parameters (osteoclast numbers/bone surface and osteoclast surface/bone surface) in GD3S KO mice became significantly lower than those in WT mice at 40 weeks of age. Collectively, this study demonstrates that deletion of GD3 synthase attenuates bone loss that emerges with aging.

Ganglioside Synthesis by Plasma Membrane-Associated Sialyltransferase in Macrophages

“…These sialosylated molecules are involved in many physiological processes, including growth, differentiation, migration and apoptosis through modulation of both cell signalling processes and cell-to-cell and cell-to-matrix interactions [3][4][5][6]. A recent report provides evidence of the role of GD3 synthase (ST8Sia-I) in bone metabolism in animals and suggests that altered ganglioside metabolism is associated with this bone loss during aging [7]. Alterations of ganglioside composition have been shown to occur upon transformation and upon cellular differentiation [8].…”

“…In addition, a new role for sialidase NEU1 on the regulation of TLR4 was demonstrated [28]. However, there is little information about the presence of endogenous ecto-ST8-SiaI in macrophages [7].…”

Deletion of Gb3 Synthase in Mice Resulted in the Attenuation of Bone Formation via Decrease in Osteoblasts

“…Glycosphingolipids are divided into three main series, i.e., ganglioside-series, globo-series, and lacto/neolacto-series. Of these, gangliosides have been reported to be involved in bone metabolism [5,6,7,8,9]. For instance, it was reported that a-series ganglioside GD1a and GM1 promote osteoblastic differentiation of bone marrow mesenchymal stem cells (MSCs) and tendon stem cells [5,6,7,8].…”

“…For instance, it was reported that a-series ganglioside GD1a and GM1 promote osteoblastic differentiation of bone marrow mesenchymal stem cells (MSCs) and tendon stem cells [5,6,7,8]. Recently, we demonstrated that a lack of GD3 synthase, which is responsible for the generation of all b-series gangliosides, in mice results in the attenuation of bone loss with aging [9]. However, there have been no reports on the presence or absence of expression of globo-series glycosphingolipids in osteoblasts and osteoclasts, and the roles of these glycosphingolipids in bone metabolism.…”

Editorial for Special Issue “Gangliosides: Modes of Action and Cell Fates”

“…Finally, little is known about roles of GD3 synthase and its products in bone metabolism. Yo et al clearly demonstrated implication of gangliosides in bone resorption using GD3 synthase-KO mice [ 24 ] as a novel function.…”