The safety of selleckchem Crizotinib PAD inhibition is a major consideration. The physiological role of the di?erent PAD enzymes is incompletely understood but there are proteins in the stratum corneum and myelin sheath that are constitu tively deiminated. Citrullination also appears to play a role in apoptosis, formation of neutrophil extracellular traps, altering chemokine function and, in the case of PAD4, regulating DNA transcription. Only PAD2 and PAD4 have been identi?ed in the synovium and most attention in RA has focused on PAD4, which has a more limited tissue distribution being mainly expressed in leucocytes. PADI4 polymorphisms are associated with RA in East Asian populations, and autocitrullinating PAD4 is itself an autoantigen in RA.

Whilst PAD2 can be found in the synovium Inhibitors,Modulators,Libraries Inhibitors,Modulators,Libraries of both osteoarthritis and RA, Foulquier and colleagues could only identify PAD4 in in?ammatory synovitis. It is therefore of interest that Makrygiannakis and colleagues found glucocorticoids to reduce PAD4 consistently, but not PAD2. PAD2 levels, however, are known to increase as monocytes di?erentiate into macrophages, which make up a large proportion of lining cells in RA synovium. Studies of synovial ?uid in our laboratory showed that PAD4 could be found in both osteoarthritis and in?ammatory arthritis, whereas PAD2 was limited to in?ammatory disease. Notably, Makrygiannakis and colleagues found synovial PAD2 levels to correlate with in?ammation rather better than PAD4. Only a small number of potentially citrullinated proteins are antigenic targets Inhibitors,Modulators,Libraries in RA, and evidence is emerging that PAD2 and PAD4 di?er in their substrate speci?city.

Further studies of these enzymes are needed to better understand their regulation, their relative contribution to citrullination in RA and, in particular, their substrate speci?city, to guide therapeutic development. Vossenaar and van Venrooij have described citrullinated proteins as sparks that may ignite the ?re of RA. Inhibitors,Modulators,Libraries The ?ndings of Makrygiannakis and colleagues suggest that PAD enzymes may also provide the fuel that keeps the ?re burning, and that their inhibition may be a key target for novel therapy. Introduction Rheumatoid arthritis is one of the most common immune mediated diseases and is characterized by syno vial inflammation and joint destruction. Mitogen activated protein kinases are highly activated in rheumatoid synovium and potentially contribute to inflammatory and destructive mechanisms.

The c Jun N terminal kinases, which belong to the MAPK family, play important Inhibitors,Modulators,Libraries roles in cytokine production and extracellular matrix degradation by reg ulating matrix metalloproteinase in fibroblast like synoviocytes and animal models of RA. Of the three JNK isoforms, JNK1 has been implicated as a pivotal regulator of synovial inflammation in murine arthritis selleck catalog due to its role in mast cell degranulation and macrophage migration.