Lectin‐like oxidized low‐density lipoprotein receptor 1 signal is a potent biomarker and therapeutic target for human rheumatoid arthritis

Abstract

To determine whether lectin-like oxidized low-density lipoprotein (ox-LDL) receptor 1 (LOX-1) and the soluble form of LOX-1 (sLOX-1) are novel target molecules for the diagnosis and treatment of rheumatoid arthritis (RA). Expression of ox-LDL and LOX-1 proteins in human RA synovium was evaluated by immunohistochemistry. Human RA fibroblast-like synoviocytes (FLS) were assessed for ox-LDL-induced expression of LOX-1 and ox-LDL-induced production of matrix metalloproteinase 1 (MMP-1) and MMP-3. Levels of sLOX-1 in the plasma and synovial fluid of patients with RA, compared with patients with osteoarthritis (OA), were determined by a specific chemiluminescence enzyme-linked immunoassay. In animal experiments, ox-LDL was injected into the knee joints of mice, with or without an anti-LOX-1 neutralizing antibody or sLOX-1, and the severity of arthritis was analyzed by histology and immunohistochemistry. Oxidized LDL and LOX-1 proteins were detected in the RA synovial tissue. Levels of MMP-1 and MMP-3 were enhanced by stimulation of RA FLS with ox-LDL, and the production of both MMPs was inhibited by blockade of the ox-LDL-LOX-1 interaction with the anti-LOX-1 neutralizing antibody or sLOX-1. Levels of sLOX-1 in the plasma and synovial fluid of RA patients were significantly higher than those in OA patients and healthy controls and were positively correlated with inflammation markers and the extent of RA disease activity. In the knees of mice, blockade of the ox-LDL-LOX-1 interaction suppressed arthritic changes and reduced the expression of MMP-3 induced by ox-LDL. These findings strongly indicate that sLOX-1 is a novel biomarker that may be useful for the diagnosis of RA and for the evaluation of disease activity in RA. Furthermore, the results suggest that LOX-1 may be a potent therapeutic target for RA.