NIHR Nottingham Biomedical Research Centre and University of Nottingham, Nottingham, UK.
University of California, Davis.
Arthritis Rheumatol. 2022 Apr;74(4):623-633. doi: 10.1002/art.42000. Epub 2022 Mar 7.
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.
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.
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.
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.
骨关节炎（OA）引起的慢性疼痛是一个主要的临床问题，现有的镇痛药通常疗效有限，/或有不良反应，因此需要开发新的疗法。环氧二十碳三烯酸（EETs）是内源性抗炎介质，可被可溶性环氧化物水解酶（EH）迅速代谢为二羟二十碳三烯酸（DHETs）。我们进行这项研究是为了评估可溶性 EH 驱动的 EETs 代谢为 DHETs 是否在与 OA 相关的慢性关节疼痛中发挥关键作用，并为治疗提供新的靶点。
在人类受试者中，研究了编码可溶性 EH 的基因中的单核苷酸多态性（SNPs）与慢性膝关节疼痛之间的潜在关联，以及循环 EETs 和 DHETs 水平与慢性膝关节疼痛之间的潜在关联。使用手术诱导的 OA 小鼠模型，确定急性和慢性选择性抑制可溶性 EH 对 N-[1-(1-氧代丙基)-4-哌啶基]-N'-(三氟甲氧基)苯基]-脲（TPPU）对负重不对称、后爪撤回阈值、关节组织学和循环 EETs 和 DHETs 浓度的影响。
在慢性膝关节疼痛的人类受试者中，3 种疼痛测量与可溶性 EH 基因 EPHX2 的 SNPs 相关，在 2 个独立的受试者队列中，循环 EETs 和 DHETs 水平也与 3 种疼痛测量相关。在 OA 小鼠模型中，TPPU 的全身给药无论是急性还是慢性给药都能逆转已建立的疼痛行为，并降低循环中 8,9-DHET 和 14,15-DHET 的水平。TPPU 给药对 EET 水平没有影响。
我们的新发现支持可溶性 EH 在 OA 疼痛中的作用，并表明抑制可溶性 EH 并保护内源性 EETs 免受代谢分解可能成为 OA 疼痛的一个新的潜在治疗靶点。
