The effects of inhibitors of NO synthesis was assessed by analysis of the gene expression of iNOS and the release of nitrite as an indicator BX-795 of NO production. Although it has been suggested that p38-dependent Involved-dependent mechanism in the regulation of the expression of iNOS and NO synthesis is, the p38a / b MAPK inhibitors tested apparently not directly prevent the induction of iNOS. Significant inhibition of the expression of iNOS was SB203580 and CBS 3868 h performed only after 24 hours. Both the humble Ma the suspension and temporal Ver changes m moderately described are consistent with multiple mechanisms of regulation of gene expression iNOS above, and best term that p38a MAPK is neither directly nor a single regulator of the expression of iNOS and the synthesis of NO .
The induction was regulated by IL 1b of the MMP13 gene expression efficiency CP-466722 and the concentration–Dependent inhibition by all test compounds. at concentrations of 1 mM and 10, is the degree of inhibition similar. 0th 1 mM, the degree of inhibition, which was with the BIRB 796 and CBS 3868 against pamapimod and SB203580, the inhibitory potency of the test compounds on p38a MAPK activity Correlated t done. A promising new approach for inhibiting cartilage degradation has been recently. By Kimura et al sented the pr a new inhibitor, SB203580 inhibited in contrast, MMP13 expression, but not the expression of MMP others. The effects of p38MAPK inhibitors on gene expression TNFRSF11B were divergent. In vivo, the receptor TNFRSF11B supposedly Decoy st Rt RANK / RANKL signaling, thereby preventing osteoclast RANKL mediation.
TNFRSF11B protein regulation has not only been described in chondrocytes treated IL 1b, but also in OA cartilage and synovial fluid of RA patients. The low level of induction, three and five times h to billing at 4 and 24, it is difficult to understand the effects of drugs clearly mediation. BIRB 796 was the lowest inhibitor TNFRSF11B gene expression, which looks forward to the contribution of the other t mechanism that mediates signaling p38a. However in osteosarcoma cells, p38a / b, but not JNK, ERK and NFkB, has been shown to affect the inhibition of IL 1b induced gene expression TNFRSF11B. It is possible to change that Hnlicher mechanism is present in chondrocytes and thus an effect mediated by P38B k Nnte an r Regulation in the expression of TNFRSF11B play.
In summary, in this study were stimulated a dependable Ssige created an in vitro model with IL 1b prim Ren human chondrocytes, with the aim to study and compare the effects of various inhibitors of MAPK P38A / b on the expression of genes. R P38MAPK and JNK isoforms analyzed in the regulation of biomarkers is shown in Figure 4. It has been shown that the effects of test compounds on the expression of COX-2 and MMP13, and release of PGE2, a good correlation with their activity t In inhibiting p38a MAPK. However its effect on seemed mPGES1 and TNFRSF11B expression to the affinity t of the compounds for P38B pleased t be used, that. The form of MAPK These observations shed new light on the r P38B of MAPK in chondrocytes and the necessary a / b t specificity P38MAPK inhibitors.