SAT0560 From a 2-year multicentre clinical trial in knee osteoarthritis, a metabolomic analysis reveals that over activation of the conversion pathway of phosphatidylcholine to lysophosphatidylcholine is associated with knee cartilage volume loss over time
Authors: G. Zhai, J.-P. Pelletier, M. Liu, E. Randell, J. Martel-Pelletier
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> While progression of osteoarthritis (OA) is variable, no tools yet exist to predict disease course. <h3>Objectives</h3> To identify, using a metabolomic approach, serum marker(s) for predicting knee cartilage volume loss over time measured by magnetic resonance imaging (MRI) in a 24 month Phase III clinical trial in patients with symptomatic knee OA. <h3>Methods</h3> 139 knee OA patients who completed the clinical trial according to protocol were selected from a 24 month DMOAD trial studying the effect of licofelone versus naproxen. MRI was performed at baseline and 24 months. Targeted metabolomic profiling was performed on serum collected at baseline. Metabolite ratios as proxies for enzymatic reaction were calculated and used in the analysis. The levels of 186 metabolites were measured and 152 met the quality control requirements. The metabolite concentrations were standardised using the Z-score. 21 952 pair wise metabolite ratios were analysed. A metabolome-wide significance level of a=2.3*10–<sup>6</sup> was defined after correcting multiple testing with the Bonferroni method. Univariable and multivariable analyses adjusted for age, sex, BMI and treatment were performed. Gene expression analysis of human OA articular cartilage (n=32) and subchondral bone (n=39) tissues from total joint replacement, and controls (non-OA) from individuals having a fracture (n=21; n=9, respectively) was done to further explore the potential metabolic pathway(s). <h3>Results</h3> Data revealed that the baseline ratio of the metabolite lysophosphatidylcholine 18:2 (lysoPC 18:2) to phosphatidylcholine 44:3 (PC44:3) was associated with the cartilage volume loss in the lateral compartment (univariable, b=–0.21±0.04, p=8.53*10–<sup>7</sup>; multivariable, b=–0.18±0.04, p=9.5*10–<sup>6</sup>). Further experiments demonstrated that the lysoPC 18:2/PC44:3 ratio was also significantly (r=0.31, p=0.0002) correlated with an articular degradation marker, COMP. The data of the increased lysoPC 18:2 to PC44:3 ratio involve a conversion pathway of PC to lysoPC which is catalysed by a phospholipase A2 (PLA2), suggesting a higher activity of PLA2. Data demonstrated that in both human cartilage and subchondral bone tissues, a PLA2, PLA2 group 5 (PLA2G5), was markedly over-expressed in OA cartilage and subchondral bone compared to these non-OA tissues (445% and 158% increase, respectively, all p&lt;0.02). Interestingly, in these tissues TNF-a was also upregulated (p=0.007; p=0.06, respectively), and positively correlated with PLA2G5 (r=0.71, p=0.02). <h3>Conclusions</h3> Our data suggest that the ratio of lysoPC 18:2/PC44:3 is predictive of greater risk of cartilage loss in OA. We speculate that this specific conversion pathway may produce a bioactive molecule like oleoylethanolamide (OEA), which has been demonstrated to bind to a novel cannabinoid receptor, GPR119, thus could be a novel therapeutic target for OA treatment. <h3>Acknowledgements</h3> This work is supported by Canadian Institutes of Health Research. The metabolomic profiling was done at Translational Metabolomics Innovation Centre. The original clinical trial was supported in part by grants from Merckle GmbH (Ulm, Germany) and ArthroLab Inc. (Montreal, Quebec, Canada). <h3>Disclosure of Interest</h3> G. Zhai: None declared, J.-P. Pelletier Shareholder of: ArthroLab Inc., M. Liu: None declared, E. Randell: None declared, J. Martel-Pelletier Shareholder of: ArthroLab Inc.