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

Shoyoku Yo,Kenjiro Tanaka,Shigemi Goto,Kosuke Hamajima,Takuma Sato,Hisataka Kondo,Akifumi Togari,Koichi Furukawa,Yoshitaka Mishima,Ken Miyazawa,Hironori Mori,Kazunori Hamamura

doi:10.3390/ijms20112825

Shoyoku Yo, Kenjiro Tanaka + Show 10 more

Open Access

https://doi.org/10.3390/ijms20112825

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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.

Highlights

Gangliosides, which are sialic-acid-containing glycosphingolipids, are highly expressed in the nervous tissues of vertebrates [1] and have been considered as being involved in the regulation of nervous systems [2,3,4,5]
B-series gangliosides were not expressed in osteoblasts, these gangliosides were detected in pre-osteoclasts such as RAW264.7 and primary cultured pre-osteoclasts derived from mouse bone marrow cells
3D-μCT and bone histomorphometric analyses using GD3 synthase-knockout (GD3S KO) mice revealed that deficiency of ganglioside D3 (GD3) synthase in mice suppressed bone resorption, leading to attenuation of a decrease in bone mass with aging

Summary

Introduction

Gangliosides, which are sialic-acid-containing glycosphingolipids, are highly expressed in the nervous tissues of vertebrates [1] and have been considered as being involved in the regulation of nervous systems [2,3,4,5]. Mice lacking GM2/GD2 synthase gene have shown that gangliosides play important roles in the transport of testosterone to the seminiferous tubules and bloodstream from Leydig cells [6]. B-series gangliosides, including GD3, GD2, GD1b, GT1b, and GQ1b, all of which contain α-2,8 sialic acid, have been considered as playing crucial roles in the maintenance of the sensory nervous system, neuroregeneration of hypoglossal nerves after injury, and secretion of leptin in adipose tissues [7,11,12]. These gangliosides have been identified as cancer-associated antigens, and are known to enhance tumor phenotypes, such as cell proliferation, and invasion in melanomas, osteosarcomas, and small cell lung cancers [13,14,15]

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