Targeting the therapeutic potential of soluble epoxide hydrolase for the treatment of osteoarthritis pain

Osteoarthritis (OA) affects ~10million adults in the UK, damaging multiple inter-connecting joint tissues. Inflammation of the joint lining (synovium), which contains nerves that detect painful signals, involves substances which promote swelling and pain, and other substances which inhibit these processes to allow healing.

Our research is focused on a group of molecules (EETs) that reduce inflammation and pain. We showed that people with lower levels of EETs and higher levels of the inactive metabolites (DHETs) have more severe OA pain and greater progression of OA joint damage. EETs are metabolised by the enzyme soluble epoxide hydrolase (sEH).

We found that levels of this enzyme in the synovium are higher in people with painful OA, and we have linked small genetic differences (variants) in the gene (EPHX2) for sEH to the amount of OA pain people experience.

Hypothesis: the effectiveness of sEH in breaking-down the beneficial EET molecules into their inactive metabolites contributes to the amount of OA pain people experience, providing an opportunity for new targeted treatments.

Here, we will determine the cellular processes by which knee joint sEH contributes to OA inflammation and pain, and demonstrate the analgesic properties and therapeutic potential of directly and locally inhibiting this enzyme. Project Outcomes will be delivered by 3 Objectives (Objs):

Obj. 1: In 120 people undergoing knee surgery for OA pain, we will determine the relationship between sEH expression and activity in the synovium and pain (assessed by validated questionnaires and nurse-led testing). The presence of known pain-related EPHX2 variants in the synovium will be tested. Relationships between levels of EETs/DHETs in plasma and synovial fluid, and their associations with pain and sEH activity, will be established.

In pre-collected knee surgery synovium, relationships between sEH expression and activity and OA joint inflammation scores will be analyzed, and sEH localization to cell populations in the synovium determined.

Obj. 2: Using human derived cells and gene editing technology, the effects of an OA-relevant inflammatory stimulus and EPHX2 variants on the ability of sEH to break-down EETs and modulate the responses of inflammatory-regulating cells (fibroblasts and macrophages) will be determined. This will establish the critical importance of sEH in the crosstalk of inflammatory processes that may contribute to OA pain.

Obj. 3: The role of sEH in regulating the signals that communicate pro- or anti-inflammatory messages between inflammatory cells and how these can impact sensory neuron function will be studied. To maximize the translational potential of our findings we will use a clinically relevant mouse model of OA pain, to test the effects of pharmacological inhibition of knee joint sEH on established OA pain behaviour responses and levels of EETs/DHETs.

Project outcomes will provide new clinical knowledge and mechanistic insight into how sEH regulates inflammation and pain signaling to support future development of new treatments for OA pain.

Outcomes will benefit academics studying mechanisms of inflammatory signalling, pathological cellular interactions in pain and other chronic inflammatory diseases linked to sEH function (Alzheimer's disease, kidney and cardiovascular disease, stroke). Outcomes for the pharmaceutical sector include new knowledge to support the development of novel efficacious treatments, which have less side effect risk.

Outcomes will be disseminated via our existing national clinical networks, the Pain Centre Versus Arthritis and the UKRI funded Advanced Pain Discovery platform, conference presentations, publications and social media.