Background/Purpose:

Paraoxonase 1 (PON1) is an HDL-associated protein, which hydrolyzes biologically active oxidized phospholipids and prevents oxidation of lipids in LDL and HDL. Increased lipid peroxidation and oxidative stress have been implicated in the pathogenesis of rheumatoid arthritis (RA), and we previously reported decreased inflammatory arthritis activity in PON1 transgenic (Tg) mice in 2 RA mouse models. The current work evaluated mechanisms for decreased inflammatory arthritis in PON1Tg mice using the K/BxN serum transfer model of RA.

Methods:

The K/BxN serum transfer-induced arthritis model (STIA) was used in B6 mice homozygous for the PON1 human transgene [PON1Tg] and wild type littermate control mice [WT] (n= 10 per group). Non-STIA PON1Tg (n= 9) and WT (n=10) mice were also evaluated. Liquid chromatography–electrospray ionization, tandem mass spectroscopy was performed for a panel of 13 circulating bioactive lipid mediators (BLM) including TXB2, 6tl 2epi LTB4, LTB4, 15d-D12,14 PGJ2, 13 HODE, 9 HODE, 17S-HDHA, 15 HETE, 14 S-HDHA, 11 HETE, 12 HETE, 5 HETE, and 5-oxoETE. Next-generation RNA sequencing analysis was done on liver tissue. Histopathologic scoring of arthritic hind limbs was performed by a blinded reviewer as were the prior clinical arthritis activity scores.

Results:

Marked reduction in histologic damage was observed in PON1Tg compared to WT mice (p values<0.0002; see Table) consistent with decreases in clinical arthritis scores. WT mice had significant increases in the majority of BLMs (11/13) after arthritis induction, however, PON1Tg mice did not have similar increases, and had significantly lower levels of 9/13 BLMs post-arthritis induction compared to WT mice (Table). Significant correlations were evident between lower levels of BLMs and lower clinical and histologic scores (r values = 0.5 – 0.8, p values < 0.05) for 10/13 BLMs. The hepatic glutathione metabolism pathway was 14-fold upregulated in PON1Tg mice versus WT mice after arthritis induction, controlling for baseline (non-arthritic) expression differences in PON1Tg and WT mice (Bonferroni p value < 1.5E-04). Increased expression of 7/8 genes in this pathway was significantly associated with decreases in circulating BLMs (r values = -0.5 – 0.8, p values <0.05; correlations of raw gene expression counts/various BLMs). Upregulation of GSTM3 (glutathione S-transferase mu 3 ) was highly correlated with both lower histologic damage scores (r = -0.8 – 0.9, p values <0.05) as well as trended with decreased clinical arthritis scores (r = -0.6, p = 0.09).

Conclusion:

Overexpression of the human PON1 transgene in the KBxN STIA model of RA suppressed inflammatory arthritis, which correlated with upregulation of the hepatic glutathione pathway and reduction of circulating BLMs. Further investigation of these findings is warranted to evaluate potentially novel therapeutic targets for treatment of RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/suppression-of-inflammatory-arthritis-in-human-paraoxonase-1-transgenic-mice-correlates-with-upregulation-of-the-hepatic-glutathione-pathway-and-reduction-of-bioactive-lipid-mediators/