Inhibitors of HDACs, phosphatase inhibitor originally developed as anti can cer agents, exhibit anti proliferative activity of the cells through multiple mechanisms, such as induction of apop tosis, cell cycle arrest, and promotion of cell differentia tion, via modulation of gene expression. It was reported that Inhibitors,Modulators,Libraries HDAC inhibitors can also reduce the expression of inflammatory mediators, such as TNF, IL 1B, IL 6, IL 8, transforming growth factor B, and nitric oxide that are involved in the pathogenesis of inflamma tory diseases. We have reported recently that FK228, an inhibitor of class I HDAC shows inhibitory effects on the proliferation of synovial Inhibitors,Modulators,Libraries fibroblasts from RA and ameliorates collagen antibody induced pathology in mice. The inhibition of cell proliferation by FK228 treatment was accompanied by the induction of p16INK4a and the up regulation of p21WAF1 Cip1 expression in RASFs.

Inhibitors,Modulators,Libraries Moreover, the expression of TNF and IL 1B was markedly reduced in the synovium of mice treated by FK228. However, it remains unknown which HDACs are specifically involved in the process of RA inflammation. This information would be necessary for the develop ment of new drugs that would avoid adverse side effects including haematological toxicity and gastrointestinal symptoms. It is unclear why the inhibition of HDAC ameliorates experimentally induced arthritis if HDAC HAT is shifted toward histone hyper acetylation. Here we investigated the expression profiles of class I and II HDACs in OA and RA synovial tis sues, to identify the candidate HDAC gene in synovial inflammation in RA.

We examined HAT and HDAC activities in the total nuclear extracts of synovial tissues from Inhibitors,Modulators,Libraries RA patients predominantly treated with conven tional DMARDs, and their relationship with the cytoplas mic level of TNF. Our data might provide new leads toward future developments of specific HDAC inhibitors for epigenetic regulation of RA. Materials and methods Patients and tissue sampling We obtained total synovial tissue specimens from 15 RA and 13 OA patients, and 3 normal control patients under going orthopedic surgery at Okayama University Hospi tal, with informed consent from the patients. All RA patients fulfilled the 1987 revised criteria of the Ameri can Rheumatism Association. The study protocol is approved by Okayama University Institutional Review Board and by local ethic com mittees at respective institute Inhibitors,Modulators,Libraries where available. Normal synovial tissues were obtained from amputation surgery for a malignant tumor, and ligament reconstruc tion surgery. Baseline characteristics of the patients are summarized in Table 1. Most RA patients were receiving nonsteroidal anti inflammatory drugs , oral corticosteroid at 7. 5 mg, and DMARDs such as methotrexate and sulfasalazine, but not anti TNF selleck products treatment.