Endocannabinoid Tone and Oxylipins in Rheumatoid Arthritis and Osteoarthritis-A Novel Target for the Treatment of Pain and Inflammation?

Abstract

Inflammation is a complicated physiological process that contributes to a variety of disorders including osteoarthritis (OA) and rheumatoid arthritis (RA). Endocannabinoids and the endocannabinoid system (ECS) play a pivotal role in the physiological response to pain and inflammation. A clinical study to investigate the role of the endocannabinoid system and related lipids in pain and inflammation in OA and RA was performed. In total, 80 subjects, namely, 25 patients with RA, 18 with OA, and 37 healthy participants, were included. Sixteen endocannabinoids and congeners, as well as 129 oxylipins, were quantified in plasma using specific, quantitative LC-MS/MS assays. The endocannabinoid analysis revealed significantly lower levels of 2-arachidonoylglycerol (2-AG) in RA and OA patients compared to healthy participants. In contrast, the EC levels of the ethanolamide group (anandamide, docosahexaenoyl-EA, palmitoleoyl-EA, and other ethanolamides) were higher in the RA study cohort and to a lesser extent also in the OA cohort. This analysis of oxylipins revealed lower levels of the pro-resolving lipid 9-oxo-octadecadienoic acid (9-oxoODE) and the ω-3 fatty acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) in RA compared to all other study cohorts. 2-AG is a key regulator of nociception and inflammation, and its relatively low levels might be a mechanistic contributor to residual pain and inflammation in RA and OA. Several changes in pro- and anti-inflammatory lipid mediators were detected, including lower levels of EPA and DHA in RA, which might reveal the potential for nutritional supplementation with these anti-inflammatory fatty acids.

Keywords: biomarkers; endocannabinoid system; inflammation; osteoarthritis; pain; rheumatoid arthritis.

Figure 1

Key inflammatory cytokines for the development and severity of RA. Values for osteoarthritis (OA) and rheumatoid arthritis (RA) compared to healthy controls (C). For abbreviations, please see the text. Data are shown as mean ± SEM. * FDR < 0.05.

Figure 2

Changes in endocannabinoids and congeners that are broken down by monoacylglycerol lipase (2-AG) and fatty-acid amide hydrolase (AEA, DEA, OLA, OEA, and PEA) in osteoarthritis (OA) and rheumatoid arthritis (RA) compared to healthy controls (C). 2-AG (top left, (A)), AEA, (top center, (B)), DEA (top right, (C)), OLA (bottom left, (D)), OEA (bottom center, (E)), and PEA (bottom right, (F)) plasma levels in osteoarthritis (n = 17), rheumatoid arthritis (n = 25) and in age-matched healthy controls (n = 37). Data are shown as mean ± SEM. * FDR < 0.05. Significance for the comparison of OA versus healthy controls is not displayed since these were statistically non-significant (FDR > 0.05).

Figure 3

Plasma levels of fatty acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) that make up the Omega-3 Index (O3I), a cardiovascular risk marker. Study groups: healthy controls (C, n = 37), patients with osteoarthritis (OA, n = 17), and patients with rheumatoid arthritis (RA, n = 25). Data are shown as mean ± SEM.