Abstract
IntroductionRheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction and disability. Focal bone erosion is due to excess bone resorption of osteoclasts. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is one of the critical mediators both in inflammatory signal pathway and differentiation and resorption activity of osteoclasts. Here we aimed to investigate TRAF6 expression in RA synovium and its correlation with histological synovitis severity and radiological joint destruction in RA.MethodsSynovitis score was determined in needle biopsied synovium from 44 patients with active RA. Synovium from nine patients with osteoarthritis (OA) and seven with orthopedic arthropathies (Orth.A) were enrolled as "less inflamed" disease controls. Serial sections were stained immunohistochemically for TRAF6 as well as CD68 (macrophage), CD3 (T cell), CD20 (B cell), CD38 (plasmocyte), CD79a (B lineage cells from pre-B cell to plasmocyte stage), and CD34 (endothelial cell). Double immunofluorescence staining of TRAF6 and CD68 were tested. Densities of positive staining cells were determined and correlated with histological disease activity (synovitis score) and radiographic joint destruction (Sharp score).ResultsTRAF6 expression was found in the intimal and subintimal area of RA synovium, with intense staining found in the endochylema and nucleus of intimal synoviocytes and subintimal inflammatory cells. Double immunofluorescence staining showed TRAF6 was expressed in most of the intimal cells and obviously expressed in CD68+ cells and some other CD68- cells in subintimal area. Synovial TRAF6 was significantly over-expressed in the RA group compared with the OA and Orth.A group (2.53 ± 0.94 vs. 0.72 ± 0.44 and 0.71 ± 0.49, P < 0.0001). Synovial TRAF6 expression in RA correlated significantly with synovitis score (r = 0.412, P = 0.006), as well as the inflammatory cell infiltration (r = 0.367, P = 0.014). Significant correlation was detected between synovial TRAF6 expression and intimal CD68+ cells, as well as the cell density of subintimal CD68+ cells, CD3+ cells, CD20+ cells, CD38+ cells, and CD79a+ cells (all P < 0.05).ConclusionsElevated synovial TRAF6 expression correlated with synovitis severity and CD68+ cell density in RA. It is, therefore, hypothesized that synovial TRAF6 is involved in the pathogenesis of synovial inflammation and osteoclast differentiation in RA.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction and disability
Elevated synovial Tumor necrosis factor receptor-associated factor 6 (TRAF6) expression correlated with synovitis severity and CD68+ cell density in RA
The pathogenesis of RA depends on a number of different cell types, including macrophages, which are the primary source of the proinflammatory cytokines, as well as dendritic cells, T cells, B cells, plasma cells, endothelial cells, synoviocytes and neutrophils, which produce a panoply of proinflammatory cytokines, chemokines, growth factors, matrix metalloproteinases (MMPs) and other proteolytic enzymes that degrade the articular matrix [35,36]
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction and disability. Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by chronic inflammatory synovitis, leading to invasion of synovial tissue into the adjacent cartilage matrix with degradation of articular cartilage and bone, which constitutes a major cause of progressive disability and crippling of RA patients [1]. Our previous study found synovial infiltration with CD79a+ B cells, but not other B cell lineage, correlated with synovitis score and joint destruction in RA, which indicated synovial CD79a+ B cells may be a helpful biomarker for histologic disease activity and involved in the pathogenesis of joint destruction in RA [7]. Recent study showed that increased osteoclast formation and activity contributes to local and systemic abnormalities of bone remodeling, including bone erosion as well as focal and systemic osteoporosis [8]. Several studies have shown that osteoclast precursors and mature osteoclasts were abundant at sites of arthritic bone erosion [9,10]
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