Their reports indicate that CTGF has a significant role for RA pathogenesis and our present data can support these previous reports. Open in a separate window Figure 7 Hypothesis of the role of connective tissue growth factor in the possible rheumatoid arthritis pathogenesis. The synovial tissue in the inflamed joints of RA can invade bones and this is supported by the invasive nature of the synovial fibroblasts gaining the capacity to move and penetrate into cartilages and bones. levels significantly were decreased by infliximab concomitant with the disease amelioration. In addition, tumour necrosis factor (TNF) can induce the CTGF production from synovial fibroblasts even though TNF can oppositely inhibit the production of CTGF from chondrocytes. CTGF promoted the induction of the quantitative and qualitative activities of osteoclasts in combination with M-CSF and receptor activator of NF-B ligand (RANKL). In addition, we newly found integrin V3 around the osteoclasts as a CTGF receptor. Conclusions These results indicate that aberrant CTGF production induced by TNF plays a central role for the abnormal osteoclastic activation in RA patients. Restoration of aberrant CTGF production may contribute to the inhibition of articular destruction in infliximab treatment. Introduction Rheumatoid arthritis (RA) is usually a chronic inflammatory disorder that ultimately leads to the destruction of the joint architecture. Although the precise pathogenic mechanisms O-Desmethyl Mebeverine acid D5 leading to the development of RA are not fully comprehended, proinflammatory cytokines, such as tumor necrosis factor- (TNF-), interleukin (IL)-1 and IL-6 play pivotal roles in the induction of RA [1-4]. Especially, TNF- is considered to O-Desmethyl Mebeverine acid D5 play a central role in bone destruction because TNF- mediates an abnormal activation of osteoclasts through either the direct or indirect mechanisms in RA [2,3]. The use of TNF- blockade reagents has been shown to have a significant impact on the therapy of RA and the success of this therapy has led to trials in other chronic inflammatory diseases such as Behcet’s disease [5-8]. Infliximab is usually chimeric IgG1 anti-TNF- antibody made up of the antigen-binding region of a mouse antibody and the constant region of human antibody [9]. The antibody binds soluble and membrane bound TNF-, thereby impairing binding to its O-Desmethyl Mebeverine acid D5 receptor. Although anti-TNF- blocking reagents possess a beneficial effect for RA therapy especially for prevention of articular destruction, the precise mechanism of the disease’s amelioration has not been clarified because TNF- has multiple functions and it is involved in many inflammatory pathways and it also regulates various physiological phenomena in RA patients [7,8]. A previous study has shown the changes in the profiles of serum protein biomarkers in infliximab-treated RA patients. It was achieved by a novel approach to proteomic research using a specially developed serum/plasma protein O-Desmethyl Mebeverine acid D5 separation device (hollow-fiber-membrane-based device; HFRD, Toray Industry, Tokyo, Japan) and a linked two-dimensional liquid chromatography system (2D LC-MS/MS) [10]. Various proteins (approximately 20 kinds of proteins) revealed great changes in their expression after the infliximab treatment using this analytical system, however, many proteins among them were cellular constitutive proteins. These were thought to be released into sera from cells destroyed by anti-TNF- antibodies because the antibodies are known to mediate the killing of cells expressing TNF- on the surface [9]. Among these proteins listed in the previous study [10], connective tissue growth factor (CTGF) appeared to be a potent strong biomarker in the infliximab-treated RA patients. CTGF was Rabbit Polyclonal to ATP5I discovered due to the cross-reactivity of a platelet derived growth factor (PDGF) antiserum with a single polypeptide with a molecular weight of 38 kDa secreted by cultured human vein endothelial cells (HUVEC), and its cDNA was isolated from a HUVEC cDNA expression library with anti-PDGF and shown to encode a 349-amino acid protein [11]. CTGF is usually a member of the CCN protein family (including Cyr61 (CCN1), CTGF (CCN2) and Nov) and believed to be a downstream mediator of transforming growth factor (TGF)- action [12]. Although a number of cell surface molecules have been nominated as candidates currently for its specific receptors, they have not been defined to date. CTGF is usually a bioactive cytokine, therefore, it is considered not to be derived from these destroyed cells. Furthermore, it has been shown that CTGF is usually associated with several biological functions such as fibrosis, tumorgenesis, angiogenesis, O-Desmethyl Mebeverine acid D5 and endochondral ossification, and it has been proposed that CTGF produced by chondrocytes might maintain a homeostasis of cartilage tissue by autocrine system [13,14]. Articular tissue consists of not only chondrocytes but also various kinds of cells such as synovial fibroblasts or osteoclasts. Especially, fibroblasts of inflamed synovial tissue and osteoclasts are thought to be the main effecter cells for the development of bone destruction in RA. However, precise functions of CTGF on these articular cells have not been elucidated so far. Based on these findings, the contribution of CTGF for RA pathogenesis was investigated in the current study. Here, we report that aberrant CTGF production mediated by TNF- can induce massive osteoclastogenesis and disturbance on homeostasis of cartilage resulting in bone and cartilage tissue damage in RA. Furthermore, we report here that phosphorylated extracellular signal-regulated kinase (ERK) 1/2 was recruited.