Clinical and preclinical evidence for roles of soluble epoxide hydrolase in osteoarthritis knee pain

AbstractObjective

Chronic pain due to osteoarthritis (OA) is a major clinical problem, existing analgesics often have limited beneficial effects and/or adverse effects, necessitating the development of novel therapies. Epoxyeicosatrienoic acids (EETs) are endogenous anti-inflammatory mediators, rapidly metabolized by soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs). We hypothesized that sEH driven metabolism of the EETs to DHETs plays a critical role in chronic joint pain associated with OA and provides a new target for treatment.

Methods

Potential associations between chronic knee pain in people and single nucleotide polymorphisms (SNPs) in the gene encoding sEH and circulating levels of the EETs and DHETs were investigated. A surgically-induced murine model of OA was used to determine the effects of both acute and chronic selective inhibition of sEH by N-[1-(1-oxopropy)-4-piperidinyl]-N’-(trifluoromethoxy)phenyl]urea (TPPU) on weight-bearing asymmetry, hind-paw withdrawal thresholds, joint histology, and circulating concentrations of the EETs and DHETs.

Results

In people with chronic knee pain, 3 pain measures were associated with SNPs of the sEH gene, EPHX2, and in two separate cohorts circulating levels of EETs and DHETs were also associated with 3 pain measures. In the murine OA model, systemic administration of TPPU both acutely and chronically reversed established pain behaviours and decreased circulating levels of 8,9-DHET and 14,15-DHET. The levels of the EETs were unchanged by TPPU administration.

Conclusion

Our novel findings support a role of sEH in OA pain and suggest that inhibition of sEH and protection of endogenous EETs from catabolism represents a potential new therapeutic target for OA pain.