Targeting Soluble Epoxide Hydrolase and Cyclooxygenases Enhance Joint Pain Control, Stimulate Collagen Synthesis, and Protect Chondrocytes From Cytokine-Induced Apoptosis

Laura Tucker, Troy N. Trumble, Donna Groschen, Erica Dobbs, Caroline F. Baldo, Erin Wendt-Hornickle, Alonso G.P. Guedes

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish (US)
Article number685824
JournalFrontiers in Veterinary Science
Volume8
DOIs
StatePublished - Aug 5 2021

Bibliographical note

Funding Information:
This project was supported by grants from Grayson Jockey Club Research Foundation, Inc (grants 2016-#209 and 2018-#239). This project was also supported in part by the College of Veterinary Medicine, University of Minnesota.

Publisher Copyright:
© Copyright © 2021 Tucker, Trumble, Groschen, Dobbs, Baldo, Wendt-Hornickle and Guedes.

Keywords

  • arthritis
  • equine model
  • lameness
  • mobility
  • osteoarthritis
  • synovitis

PubMed: MeSH publication types

  • Journal Article

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