Ganglioside GM3 Has an Essential Role in the Pathogenesis and Progression of Rheumatoid Arthritis

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

Large osteochondral defect in the lateral femoral condyle reconstructed by Atelocollagen-associated autologous chondrocyte implantation combined with anterior cruciate ligament reconstruction

Background Articular surface damage commonly associated with rupture of the anterior cruciate ligament (ACL). Large osteochondral defect, which consists of a severe depression fracture and a large cartilage defect, need to be treated due to deformation of the articular surface as it can impact the clinical outcome of ACL reconstruction. Although autologous chondrocyte implantation is one of the useful options in such cases, it can be questioned whether the reconstruction of the ACL and osteochondral defect should be performed in one procedure alone. Case presentation We report a case of a 38-year-old male with a deep depression fracture extending to the edge of the lateral femoral condyle associated with ACL injury after twisting his right knee while skiing. The patient was successfully treated with tissue-engineered cartilage transplantation covered by the periosteum with an iliac bone graft combined with anatomic double-bundle ACL reconstruction. Histopathological examination of the transplanted cartilage taken at second-look arthroscopy showed a cartilage-like tissue in the middle to deep zone in which the extracellular matrix was largely stained with Safranin O. The patient was able to return to his previous level of skiing activity without any experience of knee pain. Magnetic resonance imaging at 4 years after surgery showed that the graft integrated to the border zone and subchondral bone. The operated knee showed negative Lachman test and had a full range of motion. Conclusions To our knowledge, this is the first report of anatomic double-bundle ACL reconstruction with tissue-engineered cartilage transplantation and an iliac bone graft to restore the lateral edge of the femoral condyle

Combined Therapy of Extracorporeal Shock Waves and Etidronate Disodium as a Potential Treatment for Post-traumatic Myositis Ossificans in the Quadriceps Muscle: A Case Report

Creative Commons License CC BY-NC-ND 4.0Objective: To investigate the therapeutic effect of the combination of extracorporeal shock waves (ESWs) and Etidronate sodium (EHDP) on post-traumatic Myositis Ossificans (MO) in the quadriceps muscle. Case description: A 26-year-old male ice hockey player complained of left thigh pain and stiffness, 4 weeks after a direct blow to the thigh from the knee of an opponent in a game. A firm mass with tenderness was palpated at the antero-mid area of the Rectus Femoris. Movement of his left knee was restricted to 50 degrees of flexion from full extension. A radiograph showed a lacy pattern of new bone formation in the anterior aspect of the left femur at 4 weeks after the injury. The injury was thus diagnosed as post-traumatic MO in the left quadriceps muscle. Indomethacin was administered for the first 7 days of hospitalization. EHDP was given orally for 3 months. ESW therapy was performed for the treatment of MO without any anesthesia: 3500 pulses at an energy density of 0.03 to 0.36 mJ/mm2 per week, in seven sessions. Pain in the muscle improved with 2 weeks of complete rest with immobilization, and thereafter by moving the knee actively and passively within pain-free limits. A normal range of pain-free motion of the affected knee was achieved in 8 weeks. The athlete then started various rehabilitation exercises, such as stretching and walking. He returned to full sporting activity 5 months after the initial treatment. Conclusion: Combined therapy of ESW and EHDP was useful for the treatment of post-traumatic MO in the quadriceps muscle

Immune response of T cells in WT and GM3S^−/− mouse CIA models. A.

<p>CD4⁺, CD8⁺, B220⁺, and CD11b⁺ T cell contents of iLNs in WT and GM3S^−/− mice on day 7 after immunization with CII-CFA (<i>n</i>  = 3 per group). <b>B.</b> The Th17 cell content in CD4⁺ T cells in mouse iLNs (<i>n</i>  = 3 per group). Data shown are mean ± SEM. *<i>P</i><0.05, compared to WT mice.</p

Clinical features related to GM3 in patients with RA or OA. A.

<p>Histology of RA and OA patients. Hematoxylin and eosin (HE) staining. Scale bars  = 200 µm. <b>B.</b> Quantification of total GSL glycans in human synovium (<i>n</i>  = 5 per group). <b>C.</b> Absolute and relative amounts of GM3 glycans in human synovium (<i>n</i>  = 5 per group). <b>D.</b> Quantification of GM3S mRNA in synovium and PBMCs in RA and OA patients (<i>n</i>  = 5 per group). Data shown are mean ± SEM. *<i>P</i><0.05, compared to OA patients.</p

Phenotype of WT and GM3S^−/− CIA mice.

<p>CIA was induced in C57BL/6 WT and GM3S^−/− mice (10–15 weeks old). Mice were immunized with chicken CII emulsified with CFA on days 0 and 21(<i>n</i>  = 17 WT and <i>n</i>  = 12 GM3S^−/− mice). <b>A.</b> Cumulative incidence of arthritis. <b>B.</b> Arthritis score with CII-CFA. <b>C.</b> Photomicrographs show HE-stained paraffin sections of the right hind limbs of naïve, CIA WT, and CIA GM3S^−/− mice at day 35 of the study. Scale bars  = 200 µm <b>D.</b> Histological scores on day 35 after primary immunization with CII-CFA (<i>n</i>  = 5 per group). <b>E.</b> Serum IL-6 levels in mice on day 25 after primary immunization with CII-CFA (<i>n</i>  = 5 per group). <b>F.</b> Serum levels of total IgG, IgG1, IgG2a, IgG2b, and IgG3 anti-chicken CII antibodies with CII-CFA on day 35 after primary immunization (<i>n</i>  = 5 per group). Data shown are mean ± SEM. *<i>P</i><0.05, **<i>P</i><0.01 compared to WT mice.</p

Onset of CIA from primary immunization.

<p>Data shown are mean ± SEM. *<i>P</i><0.05, compared to WT mice.</p

Lactosylceramide (LacCer) is the key branching point of sphingolipid biosynthesis.

<p>In the synthetic pathway of sphingolipids, four alternate pathways (lacto-series, neolacto-series, globo-series, and isoglobo-series) branch-off from LacCer. GM3S^−/− mice, in which the GM3 synthase gene is disrupted, produced only o-series gangliosides, including GA2 and GA1, and not a-series or b-series gangliosides.</p

Quantification of GM3S mRNA in synovial tissues and spleens from C57BL/6 naïve and CIA mice.

<p>Mice were anesthetized and killed on day 35 after CII-CFA stimulation and synovial tissues and spleens were removed to analyze GM3S mRNA (<i>n</i>  = 5 per group). <b>A.</b> mRNA in synovial tissue. <b>B.</b> mRNA in spleen. Data shown are mean ± SEM. *<i>P</i><0.05, compared with naïve WT mice.</p