ical for IL 18 e pression, whereas the JNK 2 and NF ��B pathways were important for IL 18BP e AZD9291 pression. Compared to our previous results, we found a new specific pathway for regulating IL 18 bioactivity, that is, the JAK pathway. TNF induces many intracellular signaling pathways. The JAK pathway is activated by TNF through its binding to its type I receptor. Furthermore, e pression of che mokines induced by TNF was reduced by blocking the JAK pathway in RA synovial fibroblasts and in RA synovial macrophages. So in this model, blocking the JAK2 pathway specifically reduced TNF induced IL 18 bioactivity only by reduction of IL 18 secretion due to inhibition of functional caspase 1. In vivo, JAK2 pathway inhibition has been shown to improve inflammatory arth ritis in a rodent model and blocking JAK1 3 has been shown to reduce joint destruction.

JAK inhibitors suppress both innate and adaptative immunity in the K B N serum transfer model. In human RA, JAK inhibitors are a new attractive therapeutic option for RA management. Conclusions These results provide a novel way to regulate TNF induced IL 18 bioactivity by blocking capase 1. These results suggest an additional mechanism to e plain the beneficial effect of JAK inhibitors in RA. Introduction Osteoarthritis, which is the most common chronic degenerative joint disorder worldwide, is characterized primarily by cartilage degradation and narrowing of the joint spaces. Both genetic and acquired factors, such as obesity, mechanical influences and age, are involved in the comple pathogenesis of OA, whereby cartilage homeo stasis is disrupted by biophysical factors and biochemical factors.

The chondrocyte is a unique resident cell that synthesizes cartilage specific e tracellular matri components as GSK-3 well as various catabolic and anabolic factors. The pathogenesis of OA activates various biochemical pathways in chondrocytes, leading to proin flammatory cytokine production, inflammation, degradation of the ECM by matri metalloproteinases and a disintegrin and metalloproteinase with thrombospondin motifs, and cessation of ECM synthesis via the dedifferentiation and apoptosis of chondrocytes. How ever, the molecular mechanisms underlying OA are not yet fully understood. The elucidation of such mechanisms could facilitate the development of new and effective thera peutic targets for the treatment of OA.

The Wnt signaling pathway is involved in cartilage de velopment and homeostasis, as evidenced by the fact that a number of Wnt proteins and Frizzled receptors are e pressed in chondrocytes and the synovial tissues of arthritic cartilage. Interestingly, both chondrocyte specific conditional activation and selective inhibition of B catenin in mice have been shown to yield OA like phenotypes, selleck chemicals Tofacitinib albeit via different mechanisms. Several additional lines of evidence link Wnt B catenin signaling with OA, further supporting the notion that the Wnt B catenin pathway plays a role in the pathophysiology of cartilage. Low de