Session Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis
Session Type: Abstract Submissions (ACR)
Cyclic phosphatidic acid (cPA) is one of bioactive lipid, has been implicated as an mediator of various biological effects including i) antiproliferative effect on eukaryotic cell cycle, ii) regulation of Ca2+release, iii) regulation of actin rearrangement, iv) inhibition of tumor cell invasion. Furthermore, on human skin fibroblasts, cPA stimulates high molecular hyaluronic acid (HA) production through up-regulating HA synthase (HAS). cPA also has shown to have antinociceptive effect on animal models of acute and chronic pain. We have previously confirmed that cPA also stimulated HAS2 production on human osteoarthritic chondrocytes and synovial fibroblasts in vitro. Furthermore, we have shown that intra-articular administration of cPA suppressed pain, swelling, and articular cartilage degeneration in rabbit experimental osteoarthritis. These compelling results lead to a hypothesis that cPA may have direct role on anti-inflammation and protection of cartilage in arthritic condition. The aim of this study was to evaluate the effects of cPA on rheumatoid synovial fibroblasts which are under more severe inflammatory condition than osteoarthritis.
Methods: In vitro studies were performed using synovial fibroblasts obtained from rheumatoid arthritis patients at joint replacement surgery. cPA 0-25 μM was added to synovial fibroblasts cultures and effects of cPA on synovial fibroblasts on HAS, HYAL, ADAMTS-4, ADAMTS-5, MMP-3, TIMP-3 expression were assessed at 24 and 48hrs by real time PCR using specific primers to corresponding genes. Synovial fibroblasts were also cultured with IL-1β and/or TNF-α, to study attenuated effect of cPA. Beta-actin was used as endogenous expression control.
Results: cPA stimulated endogenous HA synthesis from synovial fibroblasts as time and dose-dependent manner in vitro. HAS2 gene was up-regulated as dose–dependent manner. IL-1β and/or TNF-α addition didn’t effect much on HAS2 expression, however addition of cPA stimulated HAS2 on synovial fibroblast with cytokines. On the other hand, cPA repressed HYAL-1 and HYAL-2 expression, and IL-1β (and/or TNF-α) stimulated HYAL-1 and -2, and cPA further repressed HYAL expression stimulated by cytokines. Not only with HYAL, cartilage degenerating enzymes, ADAMTS-4, ADAMTS-5, MMP-3 in synovial fibroblasts were all repressed by cPA, even after stimulated by cytokines.
Conclusion: The in vitro results confirmed that cPA had stimulatory effects on HA synthesis by rheumatoid synovial fibroblasts. The suppressing effect of HYAL, ADAMTS-4, ADAMTS-5, and MMP-3 on rheumatoid synovial fibroblasts by cPA shown here, might have played direct role to suppressing inflammation and also protecting articular cartilage of arthritic condition. Molecular mechanism of cPA to prevent cartilage degeneration remains to be elucidated, however, further study should be warranted for cPA as a novel candidate for therapeutic agent of arthritis.
Teijin, Eizai, Tanabe Mitsubishi, Takeda, Bristol-Myer ,
SANSHO Co. Ltd,
Abbott, AbbVie, Asahikasei , Astellas, AstraZeneca, Bristol-Myers Squib, Chugai, Daiichi Sankyo, Eisai, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, MSD, Nippon Kayaku, Pfizer, Santen, Taishotoyama, Takeda, Teijin,
Abbott, AbbVie, Astellas, AstraZeneca, Bristol-Myers Squib, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Nippon Kayaku, Pfizer, Takeda, Teijin,
Abbott, AbbVie, Astellas, Bristol-Myers Squib, Chugai, Eisai, Mitsubishi Tanabe, Pfizer, Takeda, Teijin,
Abbvie Japan, Chugai Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, Takeda Pharmaceutical,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cyclic-phosphatidic-acid-cpa-suppresses-mmp-3-a-disintegrin-and-metalloproteinase-with-thrombospondin-motifsadamts-4-5-and-stimulates-has2-expression-in-inflammatory-rheumatoid-synovial-fibrobl/