g(m3)-ganglioside and Osteoarthritis

Elucidation of the healing mechanisms in damaged tissues is a critical step for establishing breakthroughs in tissue engineering. Articular cartilage is clinically one of the most successful tissues to be repaired with regenerative medicine because of its homogeneous extracellular matrix and few cell types. However, we only poorly understand cartilage repair mechanisms, and hence, regenerated cartilage remains inferior to the native tissues. Here, we show that glycosylation is an important process for hypertrophic differentiation during articular cartilage repair. GM3, which is a precursor molecule for most gangliosides, was transiently expressed in surrounding damaged tissue, and depletion of GM3 synthase enhanced cartilage repair. Gangliosides also regulated chondrocyte hypertrophy via the Indian hedgehog pathway. These results identify a novel mechanism of cartilage healing through chondrocyte hypertrophy that is regulated by glycosylation. Manipulation of gangliosides and their synthases may have beneficial effects on articular cartilage repair.

Topics: Animals; Biomarkers; Bone Regeneration; Cartilage, Articular; Cell Differentiation; Chondrocytes; Chondrogenesis; Collagen; Disease Models, Animal; Female; G(M3) Ganglioside; Gangliosides; Gene Expression; Hedgehog Proteins; Mice; Mice, Knockout; Osteoarthritis; Signal Transduction; Tissue Engineering; Wound Healing

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.

Topics: Animals; Antibodies; Arthritis, Experimental; Arthritis, Rheumatoid; Biosynthetic Pathways; CD3 Complex; Cell Proliferation; Disease Progression; G(M3) Ganglioside; Gene Deletion; Gene Expression Regulation, Enzymologic; Humans; Immunization; Mice; Mice, Inbred C57BL; Osteoarthritis; Phenotype; RNA, Messenger; Sialyltransferases; Synovial Membrane; Th17 Cells

A decrease in all major gangliosides, contrasting with a marked increase in the GM3 third band (3B-GM3), has been demonstrated in osteoarthritic fibrillated cartilage. We found the 3B-GM3 in osteoarthritic fibrillated, grossly intact and osteophytic human cartilage, but it was undetectable in pig and bovine cartilage, bone, synovium, synovial fluid white cells, erythrocytes, and various extracellular tissues. We made a similar finding with lactosyl ceramide, the GM3 neutral glycolipid precursor. The search for an antibody against the 3B-GM3, as a possible specific antigenic marker of osteoarthritis (OA), was unsuccessful. However, an antibody against a molecule very close to 3B-GM3 on high performance thin layer chromatography, which will probably be identified as a glycosylphosphatidylinositol, was found in the serum of some patients with OA.

Topics: Animals; Biomarkers; Cartilage, Articular; Culture Techniques; G(M3) Ganglioside; Gangliosides; Humans; Immunoglobulin M; Osteoarthritis; Synovial Membrane