Abstract
Inflammatory joint conditions are characterized by synovial inflammation, which involves activation of fibroblast-like synoviocytes (FLSs) and production of inflammatory mediators and matrix metalloproteases (MMPs) in joints. This study showed that the snake venom metalloprotease (SVMP) BaP1 activates FLSs to produce PGE2 by a mechanism dependent on COX-2, mPGES-1 and iPLA2s. BaP1 also induces IL-1β release, which up-regulates the production of PGE2 at a late stage of the stimulation. Expression of COX-2 and mPGES-1 are induced by BaP1 via activation of NF-κB pathway. While NF-κB p50 and p65 subunits are involved in up-regulation of COX-2 expression, only p65 is involved in BaP1-induced mPGES-1 expression. In addition, BaP1 up-regulates EP4 receptor expression. Engagement of this receptor by PGE2 triggers a positive feedback loop for its production by up-regulating expression of key components of the PGE2 biosynthetic cascade (COX-2, mPGES-1 and the EP4 receptor), thus contributing to amplification of BaP1-induced effects in FLSs. These data highlight the importance of FLS as a target for metalloproteases in joint inflammation and provide new insights into the roles of MMPs in inflammatory joint diseases. Moreover, our results may give insights into the importance of the catalytic domain, of MMPs for the inflammatory activity of these enzymes.
Highlights
Inflammatory joint conditions are characterized by synovial inflammation, which involves activation of fibroblast-like synoviocytes (FLSs) and production of inflammatory mediators and matrix metalloproteases (MMPs) in joints
prostaglandin E2 (PGE2) is recognized as a key mediator in the pathogenesis of inflammatory arthropathies[30,31].The release of this prostanoid from macrophages has been reported to be induced by MMPs, which are present in high levels in inflamed articular joints[19]
The ability of MMP-1 and -3 to release PGE2 from isolated macrophages has been described previously in the literature[19], to our knowledge this is the first report that provides evidence of a metalloprotease inducing production of PGE2 in FLSs. As these synoviocytes are a major source of PGE2 in joints and PGE2 is a crucial mediator of inflammatory arthropathies, our findings may help in the design of new therapeutic agents to treat inflammatory joint diseases
Summary
Inflammatory joint conditions are characterized by synovial inflammation, which involves activation of fibroblast-like synoviocytes (FLSs) and production of inflammatory mediators and matrix metalloproteases (MMPs) in joints. Fibroblast-like synoviocytes, which are known as B-type synoviocytes, are key cells implicated in synovitis They play a crucial role in driving persistent inflammation and articular damage by releasing various inflammatory mediators and take on an aggressive, invasive phenotype, leading to the breakdown of cartilage by matrix metalloproteases, which are found in high levels in synovial fluid during articular inflammatory processes[3,4,5,6,7]. PGE2, which is converted from arachidonic acid (AA) by the cyclooxygenases (COXs) enzymes and terminal PGE-synthases, plays a pivotal role in the pathogenesis of inflammatory arthropathies by mediating vasodilation, vascular permeability and pain[14,15] This prostanoid has been shown to modulate bone resorption by stimulating osteoclast formation from precursor stem cells, suggesting its involvement in tissue destruction, a characteristic of arthritic diseases[16]. PGE2 has been detected in high concentrations in the synovial fluid, synovial membrane and serum of patients with rheumatoid arthritis and osteoarthritis, together with MMPs and other inflammatory mediators[18]
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