Depletion of gangliosides enhances cartilage degradation in mice

Sasazawa, Fumio; Onodera, Tomohiro; Yamashita, Tadashi; Seito, Naoki; Tsukuda, Yoko; Fujitani, Naoki; Shinohara, Yasuro; Iwasaki, Norimasa

doi:10.1016/j.joca.2013.11.015

Cited by 25 publications

(23 citation statements)

References 47 publications

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“…To identify a novel therapeutic target against OA, the authors performed a functional analysis of gangliosides in OA pathogenesis 11,13 . Mice that are homozygous null for Ugcg, and consequently lack all GSLs, have an embryonic lethal phenotype 10 , whereas mice with a chondrocyte-specific KO of Ugcg progress to OA 11 .…”

Section: Discussionmentioning

confidence: 99%

“…Glucosylceramide synthase (Ugcg), the first committed step in GSL synthesis, is a vital protein for multiple organs and cartilage; furthermore, mice with chondrocyte-specific knockout (KO) of the Ugcg gene have been used to demonstrate that GSLs are critical for the maintenance of chondrocyte homeostasis 10,11 . Moreover, systemic KO of GM3 synthase (GM3S), a downstream step in GSL synthesis, dramatically enhances cartilage degeneration without altering development, and the total ganglioside content of OA cartilage is decreased by 40% 12,13 . Considering that gangliosides are a therapeutic target has little influence on systemic conditions, specific molecules that act downstream of the ganglioside synthetic pathway are ideal candidates for a DMOAD.…”

Section: Introductionmentioning

confidence: 99%

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Coordinated existence of multiple gangliosides is required for cartilage metabolism

Momma

Onodera

Homan

et al. 2019

Osteoarthritis and Cartilage

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s u m m a r yObjective: Gangliosides, ubiquitously existing membrane components that modulate transmembrane signaling and mediate cell-to-cell and cell-to-matrix interactions, are key molecules of inflammatory and neurological disorders. However, the functions of gangliosides in the cartilage degradation process remain unclear. We investigated the functional role of gangliosides in cartilage metabolism related to osteoarthritis (OA) pathogenesis.Design: We generated knockout (KO) mice by targeting the b1, 4-N-acetylgalactosaminyltransferase (GalNAcT) gene, which encodes an enzyme of major gangliosides synthesis, and the GD3 synthase (GD3S) gene, which encodes an enzyme of partial gangliosides synthesis. In vivo OA and in vitro cartilage degradation models were used to evaluate the effect of gangliosides on the cartilage degradation process. Results: The GalNAcT and GD3S KO mice developed and grew normally; nevertheless, OA changes in these mice were enhanced with aging. The GalNAcT KO mice showed significantly enhanced OA progression compared to GD3S mice in vivo. Both GalNAcT and GD3S KO mice showed severe IL-1aeinduced cartilage degradation ex vivo. Phosphorylation of MAPKs was enhanced in both GalNAcT and GD3S KOs after IL-1a stimulation. Gangliosides modulated by GalNAcT or GD3S rescued an increase of MMP-13 induced by IL-1a in mice lacking GalNAcT or GD3S after exogenous replenishment in vitro. Conclusion: These data show that the deletion of gangliosides in mice enhanced OA development. Moreover, the gangliosides modulated by GalNAcT are important for cartilage metabolism, suggesting that GalNAcT is a potential target molecule for the development of novel OA treatments.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Coordinated existence of multiple gangliosides is required for cartilage metabolism

Momma

Onodera

Homan

et al. 2019

Osteoarthritis and Cartilage

Self Cite

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“…Gangliosides, i.e., sialylated glycosphingolipids, are produced from LacCer (36) and are abundant in cartilage matrix (46). Gangliosides show a dual role in cartilage homeostasis, as their depletion can enhance cartilage repair by preventing chondrocyte hypertrophy (50) or accelerate its degradation during experimental OA (37).…”

Section: Discussionmentioning

confidence: 99%

“…LacCer is the most important and abundant of the diosylceramides. It serves as the metabolic branch point for the formation of the different classes of complex glycosphingolipids in mammals (36,37). In addition to its pivotal role in the biosynthesis of nearly all major glycosphingolipids, LacCer is also thought to regulate several aspects of cellular function (36).…”

Section: Discussionmentioning

confidence: 99%

Optimal bone fracture repair requires 24R,25-dihydroxyvitamin D3 and its effector molecule FAM57B2

Martineau¹,

Naja²,

Husseini³

et al. 2018

Journal of Clinical Investigation

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The biological activity of 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] remains controversial, but it has been suggested that it contributes to fracture healing. Cyp24a1-/- mice, synthesizing no 24R,25(OH)2D3, show suboptimal endochondral ossification during fracture repair, with smaller callus and reduced stiffness. These defects were corrected by 24R,25(OH)2D3 treatment, but not by 1,25-dihydroxyvitamin D3. Microarrays with Cyp24a1-/- callus mRNA identified FAM57B2 as a mediator of the 24R,25(OH)2D3 effect. FAM57B2 produced lactosylceramide (LacCer) upon specific binding of 24R,25(OH)2D3. Fam57b inactivation in chondrocytes (Col2-Cre Fam57bfl/fl) phenocopied the callus formation defect of Cyp24a1-/- mice. LacCer or 24R,25(OH)2D3 injections restored callus volume, stiffness, and mineralized cartilage area in Cyp24a1-null mice, but only LacCer rescued Col2-Cre Fam57bfl/fl mice. Gene expression in callus tissue suggested that the 24R,25(OH)2D3/FAM57B2 cascade affects cartilage maturation. We describe a previously unrecognized pathway influencing endochondral ossification during bone repair through LacCer production upon binding of 24R,25(OH)2D3 to FAM57B2. Our results identify potential new approaches to ameliorate fracture healing.

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“…Moreover, the overexpression of GM3-synthetase (GM3S) in vitro suppressed MMP-13 and ADAMTS-5 expression [40]. These results suggest that gangliosides suppress OA development and may provide a target for the design of novel anti-OA therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Effects of gangliosides from deer bone extract on the gene expressions of matrix metalloproteinases and collagen type II in interleukin-1β-induced osteoarthritic chondrocytes

Suh

Lee

Min³

et al. 2016

Nutr Res Pract

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BACKGROUND/OBJECTIVESWe investigated the anti-osteoarthritic effects of deer bone extract on the gene expressions of matrix metalloproteinases (MMPs) and collagen type II (COL2) in interleukin-1β-induced osteoarthritis (OA) chondrocytes.MATERIALS/METHODSPrimary rabbit chondrocytes were treated as follows: CON (PBS treatment), NC (IL-1β treatment), PC (IL-1β + 100 µg/mL glucosamine sulphate/chondroitin sulphate mixture), and DB (IL-1β + 100 µg/mL deer bone extract).RESULTSThe results of the cell viability assay indicated that deer bone extract at doses ranging from 100 to 500 µg/mL inhibits cell death in chondrocytes induced by IL-1β. Deer bone extract was able to significantly recover the mRNA expression of COL2 that was down-regulated by IL-1β (NC: 0.79 vs. DB: 0.87, P < 0.05) and significantly decrease the mRNA expression of MMP-3 (NC: 2.24 vs. DB: 1.75) and -13 (NC: 1.28 vs. DB: 0.89) in OA chondrocytes (P < 0.05).CONCLUSIONSWe concluded that deer bone extract induces accumulation of COL2 through the down-regulation of MMPs in IL-1β-induced OA chondrocytes. Our results suggest that deer bone extract, which contains various components related to OA, including chondroitin sulphate, may possess anti-osteoarthritic properties and be of value in inhibiting the pathogenesis of OA.

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Depletion of gangliosides enhances cartilage degradation in mice

Abstract: Gangliosides play a critical role in OA pathogenesis by regulating the expression of MMP-13 and ADAMTS-5 and chondrocyte apoptosis. Based on the obtained results, we propose that gangliosides are potential target molecules for the development of novel OA treatments.

Cited by 25 publications

References 47 publications

Coordinated existence of multiple gangliosides is required for cartilage metabolism

Coordinated existence of multiple gangliosides is required for cartilage metabolism

Optimal bone fracture repair requires 24R,25-dihydroxyvitamin D3 and its effector molecule FAM57B2

Effects of gangliosides from deer bone extract on the gene expressions of matrix metalloproteinases and collagen type II in interleukin-1β-induced osteoarthritic chondrocytes

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