Pathological roles of oxidized low-density lipoprotein receptor in rheumatoid arthritis
| Project/Area Number |
16591488
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Orthopaedic surgery
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| Research Institution | Tenri University |
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Principal Investigator |
YASUDA Tadashi Tenri University, Faculty of Health, Budo, and Sports Studies, Professor, 体育学部, 教授 (40314223)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAMURA Takashi Kyoto University, Graduate School of Medicine, Department of Orthopaedic Surgery, Professor, 医学研究科, 教授 (10201675)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2004: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | Rheumatoid arthritis / Oxidized LDL / Lectin-like oxidized LDL receptor / Biomarker / Joint destruction / MMP / 関節液検査 / 関節軟骨 |
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| Research Abstract |
We attempted to detect the presence of oxidized low-density lipoprotein (ox-LDL) and lectin-like oxidized LDL receptor-1 (LOX-1) in cartilage specimens from rheumatoid arthritis (RA) joints and to investigate whether interaction of ox-LDL with LOX-1 can induce matrix metalloproteinase (MMP)-3 in articular cartilage explant culture. When human articular cartilage specimens obtained from patients with RA, osteoarthritis (OA) and femoral neck fracture were examined with confocal fluorescence microscopy for LOX-1 and ox-LDL, the majority of RA chondrocytes were positively stained with both anti-LOX-1 and anti-ox-LDL antibodies. In contrast, no positive cells were found in OA and normal cartilage specimens. When association between ox-LDL and LOX-1 was evaluated by immunofluorescence analysis, anti-LOX-1 antibody suppressed the binding of DiI-labeled ox-LDL to chondrocytes in explant culture, suggesting that the interaction was mediated by LOX-1. When articular cartilage specimens from pati
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ents with femoral neck fracture were incubated with ox-LDL, with pre-incubation with neutralizing anti-LOX-1 antibody, ox-LDL induced MMP-3 synthesis by articular chondrocytes in association with induction of LOX-1, resulting in enhanced secretion of MMP-3 into the culture media. Anti-LOX-1 antibody reversed ox-LDL-stimulated MMP-3 synthesis to control levels. Thus, increased accumulation of ox-LDL with elevated expression of LOX-1 in RA cartilage indicates a specific role of the receptor-ligand interaction in cartilage pathology in RA.
Our next attempt was to determine the levels of soluble form of LOX-1 (sLOX-1) in synovial fluid from diseased joint. The levels of sLOX-1 were significantly increased in RA synovial fluid, in contrast to those in OA. In patients with knee OA, there was no significant correlation between sLOX-1 levels and CRP or ESR. The levels of sLOX-1 in RA synovial fluid significantly correlated with CRP, but not with ESR. These results indicate that sLOX-1 could be a useful tool of diagnosis of RA and a biomarker of RA activity. Less
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