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author:("kudoh, K")
1.  Implication of interleukin 18 in production of matrix metalloproteinases in articular chondrocytes in arthritis: direct effect on chondrocytes may not be pivotal 
Annals of the Rheumatic Diseases  2005;64(5):735-742.
Objective: To clarify the effect of interleukin (IL) 18 on cartilage degeneration by studying the profile of IL18 receptor (IL18R) on chondrocytes and the direct effect of IL18 on production of matrix metalloproteinases (MMPs), aggrecanases, and tissue inhibitors of metalloproteinases (TIMPs) in articular chondrocytes.
Methods: Monolayer cultured human articular chondrocytes were isolated from non-arthritic subjects and patients with rheumatoid arthritis or osteoarthritis. Gene expression of IL18, IL18Rα, IL18Rß, MMPs, and aggrecanases was detected by RT-PCR. Protein levels of IL18Rα were analysed by flow cytometry. Protein levels of IL18, MMPs, and TIMPs were measured by ELISA. Aggrecanase-2 mRNA expression was quantitatively analysed by real time RT-PCR. Protein levels of signalling molecules were assayed by western blotting.
Results: IL18 mRNA was constitutively expressed in chondrocytes, and was enhanced by IL1ß stimulation. Flow cytometric analysis showed that IL1ß, tumour necrosis factor α, and IL18 up regulated IL18Rα expression levels. The level of IL18Rß mRNA was much lower than that of IL18Rα, and was slightly up regulated by IL1ß. In chondrocytes responding to IL18, IL18 (1–100 ng/ml) slightly increased the production of MMP-1, MMP-3, and MMP-13, which was blocked by NF-κB inhibitor and p38 mitogen activated protein kinase inhibitor. IL18 up regulated mRNA expression of aggrecanase-2, but not aggrecanase-1. IL18 also slightly stimulated TIMP-1 production?through extracellular signal regulated kinase activation.
Conclusion: IL18 induces production of MMPs from chondrocytes in inflammatory arthritis. Although the direct effect of IL18 on chondrocytes may not be pivotal for the induction of cartilage degeneration, IL18 seems to play some part in the degradation of articular cartilage in arthritis.
doi:10.1136/ard.2004.026088
PMCID: PMC1755478  PMID: 15834055
2.  Interleukin (IL) 18 stimulates osteoclast formation through synovial T cells in rheumatoid arthritis: comparison with IL1ß and tumour necrosis factor α 
Annals of the Rheumatic Diseases  2004;63(11):1379-1386.
Objective: To determine whether IL18 has any indirect effects on osteoclastogenesis mediated by T cells in RA synovium, and compare its effects with those of IL1ß and TNFα.
Methods: Resting T cells were isolated from peripheral blood of healthy donors, and stimulated with 2 µg/ml phytohaemagglutinin (PHA) and 0.5 ng/ml IL2 for 24 hours. Synovial T cells were isolated from RA synovial tissue. The levels of soluble receptor activator of the NF-κB ligand (RANKL), osteoprotegerin (OPG), IFNγ, M-CSF, and GM-CSF were determined by ELISA. Membrane bound RANKL expression was analysed by flow cytometry. Commercially available human osteoclast precursors were cocultured with T cells to induce osteoclast formation, which was determined with tartrate resistant acid phosphatase staining and pit formation assay.
Results: In PHA prestimulated T cells or RA synovial T cells, IL18, IL1ß, or TNFα increased soluble RANKL production and membrane bound RANKL expression in a dose dependent manner. IL18, IL1ß, and TNFα did not induce M-CSF, GM-CSF, IFNγ, or OPG production in PHA prestimulated T cells or RA synovial T cells. IL18 increased the number of osteoclasts and bone resorption area on dentine slices in the coculture of human osteoclast precursors with PHA prestimulated T cells or RA synovial T cells; its ability was equivalent to that of IL1ß, but less potent than that of TNFα. In the coculture system, OPG completely blocked osteoclast induction by IL18 or IL1ß, and greatly inhibited induction by TNFα.
Conclusion: IL18, IL1ß, or TNFα can indirectly stimulate osteoclast formation through up regulation of RANKL production from T cells in RA synovitis; IL18 is as effective as IL1ß, but less potent than TNFα.
doi:10.1136/ard.2003.018481
PMCID: PMC1754791  PMID: 15479886
5.  Concentration of vascular endothelial growth factor in the tumour tissue as a prognostic factor of soft tissue sarcomas 
British Journal of Cancer  2001;84(12):1610-1615.
Previous studies have shown that the prognosis of patients who have tumours with high microvessel density (MVD) is worse than that of patients who have a lower density in a variety of cancers. In this study, we investigated the clinical relevance of neovascularity assessed by MVD and the concentration of vascular endothelial growth factor (VEGF) in the tumour tissue of patients with soft tissue sarcoma in comparison with major clinicohistologic parameters by univariate and multivariate analysis. In 115 patients with soft tissue sarcoma, MVD was measured by counting vessels stained with factor VIII antibody. The concentration of VEGF in the tumour tissue was determined by enzyme-linked immunosorbent assay. These parameters were then compared with disease outcome. The concentration of VEGF in the tumour tissue, but not MVD, was found to be correlated with disease outcome in patients with soft tissue, sarcoma. VEGF concentration in the tumour tissue showed a relationship with the clinical stage and histologic grade of the tumour. There was no significant difference in the levels of tissue VEGF concentration and MVD among soft tissue sarcomas classified according to histologic type. The level of tissue VEGF concentration in patients who had subsequent local recurrence and metastasis were significantly higher than the respective values in patients who did not have such disease outcome. No significant correlation existed between MVD and the concentration of VEGF in the tumour tissue. Univariate analysis showed that a high tissue VEGF concentration was associated with poor overall survival of the patient and a greater probability that local recurrence and metastasis had occurred. Multivariate analysis revealed that the tissue concentration of VEGF is an independent prognostic factor for the disease outcome of patients with soft tissue sarcoma. VEGF concentration in the tumour tissue, but not MVD, is an additional prognostic parameter for disease outcome in patients with soft tissue sarcoma, regardless of histologic type. © 2001 Cancer Research Campaign http://www.bjcancer.com
doi:10.1054/bjoc.2001.1837
PMCID: PMC2363691  PMID: 11401313
microvessel density; vascular endothelial growth factor; overall survival; tumour recurrence; metastasis; soft tissuearcoma
6.  Cementless cup supporter for protrusio acetabuli in patients with rheumatoid arthritis 
International Orthopaedics  2000;24(1):15-18.
Abstract 
The MC cup supporter is an acetabular reinforcement ring for the Harris-Galante (HG) cementless porous-coated socket. This supporting ring has been used with autogenous bone graft since 1991 in the management of protrusio acetabuli in patients with rheumatoid arthritis (RA). We have reviewed 15 hips in 13 patients at an average of 53.6 months (range 24–84 months) after operation. The clinical results of total hip arthroplasty (THA) in protrusio acetabuli using this ring were satisfactory. All grafts appeared to have united radiologically with no radiolucent lines between graft and acetabulum.
doi:10.1007/s002640050004
PMCID: PMC3619865  PMID: 10774855

Results 1-6 (6)