Taken together, a schematic hypothesis of the role of CTGF in the RA pathogenesis is presented in Figure 7. It has been reported http://www.selleckchem.com/products/arq-197.html that CTGF adenovirus vector transfection into knee joints of mice induces linier overexpression of CTGF in the synovium and results in cartilage damages with increas ing of mRNA cording for degradative enzymes such as MMP Inhibitors,Modulators,Libraries 3. Manns and co workers also reported that CTGF is up regulated in an experimental animal model of RA, and they have shown that treatment with thrombospondin 1 derived peptide is associated with down regulation of CTGF concomitant Inhibitors,Modulators,Libraries with the disease amelioration. Furthermore, the null knock down of the CTGF gene dramatically inhibits osteoclast like formation in mice. Their reports indicate that CTGF has a significant role for RA pathogenesis and our present data can support these previous reports.

The synovial tissue in the inflamed joints of RA can invade bones and this is supported by the invasive nature of the syn ovial fibroblasts gaining the capacity to move and penetrate into cartilages and bones. Osteoclasts are the sole bone absorbing cells and the functions of osteoclasts Inhibitors,Modulators,Libraries are increased in RA patients as well as in patients with osteoporosis. Osteo clasts are commonly found within the erosive pit at the interfer ence of synovial inflammatory tissue and subchondral bone. RANKL is a membrane residing protein on osteoblasts and recognizes its receptor expressed on marrow macrophages, promoting them to differentiate into the osteo clast phenotype in the presence of M CSF.

These molecules are expressed locally in Inhibitors,Modulators,Libraries the synovial tissues of RA patients and TNF is an inducer of RANKL expression as well Inhibitors,Modulators,Libraries as IL 1 and IL 6. Therefore, aberrant osteoclastogen esis play an important role in the development of RA and this process is further positively regulated by proinflammatory cytokines like TNF under pathogenic conditions. As shown in Figure 2, strong CTGF expression appeared to be observed at inflamed synovial fibroblasts derived from surgical samples of RA patients. Furthermore, CTGF was upregulated by TNF in human synovial fibroblasts cell line, MH7A, as shown in Figure 3A. The present data indicate that excessive CTGF pro duction from synovial fibroblasts with RA patients induced by TNF can promote aberrant activation of osteoclasts in com bination with RANKL M CSF, resulting in bone destruction. In addition, we found a CTGF receptor, integrin V 3, on the osteoclasts. Integrins are heterodimec adhesion receptors that mediate mostly cell matrix interaction.