Abstract
IntroductionTNF-like weak inducer of apoptosis (TWEAK) has been proposed as a mediator of inflammation and bone erosion in rheumatoid arthritis (RA). This study aimed to investigate TWEAK and TWEAK receptor (Fn14) expression in synovial tissue from patients with active and inactive rheumatoid arthritis (RA), osteoarthritis (OA) and normal controls and assess soluble (s)TWEAK levels in the synovial fluids from patients with active RA and OA. Effects of sTWEAK on osteoclasts and osteoblasts were investigated in vitro.MethodsTWEAK and Fn14 expression were detected in synovial tissues by immunohistochemistry (IHC). Selected tissues were dual labelled with antibodies specific for TWEAK and lineage-selective cell surface markers CD68, Tryptase G, CD22 and CD38. TWEAK mRNA expression was examined in human peripheral blood mononuclear cells (PBMC) sorted on the basis of their expression of CD22. sTWEAK was detected in synovial fluid from OA and RA patients by ELISA. The effect of sTWEAK on PBMC and RAW 264.7 osteoclastogenesis was examined. The effect of sTWEAK on cell surface receptor activator of NF Kappa B Ligand (RANKL) expression by human osteoblasts was determined by flow cytometry.ResultsTWEAK and Fn14 expression were significantly higher in synovial tissue from all patient groups compared to the synovial tissue from control subjects (P < 0.05). TWEAK was significantly higher in active compared with inactive RA tissues (P < 0.05). TWEAK expression co-localised with a subset of CD38+ plasma cells and with CD22+ B-lymphocytes in RA tissues. Abundant TWEAK mRNA expression was detected in normal human CD22+ B cells. Higher levels of sTWEAK were observed in synovial fluids isolated from active RA compared with OA patients. sTWEAK did not stimulate osteoclast formation directly from PBMC, however, sTWEAK induced the surface expression of RANKL by human immature, STRO-1+ osteoblasts.ConclusionsThe expression of TWEAK by CD22+ B cells and CD38+ plasma cells in RA synovium represents a novel potential pathogenic pathway. High levels of sTWEAK in active RA synovial fluid and of TWEAK and Fn14 in active RA tissue, together with the effect of TWEAK to induce osteoblastic RANKL expression, is consistent with TWEAK/Fn14 signalling being important in the pathogenesis of inflammation and bone erosion in RA.
Highlights
Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) has been proposed as a mediator of inflammation and bone erosion in rheumatoid arthritis (RA)
Levels of soluble (s) TNF-like weak inducer of apoptosis (TWEAK) in the synovial fluids of active RA compared with OA patients were determined
Immunohistochemistry Immunohistochemical staining demonstrated that TWEAK was expressed at significantly higher levels in synovial tissue from active RA, inactive RA and OA patients (Figure 1A-C, respectively) compared to normal
Summary
TNF-like weak inducer of apoptosis (TWEAK) has been proposed as a mediator of inflammation and bone erosion in rheumatoid arthritis (RA). TWEAK induces the production of a large number of pro-inflammatory molecules, such as matrix metalloproteinase (MMP1), IL-6, IL-8, MCP-I and Regulated upon Activation Normal T Cell Expressed and Secreted (RANTES) by synoviocytes and fibroblasts, as well as ICAM-1, E-selectin, IL-8, and MCP-1 by endothelial cells [4]. The majority of these cytokines are induced by TWEAK/Fn14 induction of the NF-b signalling pathway [3,5]. The pro-inflammatory effects of TWEAK are seen in various cell types including glomerular mesangial cells [6], human umbilical vein endothelial cells (HUVEC) [7], human gingival fibroblasts [8], human dermal fibroblasts, synoviocytes [9], chondrocytes, and fibroblasts [2]
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