Background/Purpose: In rheumatoid arthritis (RA), synovial fibroblasts (SF) secrete large amounts of IL-6, IL-8 and matrix metalloproteinases (MMPs) which are crucial for cartilage destruction. RASFs are sensitive to the action of cannabinoids and they express cannabinoid receptors type I and II (CB₁ and CB₂), the vanilloid receptor (TRPV1) as well as endocannabinoid degrading enzymes (FAAH and COX-2). Cannabinoids are regarded as antiinflammatory and since anandamide (AEA) is found in RA synovial fluid we investigated how this endocannabinoid affects adhesion, proliferation and production of inflammatory mediators of RASF.

Methods: Adhesion was assessed by the XCELLigence system. Proliferation was quantified by the amount of incorporated fluorescent dye into cellular DNA. MMP-3 and cytokines were detected by ELISA. Collagen II induced arthritis was used a s a mouse model of RA.

Results:   AEA dose-dependently decreased IL-1β induced production of MMP-3, IL-6 and IL-8 in RASFs and OASFs under normoxic conditions (20% O₂). The efficacy of AEA was significantly enhanced by addition of the COX-2 inhibitor nimesulide. The effects of AEA were not inhibited by CB₁, CB₂ or GPR55 antagonists but were blocked by the TRPV1 antagonist capsazepine in RASFs but not OASFs.  Under hypoxic conditions (1% O₂) and TNF stimulation, the effects of AEA on cytokine and MMP-3 production were blocked by TRPA1 and TRPV1 antagonists.In mixed synovial cell cultures however, AEA increased the production of TNF (100%) which was enhanced by inhibition of AEA degradation.Furthermore, AEA increased adhesion of OASFs and RASFs to fibronectin. Adhesion was modulated by CB₁, GPR55, and TRPV1 antagonists in OASFs but not in RASFs. Combined FAAH and COX-2 inhibition blocked the stimulatory effect of AEA on adhesion in OASF. Proliferation was decreased by AEA in RASFs and OASFs via a cyclooxygenase-2 but not via CB₁, CB₂ or TRPV1 dependent mechanism.Elevation of endogenous AEA by inhibition of its degradation showed beneficial effects in collagen-induced arthritis in mice.

Conclusion: In conclusion, AEA promotes an antiinflammatory phenotype of RASFs and OASFs by activating/desensitizing TRPV1 and TRPA1 under hypoxic conditions. Furthermore, COX-2 inhibition is necessary to fully exploit the therapeutic potential of AEA. This might be important in RA where low oxygen and abundant cytokine expression up-regulate COX-2 in the joint.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-endocannabinoid-anandamide-modulates-adhesion-proliferation-and-the-production-of-inflammatory-mediators-in-rheumatoid-arthritis-synovial-fibroblasts-by-activating-cb1-trpv1-trpa1-and-non-canna/