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Clinical and Preclinical Evidence for Roles of Soluble Epoxide Hydrolase in Osteoarthritis Knee Pain

Gowler, Peter R. W.; Turnbull, James; Shahtaheri, Mohsen; Gohir, Sameer; Kelly, Tony; McReynolds, Cindy; Yang, Jun; Jha, Rakesh R.; Fernandes, Gwen S.; Zhang, Weiya; Doherty, Michael; Walsh, David A.; Hammock, Bruce D.; Valdes, Ana M.; Barrett, David A.; Chapman, Victoria

Clinical and Preclinical Evidence for Roles of Soluble Epoxide Hydrolase in Osteoarthritis Knee Pain Thumbnail


Peter R. W. Gowler

James Turnbull

Mohsen Shahtaheri

Sameer Gohir

Research Fellow

Cindy McReynolds

Jun Yang

Research Fellow

Gwen S. Fernandes

Michael Doherty

Professor of Rheumatology

Bruce D. Hammock

David A. Barrett


Objective: Chronic pain due to osteoarthritis (OA) is a major clinical problem, and existing analgesics often have limited beneficial effects and/or adverse effects, necessitating the development of novel therapies. Epoxyeicosatrienoic acids (EETs) are endogenous antiinflammatory mediators, rapidly metabolized by soluble epoxide hydrolase (EH) to dihydroxyeicosatrienoic acids (DHETs). We undertook this study to assess whether soluble EH–driven metabolism of EETs to DHETs plays a critical role in chronic joint pain associated with OA and provides a new target for treatment. Methods: Potential associations of chronic knee pain with single-nucleotide polymorphisms (SNPs) in the gene-encoding soluble EH and with circulating levels of EETs and DHETs were investigated in human subjects. A surgically induced murine model of OA was used to determine the effects of both acute and chronic selective inhibition of soluble EH 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 EETs and DHETs. Results: In human subjects with chronic knee pain, 3 pain measures were associated with SNPs of the soluble EH gene EPHX2, and in 2 separate cohorts of subjects, 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 behaviors and decreased circulating levels of 8,9-DHET and 14,15-DHET. EET levels were unchanged by TPPU administration. Conclusion: Our novel findings support a role of soluble EH in OA pain and suggest that inhibition of soluble EH and protection of endogenous EETs from catabolism represents a potential new therapeutic target for OA pain.


Gowler, P. R. W., Turnbull, J., Shahtaheri, M., Gohir, S., Kelly, T., McReynolds, C., …Chapman, V. (2022). Clinical and Preclinical Evidence for Roles of Soluble Epoxide Hydrolase in Osteoarthritis Knee Pain. Arthritis and Rheumatology, 74(4), 623-633.

Journal Article Type Article
Acceptance Date Sep 23, 2021
Online Publication Date Mar 7, 2022
Publication Date 2022-04
Deposit Date Oct 12, 2021
Publicly Available Date Mar 8, 2023
Journal Arthritis and Rheumatology
Print ISSN 2326-5191
Electronic ISSN 2326-5205
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 74
Issue 4
Pages 623-633
Keywords Immunology; Rheumatology; Immunology and Allergy
Public URL
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