Objective. The process of N-glycosylation is involved in the pathogenesis of various diseases. However, little is known about the contribution of changes in N-glycans in osteoarthritis (OA). The aim of this study was to identify the alterations in N-glycans in human OA cartilage, to characterize the messenger RNA (mRNA) expression of N-glycan biosynthesis enzyme genes (N-glycogenes) in mouse articular chondrocytes during cartilage degradation, and to analyze the relationship between altered N-glycan patterns and mechanisms of cartilage degradation.Methods. Alterations in N-glycans were analyzed in human OA cartilage and degraded mouse cartilage by high-performance liquid chromatography and mass spectrometry. N-glycogene mRNA expression in mouse chondrocytes was measured using reverse transcription-polymerase chain reaction. To assess the relationship between the altered N-glycans and degradation of mouse cartilage, experiments involving either knockdown or overexpression of N-glycogenes were performed in mouse articular chondrocytes.Results. Alterations in high-mannose type N-glycans were observed in both human OA cartilage and degraded mouse cartilage. The expression of ␤1,2N-acetylglucosaminyltransferase I (GlcNAc-TI) mRNA, which converts high-mannose type N-glycans, was significantly increased in degraded mouse cartilage. Mouse chondrocytes with suppressed GlcNAc-TI expression had reduced levels of matrix metalloproteinase 13 (MMP-13) and ADAMTS-5 (aggrecanase 2) mRNA following stimulation with interleukin-1␣ (IL-1␣). In contrast, mouse chondrocytes overexpressing GlcNAc-TI had increased levels of MMP-13 and ADAMTS-5 mRNA following stimulation with IL-1␣.Conclusion. These findings indicate that alterations in high-mannose type N-glycans and N-glycogenes in chondrocytes correlate with the release of MMP-13 and ADAMTS-5 during cartilage degradation. These findings suggest that N-glycans play a crucial role in the initiation and progression of OA.Osteoarthritis (OA), the most common joint disease, is characterized by the degradation of articular cartilage, which frequently leads to disability in older persons, particularly in performing daily activities. Chondrocytes are the only cells in cartilage responsible for the synthesis and degradation of the extracellular matrix (ECM). Chondrocyte metabolism is regulated by genetic and environmental factors, such as the composition of the ECM, soluble mediators, and mechanical factors. A breakdown in the balance of this metabolism results in cartilage degradation. Elucidation of the pathogenesis of OA requires a better understanding of the mechanism of cartilage degradation. Despite the large number of biomechanical and biochemical studies performed to clarify the mechanisms of cartilage degradation (1-7), these mechanisms remain unclear.Glycobiology, the study of the biologic functions of sugar chains bound to proteins and lipids, was recently applied to molecular-based studies in the biomedical field (8-11). The majority of glycans attached to proteins

Rheumatoid arthritis (RA), a chronic systemic inflammatory disorder that principally attacks synovial joints, afflicts over 2 million people in the United States. Interleukin (IL)-17 is considered to be a master cytokine in chronic, destructive arthritis. Levels of the ganglioside GM3, one of the most primitive glycosphingolipids containing a sialic acid in the structure, are remarkably decreased in the synovium of patients with RA. Based on the increased cytokine secretions observed in in vitro experiments, GM3 might have an immunologic role. Here, to clarify the association between RA and GM3, we established a collagen-induced arthritis mouse model using the null mutation of the ganglioside GM3 synthase gene. GM3 deficiency exacerbated inflammatory arthritis in the mouse model of RA. In addition, disrupting GM3 induced T cell activation in vivo and promoted overproduction of the cytokines involved in RA. In contrast, the amount of the GM3 synthase gene transcript in the synovium was higher in patients with RA than in those with osteoarthritis. These findings indicate a crucial role for GM3 in the pathogenesis and progression of RA. Control of glycosphingolipids such as GM3 might therefore provide a novel therapeutic strategy for RA.

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.

Objective Glycosphingolipids (GSLs) are ubiquitous membrane components that modulate transmembrane signaling and mediate cell-to-cell and cell-to-matrix interactions. GSL expression is decreased in the articular cartilage of humans with osteoarthritis (OA). The aim of this study was to determine the functional role of GSLs in cartilage metabolism related to OA pathogenesis. Methods We generated mice with knockout of the chondrocyte-specific Ugcg, which encodes an initial enzyme of major GSL synthesis, (Col2-Ugcg−/−), using the Cre/loxP system. In vivo OA and in vitro cartilage degradation models were used to evaluate the effect of GSLs on cartilage degradation process. Results Although Col2-Ugcg−/− mice developed and grew normally, osteoarthritic changes were dramatically enhanced with aging through the overexpression of MMP-13 and chondrocyte apoptosis compared to their wild-type (WT) littermates. Col2-Ugcg−/− mice showed more severe instability-induced pathologic OA in vivo and interleukin-1α (IL-1α) induced cartilage degradation in vitro. IL-1α stimulation of chondrocytes from WT mice significantly increased Ugcg mRNA expression and upregulated GSL metabolism. Conclusion GSL deficiency in chondrocytes enhances the development of OA. On the other hand, the deficiency does not affect the development and organization of cartilage tissue at a young age. These findings indicate that GSLs maintain cartilage molecular metabolism and prevent disease progression, although GSLs are not essential for chondrogenesis of progenitor and stem cells and cartilage development in young mice. GSL metabolism in the cartilage is a potential target for developing a novel treatment for OA.

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