Lectin-like oxidized low-density lipoprotein receptor 1 mediates matrix metalloproteinase 3 synthesis enhanced by oxidized low-density lipoprotein in rheumatoid arthritis cartilage
Takumi Kakinuma
Kyoto University Graduate School of Medicine, Kyoto, Japan, and National Cardiovascular Center Research Institute, Osaka, Japan
Search for more papers by this authorCorresponding Author
Tadashi Yasuda
Kyoto University Graduate School of Medicine, Kyoto, Japan, and Faculty of Health, Budo, and Sports Studies, Tenri University, Tenri, Japan
Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, JapanSearch for more papers by this authorTakefumi Nakagawa
Kyoto University Graduate School of Medicine, Kyoto, Japan
Search for more papers by this authorTeruko Hiramitsu
Kyoto University Graduate School of Medicine, Kyoto, Japan
Search for more papers by this authorMiki Akiyoshi
Kyoto University Graduate School of Medicine, Kyoto, Japan
Search for more papers by this authorTatsuya Sawamura
National Cardiovascular Center Research Institute, Osaka, Japan
Search for more papers by this authorTakashi Nakamura
Kyoto University Graduate School of Medicine, Kyoto, Japan
Search for more papers by this authorTakumi Kakinuma
Kyoto University Graduate School of Medicine, Kyoto, Japan, and National Cardiovascular Center Research Institute, Osaka, Japan
Search for more papers by this authorCorresponding Author
Tadashi Yasuda
Kyoto University Graduate School of Medicine, Kyoto, Japan, and Faculty of Health, Budo, and Sports Studies, Tenri University, Tenri, Japan
Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, JapanSearch for more papers by this authorTakefumi Nakagawa
Kyoto University Graduate School of Medicine, Kyoto, Japan
Search for more papers by this authorTeruko Hiramitsu
Kyoto University Graduate School of Medicine, Kyoto, Japan
Search for more papers by this authorMiki Akiyoshi
Kyoto University Graduate School of Medicine, Kyoto, Japan
Search for more papers by this authorTatsuya Sawamura
National Cardiovascular Center Research Institute, Osaka, Japan
Search for more papers by this authorTakashi Nakamura
Kyoto University Graduate School of Medicine, Kyoto, Japan
Search for more papers by this authorAbstract
Objective
To investigate for 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 determine whether the interaction of ox-LDL with LOX-1 can induce matrix metalloproteinase 3 (MMP-3) in articular cartilage explant culture.
Methods
Human articular cartilage specimens obtained from patients with RA, osteoarthritis (OA), and femoral neck fractures were examined for LOX-1 and ox-LDL by confocal fluorescence microscopy. The association between ox-LDL and LOX-1 was evaluated by immunofluorescence analysis. Articular cartilage specimens from patients with femoral neck fractures were incubated with ox-LDL, with or without preincubation with neutralizing anti–LOX-1 antibody. MMP-3 synthesis by chondrocytes in explant cartilage was evaluated by immunofluorescence, and protein secretion into conditioned medium was monitored by immunoblotting and enzyme-linked immunosorbent assay.
Results
The majority of the RA chondrocytes stained positively with both anti–LOX-1 and anti–ox-LDL antibodies; however, no positive cells were found in OA and normal cartilage specimens. 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. In contrast to native LDL, ox-LDL induced MMP-3 synthesis by articular chondrocytes in association with the induction of LOX-1, which resulted in enhanced secretion of MMP-3 into the culture medium. Anti–LOX-1 antibody reversed ox-LDL–stimulated MMP-3 synthesis to control levels.
Conclusion
Ox-LDL, principally mediated by LOX-1, enhanced MMP-3 production in articular chondrocytes. 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.
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