Lectin‐like oxidized low‐density lipoprotein receptor 1 mediates matrix metalloproteinase 3 synthesis enhanced by oxidized low‐density lipoprotein in rheumatoid arthritis cartilage

• Published in: Arthritis and rheumatism 2004-11, Vol.50 (11), p.3495-3503
• Main Authors: Kakinuma, Takumi, Yasuda, Tadashi, Nakagawa, Takefumi, Hiramitsu, Teruko, Akiyoshi, Miki, Akagi, Masao, Sawamura, Tatsuya, Nakamura, Takashi
• Format: Article
• Language: English
• Subjects: Antibodies - pharmacology; Arthritis, Rheumatoid - enzymology; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; Biological and medical sciences; Cartilage, Articular - enzymology; Cartilage, Articular - metabolism; Cartilage, Articular - pathology; Chondrocytes - drug effects; Chondrocytes - metabolism; Diseases of the osteoarticular system; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Humans; Immunoblotting; Inflammatory joint diseases; Lipoproteins, LDL - antagonists & inhibitors; Lipoproteins, LDL - biosynthesis; Lipoproteins, LDL - metabolism; Lipoproteins, LDL - pharmacology; Matrix Metalloproteinase 3 - biosynthesis; Medical sciences; Microscopy, Fluorescence; Receptors, LDL - immunology; Receptors, LDL - metabolism; Receptors, Oxidized LDL; Scavenger Receptors, Class E; Tissue Culture Techniques
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/art.20581

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.