There is substantial evidence that IL-6 plays an important role in rheumatoid inflammation [58]. In addition, IL-6 is suggested to have a pathogenetic role in
abnormal bone resorption in RA [72]. IL-6 induces abnormal osteoclastogenesis in the inflamed joints of RA via the induction of RANKL expression in osteoblasts and synoviocytes [72] and [73]. With regard to joint cartilage, matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) are thought to play crucial roles in cartilage matrix degradation. IL-6 induces the production of MMPs (MMP-1, MMP-3 and MMP-13) and ADAMTS-4 from chondrocytes [74]. These findings suggest that IL-6 plays a number of critical roles in the pathogenesis of joint diseases. We have shown that FLS constitutively expresses gp130, but not IL-6R (Fig. Alectinib 3) [75]. In contrast, sIL-6R was detected in synovial fluids from patients
with ID and/or OA of TMJ [65]. In the interacapsular pathologic condition of TMJ, MMP production may be enhanced in FLS through the IL-6/sIL-6R/gp 130 complex, as sIL-6R exists in synovial fluids and IL-6 is produced by FLS in the presence of IL-1β and/or TNF-α. Cyclooxygenase (COX) -2, also known as prostaglandin-endoperoxide synthase 2 (PTGS2), was ranked 8 among the top 10 up-regulated genes in FLS treated with IL-1β (Table 1). In contrast, COX-2 was not observed among the top 10 up-regulated genes with TNF-α, although it was rank 17 (data not shown). COXs GPCR Compound Library price are the rate-limiting enzyme
in the synthesis of biological mediators known as prostanoids, consisting of prostaglandin (PG) D2, PGE2, PGF2a, prostacyclin PGI2 and thromboxane A2[76]. Following cellular activation, arachidonic acid (AA) is released from membrane phospholipids by phospholipase A2 and is then converted to the PGs intermediate PGH2 by COXs. Short-lived PGH2 is then quickly converted most to five prostanoids by each prostanoid synthase. COX-1 is a constitutive enzyme in the majority of cells. In contrast, COX-2 is inducible in response to inflammation, its gene expression can be induced by multiple cytokines and growth factors, via activation of transcriptional regulatory proteins that act on the promoter sites, such as NFkB, AP1 and C/EBP [77] and [78]. COX-3 is a splice variant of COX-1 [79]. PGE2 is the most studied member of the eicosanoid family and is generated from unsaturated 20-carbon fatty acids such as AA, playing a pivotal role in inflammation by mediating local dilatation of blood vessels, increasing blood vessel permeability and sensitizing peripheral nociceptors [80]. PGE2 exerts a range of biological activities that include stimulation of inflammation-associated bone resorption [81].