Abstract
Objective: To determine the symptomatic and disease-modifying capabilities of sEH and COX inhibitors during joint inflammation.Methods: Using a blinded, randomized, crossover experimental design, 6 adult healthy horses were injected with lipopolysaccharide (LPS; 3 μg) from E. coli in a radiocarpal joint and concurrently received the non-selective cyclooxygenase (COX) inhibitor phenylbutazone (2 mg/kg), the sEH inhibitor t-TUCB (1 mg/kg) or both (2 mg/kg phenylbutazone and 0.1, 0.3, and 1 mg/kg t-TUCB) intravenously. There were at least 30 days washout between treatments. Joint pain (assessed via inertial sensors and peak vertical forces), synovial fluid concentrations of prostanoids (PGE2, TxB2), cytokines (IL-1β, IL-6, TNF-α) and biomarkers of collagen synthesis (CPII) and degradation (C2C) were measured at pre-determined intervals over a 48-h period. The anti-apoptotic effect of COX and sEH inhibitors was determined via ELISA technique in primary equine chondrocytes incubated with TNF-α (10 ng/ml) for 24 h. Apoptosis was also determined in chondrocytes incubated with sEH-generated metabolites.Results: Combined COX and sEH inhibition produced significantly better control of joint pain, prostanoid responses, and collagen synthesis-degradation balance compared to each compound separately. When administered separately, pain control was superior with COX vs. sEH inhibition. Cytokine responses were not different during COX and/or sEH inhibition. In cultured chondrocytes, sEH inhibition alone or combined with COX inhibition, but not COX inhibition alone had significant anti-apoptotic effects. However, sEH-generated metabolites caused concentration-dependent apoptosis.Conclusions: Combined COX and sEH inhibition optimize pain control, attenuate loss of articular cartilage matrix during joint inflammation and cytokine-induced chondrocyte apoptosis.
Highlights
Inflammation of the synovial lining and cartilage damage are prominent features of osteoarthritis (OA), strongly correlating with pain sensitization and disease severity
Combined COX and soluble epoxide hydrolase (sEH) inhibition produced significantly better control of joint pain, prostanoid responses, and collagen synthesis-degradation balance compared to each compound separately
Chondrocytes are especially susceptible to endoplasmic reticulum (ER) stress, an important mechanism leading to chondrocyte apoptosis [10,11,12] which correlates with synovitis in OA [13]
Summary
Inflammation of the synovial lining (i.e., synovitis) and cartilage damage are prominent features of osteoarthritis (OA), strongly correlating with pain sensitization and disease severity. The arachidonic acid-derived metabolites 8,9, 11,12-, and 14,15-dihydroxyeicosatrienoic acids (DiHETs), which are converted by soluble epoxide hydrolase (sEH) from the corresponding epoxyeicosatrienoic acid (EETs) regioisomers (Figure 1), were found to be significantly associated with the prevalence and progression of knee OA in older adults [18] This finding is important because a growing body of evidence suggests that, by preventing conversion of EETs to DiHETs, sEH inhibitors promote inflammatory resolution [19], antinociception [20,21,22,23,24,25], prevent ER stress and apoptosis [26,27,28], and support organ and tissue repair [29]. SEH inhibition alone or combined with COX inhibition could represent a significant development in the management of OA by conferring both symptom- and disease-modifying effects
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