FREE SHIPPING over $40
OVER 9000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Home / Equine Research Bank / Front Vet Sci / Targeting Soluble Epoxide Hydrolase and Cyclooxygenases Enha...
Frontiers in veterinary science2021; 8; 685824; doi: 10.3389/fvets.2021.685824

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

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.
Copyright © 2021 Tucker, Trumble, Groschen, Dobbs, Baldo, Wendt-Hornickle and Guedes.
Get Full Text
Publication Date: 2021-08-05 PubMed ID: 34422942PubMed Central: PMC8375305DOI: 10.3389/fvets.2021.685824Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research study explores how pairing inhibitors of the enzymes Soluble Epoxide Hydrolase (sEH) and Cyclooxygenases (COX) can potentially optimize joint pain management, encourage collagen production, and protect cartilage cells during inflammation.

Research Design and Methodology

  • Researchers implemented a blinded, randomized, crossover experimental design, featuring six healthy adult horses.
  • Each horse received an injection of lipopolysaccharide (LPS), a substance known to induce inflammation, directly into a joint, along with either the non-selective COX inhibitor phenylbutazone, the sEH inhibitor -TUCB, or both.
  • A break of at least 30 days was allowed between treatments to clear out any remaining substances from the body.
  • Multiple factors such as joint pain, concentrations of pro-inflammatory molecules, and levels of collagen synthesis markers were measured over a period of 48 hours since the injection.
  • The study also included an evaluation of the potential anti-apoptotic (anti-cell death) effects of the experimental treatments on chondrocyte cells (cells present in healthy cartilage) exposed to a cytotoxic substance in laboratory conditions.

Results and Findings

  • This research revealed that when combined, the COX and sEH inhibitors resulted in improved control of joint pain and enhanced the balance of collagen synthesis-degradation when compared to each compound applied separately.
  • When these inhibitors were given separately, the pain control was better with the COX inhibitor than with the sEH one.
  • No significant changes were noticed in the cytokine responses when COX and/or sEH were being inhibited.
  • In lab-grown chondrocytes, the sEH inhibitor alone or in combination with the COX inhibitor was found to prevent apoptosis to a notable level. On the other hand, the COX inhibitor did not show significant anti-apoptotic effects.
  • Interestingly, the research additionally found that certain by-products of sEH enzyme activity induced apoptosis in a concentration-dependent manner.

Conclusion

  • The findings conclude that combined therapy of COX and sEH inhibitors can potentially improve pain control, reduce cartilage loss during joint inflammation, and protect chondrocytes from cytokine-induced apoptosis.

Cite This Article

APA
Tucker L, Trumble TN, Groschen D, Dobbs E, Baldo CF, Wendt-Hornickle E, Guedes AGP. (2021). Targeting Soluble Epoxide Hydrolase and Cyclooxygenases Enhance Joint Pain Control, Stimulate Collagen Synthesis, and Protect Chondrocytes From Cytokine-Induced Apoptosis. Front Vet Sci, 8, 685824. https://doi.org/10.3389/fvets.2021.685824

Publication

Frontiers in veterinary science
ISSN: 2297-1769
NlmUniqueID: 101666658
Country: Switzerland
Language: English
Volume: 8
Pages: 685824

Researcher Affiliations

Tucker, Laura
  • Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, United States.
Trumble, Troy N
  • Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, United States.
Groschen, Donna
  • Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, United States.
Dobbs, Erica
  • Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, United States.
Baldo, Caroline F
  • Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, United States.
Wendt-Hornickle, Erin
  • Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, United States.
Guedes, Alonso G P
  • Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, United States.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

This article includes 71 references
  1. Loeuille D, Chary-Valckenaere I, Champigneulle J, Rat AC, Toussaint F, Pinzano-Watrin A. Macroscopic and microscopic features of synovial membrane inflammation in the osteoarthritic knee: correlating magnetic resonance imaging findings with disease severity.. Arthritis Rheum (2005) 52:3492–501.
    doi: 10.1002/art.21373pubmed: 16255041google scholar: lookup
  2. Orita S, Koshi T, Mitsuka T, Miyagi M, Inoue G, Arai G. Associations between proinflammatory cytokines in the synovial fluid and radiographic grading and pain-related scores in 47 consecutive patients with osteoarthritis of the knee.. BMC Musculoskelet Disord (2011) 12:144.
    doi: 10.1186/1471-2474-12-144pmc: PMC3144455pubmed: 21714933google scholar: lookup
  3. Neogi T, Guermazi A, Roemer F, Nevitt MC, Scholz J, Arendt-Nielsen L. Association of joint inflammation with pain sensitization in knee osteoarthritis: the Multicenter Osteoarthritis Study.. Arthritis Rheumatol (2016) 68:654–61.
    doi: 10.1002/art.39488pmc: PMC4827020pubmed: 26554395google scholar: lookup
  4. Mathiessen A, Conaghan PG. Synovitis in osteoarthritis: current understanding with therapeutic implications.. Arthritis Res Ther (2017) 19:18.
    doi: 10.1186/s13075-017-1229-9pmc: PMC5289060pubmed: 28148295google scholar: lookup
  5. Wallace G, Cro S, Dore C, King L, Kluzek S, Price A. Associations between clinical evidence of inflammation and synovitis in symptomatic knee osteoarthritis: a cross-sectional substudy.. Arthritis Care Res (2017) 69:1340–8.
    doi: 10.1002/acr.23162pubmed: 27998036google scholar: lookup
  6. Bertone AL, Palmer JL, Jones J. Synovial fluid cytokines and eicosanoids as markers of joint disease in horses.. Vet Surg (2001) 30:528–38.
    doi: 10.1053/jvet.2001.28430pubmed: 11704948google scholar: lookup
  7. Stannus O, Jones G, Cicuttini F, Parameswaran V, Quinn S, Burgess J. Circulating levels of IL-6 and TNF-alpha are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults.. Osteoarthritis Cartilage (2010) 18:1441–7.
    doi: 10.1016/j.joca.2010.08.016pubmed: 20816981google scholar: lookup
  8. Bertuglia A, Pagliara E, Grego E, Ricci A, Brkljaca-Bottegaro N. Pro-inflammatory cytokines and structural biomarkers are effective to categorize osteoarthritis phenotype and progression in Standardbred racehorses over five years of racing career.. BMC Vet Res (2016) 12:246.
    doi: 10.1186/s12917-016-0873-7pmc: PMC5100096pubmed: 27821120google scholar: lookup
  9. Leung YY, Huebner JL, Haaland B, Wong SBS, Kraus VB. Synovial fluid pro-inflammatory profile differs according to the characteristics of knee pain.. Osteoarthritis Cartilage (2017) 25:1420–7.
    doi: 10.1016/j.joca.2017.04.001pubmed: 28433814google scholar: lookup
  10. Ruiz-Romero C, Carreira V, Rego I, Remeseiro S, López-Armada MJ, Blanco FJ. Proteomic analysis of human osteoarthritic chondrocytes reveals protein changes in stress and glycolysis.. Proteomics (2008) 8:495–507.
    doi: 10.1002/pmic.200700249pubmed: 18186017google scholar: lookup
  11. Nugent AE, Speicher DM, Gradisar I, McBurney DL, Baraga A, Doane KJ. Advanced osteoarthritis in humans is associated with altered collagen VI expression and upregulation of ER-stress markers Grp78 and bag-1.. J Histochem Cytochem (2009) 57:923–31.
    doi: 10.1369/jhc.2009.953893pmc: PMC2746726pubmed: 19546472google scholar: lookup
  12. Takada K, Hirose J, Senba K, Yamabe S, Oike Y, Gotoh T. Enhanced apoptotic and reduced protective response in chondrocytes following endoplasmic reticulum stress in osteoarthritic cartilage.. Int J Exp Pathol (2011) 92:232–42.
    doi: 10.1111/j.1365-2613.2010.00758.xpmc: PMC3144511pubmed: 21294793google scholar: lookup
  13. de Seny D, Bianchi E, Baiwir D, Cobraiville G, Collin C, Deliège M. Proteins involved in the endoplasmic reticulum stress are modulated in synovitis of osteoarthritis, chronic pyrophosphate arthropathy and rheumatoid arthritis, and correlate with the histological inflammatory score.. Sci Rep (2020) 10:14159.
    doi: 10.1038/s41598-020-70803-7pmc: PMC7473860pubmed: 32887899google scholar: lookup
  14. Smith SR, Deshpande BR, Collins JE, Katz JN, Losina E. Comparative pain reduction of oral non-steroidal anti-inflammatory drugs and opioids for knee osteoarthritis: systematic analytic review.. Osteoarthritis Cartilage (2016) 24:962–72.
    doi: 10.1016/j.joca.2016.01.135pmc: PMC4996269pubmed: 26844640google scholar: lookup
  15. Contino EK. Management and rehabilitation of joint disease in sport horses.. Vet Clin North Am Equine Pract (2018) 34:345–58.
    doi: 10.1016/j.cveq.2018.04.007pubmed: 29793734google scholar: lookup
  16. Tsutsumi S, Gotoh T, Tomisato W, Mima S, Hoshino T, Hwang HJ. Endoplasmic reticulum stress response is involved in nonsteroidal anti-inflammatory drug-induced apoptosis.. Cell Death Differ (2004) 11:1009–16.
    doi: 10.1038/sj.cdd.4401436pubmed: 15131590google scholar: lookup
  17. Timur UT, Caron MMJ, Jeuken RM, Bastiaansen-Jenniskens YM, Welting TJM, Van Rhijn LW. Chondroprotective actions of selective COX-2 inhibitors in vivo: a systematic review.. Int J Mol Sci (2020) 21:6962.
    doi: 10.3390/ijms21186962pmc: PMC7555215pubmed: 32971951google scholar: lookup
  18. Valdes AM, Ravipati S, Pousinis P, Menni C, Mangino M, Abhishek A. Omega-6 oxylipins generated by soluble epoxide hydrolase are associated with knee osteoarthritis.. J Lipid Res (2018) 59:1763–70.
    doi: 10.1194/jlr.P085118pmc: PMC6121933pubmed: 29986999google scholar: lookup
  19. Schmelzer KR, Kubala L, Newman JW, Kim IH, Eiserich JP, Hammock BD. Soluble epoxide hydrolase is a therapeutic target for acute inflammation.. Proc Natl Acad Sci USA (2005) 102:9772–7.
    doi: 10.1073/pnas.0503279102pmc: PMC1168955pubmed: 15994227google scholar: lookup
  20. Inceoglu B, Jinks SL, Schmelzer KR, Waite T, Kim IH, Hammock BD. Inhibition of soluble epoxide hydrolase reduces LPS-induced thermal hyperalgesia and mechanical allodynia in a rat model of inflammatory pain.. Life Sci (2006) 79:2311–9.
    doi: 10.1016/j.lfs.2006.07.031pmc: PMC1904345pubmed: 16962614google scholar: lookup
  21. Inceoglu B, Schmelzer KR, Morisseau C, Jinks SL, Hammock BD. Soluble epoxide hydrolase inhibition reveals novel biological functions of epoxyeicosatrienoic acids (EETs).. Prostaglandins Other Lipid Mediat (2007) 82:42–9.
    doi: 10.1016/j.prostaglandins.2006.05.004pmc: PMC1904338pubmed: 17164131google scholar: lookup
  22. Inceoglu B, Jinks SL, Ulu A, Hegedus CM, Georgi K, Schmelzer KR. Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct analgesic pathways.. Proc Natl Acad Sci USA (2008) 105:18901–6.
    doi: 10.1073/pnas.0809765105pmc: PMC2596245pubmed: 19028872google scholar: lookup
  23. Inceoglu B, Wagner K, Schebb NH, Morisseau C, Jinks SL, Ulu A. Analgesia mediated by soluble epoxide hydrolase inhibitors is dependent on cAMP.. Proc Natl Acad Sci USA (2011) 108:5093–7.
    doi: 10.1073/pnas.1101073108pmc: PMC3064364pubmed: 21383170google scholar: lookup
  24. Inceoglu B, Wagner KM, Yang J, Bettaieb A, Schebb NH, Hwang SH. Acute augmentation of epoxygenated fatty acid levels rapidly reduces pain-related behavior in a rat model of type I diabetes.. Proc Natl Acad Sci USA (2012) 109:11390–5.
    doi: 10.1073/pnas.1208708109pmc: PMC3396532pubmed: 22733772google scholar: lookup
  25. Wagner K, Inceoglu B, Dong H, Yang J, Hwang SH, Jones P. Comparative efficacy of 3 soluble epoxide hydrolase inhibitors in rat neuropathic and inflammatory pain models.. Eur J Pharmacol (2013) 700:93–101.
    doi: 10.1016/j.ejphar.2012.12.015pmc: PMC3578047pubmed: 23276668google scholar: lookup
  26. Bettaieb A, Nagata N, AbouBechara D, Chahed S, Morisseau C, Hammock BD. Soluble epoxide hydrolase deficiency or inhibition attenuates diet-induced endoplasmic reticulum stress in liver and adipose tissue.. J Biol Chem (2013) 288:14189–99.
    doi: 10.1074/jbc.M113.458414pmc: PMC3656275pubmed: 23576437google scholar: lookup
  27. Inceoglu B, Bettaieb A, Trindade da Silva CA, Lee KS, Haj FG, Hammock BD. Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain.. Proc Natl Acad Sci USA (2015) 112:9082–7.
    doi: 10.1073/pnas.1510137112pmc: PMC4517273pubmed: 26150506google scholar: lookup
  28. Trindade-da-Silva CA, Bettaieb A, Napimoga MH, Lee KSS, Inceoglu B, Ueira-Vieira C. Soluble epoxide hydrolase pharmacological inhibition decreases alveolar bone loss by modulating host inflammatory response, RANK-related signaling, endoplasmic reticulum stress, and apoptosis.. J Pharmacol Exp Ther (2017) 361:408–16.
    doi: 10.1124/jpet.116.238113pmc: PMC5443319pubmed: 28356494google scholar: lookup
  29. Panigrahy D, Kalish BT, Huang S, Bielenberg DR, Le HD, Yang J. Epoxyeicosanoids promote organ and tissue regeneration.. Proc Natl Acad Sci USA (2013) 110:13528–33.
    doi: 10.1073/pnas.1311565110pmc: PMC3746918pubmed: 23898174google scholar: lookup
  30. Wagner K, Gilda J, Yang J, Wan D, Morisseau C, Gomes AV. Soluble epoxide hydrolase inhibition alleviates neuropathy in Akita (Ins2 Akita) mice.. Behav Brain Res (2017) 326:69–76.
    doi: 10.1016/j.bbr.2017.02.048pmc: PMC5409858pubmed: 28259677google scholar: lookup
  31. Schmelzer KR, Inceoglu B, Kubala L, Kim IH, Jinks SL, Eiserich JP. Enhancement of antinociception by coadministration of nonsteroidal anti-inflammatory drugs and soluble epoxide hydrolase inhibitors.. Proc Natl Acad Sci USA (2006) 103:13646–51.
    doi: 10.1073/pnas.0605908103pmc: PMC1564210pubmed: 16950874google scholar: lookup
  32. Goswami SK, Wan D, Yang J, Trindade da Silva CA, Morisseau C, Kodani SD. Anti-ulcer efficacy of soluble epoxide hydrolase inhibitor TPPU on diclofenac-induced intestinal ulcers.. J Pharmacol Exp Ther (2016) 357:529–36.
    doi: 10.1124/jpet.116.232108pmc: PMC4885505pubmed: 26989141google scholar: lookup
  33. Guedes AGP, Aristizabal F, Sole A, Adedeji A, Brosnan R, Knych H. Pharmacokinetics and antinociceptive effects of the soluble epoxide hydrolase inhibitor t-TUCB in horses with experimentally induced radiocarpal synovitis.. J Vet Pharmacol Ther (2018) 41:230–8.
    doi: 10.1111/jvp.12463pmc: PMC5920688pubmed: 29067696google scholar: lookup
  34. Guedes AG, Morisseau C, Sole A, Soares JH, Ulu A, Dong H. Use of a soluble epoxide hydrolase inhibitor as an adjunctive analgesic in a horse with laminitis.. Vet Anaesth Analg (2013) 40:440–8.
    doi: 10.1111/vaa.12030pmc: PMC3956586pubmed: 23463912google scholar: lookup
  35. Guedes A, Galuppo L, Hood D, Hwang SH, Morisseau C, Hammock BD. Soluble epoxide hydrolase activity and pharmacologic inhibition in horses with chronic severe laminitis.. Equine Vet J (2017) 49:345–51.
    doi: 10.1111/evj.12603pmc: PMC5580818pubmed: 27338788google scholar: lookup
  36. Eitner A, Pester J, Nietzsche S, Hofmann GO, Schaible HG. The innervation of synovium of human osteoarthritic joints in comparison with normal rat and sheep synovium.. Osteoarthritis Cartilage (2013) 21:1383–91.
    doi: 10.1016/j.joca.2013.06.018pubmed: 23973153google scholar: lookup
  37. Pujol R, Girard CA, Richard H, Hassanpour I, Binette MP, Beauchamp G. Synovial nerve fiber density decreases with naturally-occurring osteoarthritis in horses.. Osteoarthritis Cartilage (2018) 26:1379–88.
    doi: 10.1016/j.joca.2018.06.006pubmed: 29958917google scholar: lookup
  38. Jones E, Vinuela-Fernandez I, Eager RA, Delaney A, Anderson H, Patel A. Neuropathic changes in equine laminitis pain.. Pain (2007) 132:321–31.
    doi: 10.1016/j.pain.2007.08.035pubmed: 17935886google scholar: lookup
  39. Trindade-da-Silva CA, Clemente-Napimoga JT, Abdalla HB, Rosa SM, Ueira-Vieira C, Morisseau C. Soluble epoxide hydrolase inhibitor, TPPU, increases regulatory T cells pathway in an arthritis model.. FASEB J (2020) 34:9074–86.
    doi: 10.1096/fj.202000415Rpmc: PMC7383812pubmed: 32400048google scholar: lookup
  40. McReynolds CB, Hwang SH, Yang J, Wan D, Wagner K, Morisseau C. Pharmaceutical effects of inhibiting the soluble epoxide hydrolase in canine osteoarthritis.. Front Pharmacol (2019) 10:533.
    doi: 10.3389/fphar.2019.00533pmc: PMC6554663pubmed: 31214021google scholar: lookup
  41. Jones PD, Tsai HJ, Do ZN, Morisseau C, Hammock BD. Synthesis and SAR of conformationally restricted inhibitors of soluble epoxide hydrolase.. Bioorg Med Chem Lett (2006) 16:5212–6.
    doi: 10.1016/j.bmcl.2006.07.009pmc: PMC1904344pubmed: 16870439google scholar: lookup
  42. Morisseau C, Newman JW, Tsai HJ, Baecker PA, Hammock BD. Peptidyl-urea based inhibitors of soluble epoxide hydrolases.. Bioorg Med Chem Lett (2006) 16:5439–44.
    doi: 10.1016/j.bmcl.2006.07.073pmc: PMC1892215pubmed: 16908134google scholar: lookup
  43. Rose TE, Morisseau C, Liu JY, Inceoglu B, Jones PD, Sanborn JR. 1-Aryl-3-(1-acylpiperidin-4-yl)urea inhibitors of human and murine soluble epoxide hydrolase: structure-activity relationships, pharmacokinetics, and reduction of inflammatory pain.. J Med Chem (2010) 53:7067–75.
    doi: 10.1021/jm100691cpmc: PMC3285450pubmed: 20812725google scholar: lookup
  44. Tsai HJ, Hwang SH, Morisseau C, Yang J, Jones PD, Kasagami T. Pharmacokinetic screening of soluble epoxide hydrolase inhibitors in dogs.. Eur J Pharm Sci (2010) 40:222–38.
    doi: 10.1016/j.ejps.2010.03.018pmc: PMC3285443pubmed: 20359531google scholar: lookup
  45. Welch RD, Watkins JP, DeBowes RM, Leipold HW. Effects of intra-articular administration of dimethylsulfoxide on chemically induced synovitis in immature horses.. Am J Vet Res (1991) 52:934–9.
    pubmed: 1883099
  46. Smith G, Bertone AL, Kaeding C, Simmons EJ, Apostoles S. Anti-inflammatory effects of topically applied dimethyl sulfoxide gel on endotoxin-induced synovitis in horses.. Am J Vet Res (1998) 59:1149–52.
    pubmed: 9736394
  47. Keegan KG, Yonezawa Y, Pai PF, Wilson DA, Kramer J. Evaluation of a sensor-based system of motion analysis for detection and quantification of forelimb and hind limb lameness in horses.. Am J Vet Res (2004) 65:665–70.
    doi: 10.2460/ajvr.2004.65.665pubmed: 15141889google scholar: lookup
  48. Keegan KG, Kramer J, Yonezawa Y, Maki H, Pai PF, Dent EV. Assessment of repeatability of a wireless, inertial sensor-based lameness evaluation system for horses.. Am J Vet Res (2011) 72:1156–63.
    doi: 10.2460/ajvr.72.9.1156pubmed: 21879972google scholar: lookup
  49. de Grauw JC, Brama PA, Wiemer P, Brommer H, van de Lest CH, van Weeren PR. Cartilage-derived biomarkers and lipid mediators of inflammation in horses with osteochondritis dissecans of the distal intermediate ridge of the tibia.. Am J Vet Res (2006) 67:1156–62.
    doi: 10.2460/ajvr.67.7.1156pubmed: 16817736google scholar: lookup
  50. Beretta C, Garavaglia G, Cavalli M. COX-1 and COX-2 inhibition in horse blood by phenylbutazone, flunixin, carprofen and meloxicam: an in vitro analysis.. Pharmacol Res (2005) 52:302–6.
    doi: 10.1016/j.phrs.2005.04.004pubmed: 15939622google scholar: lookup
  51. Keegan KG, Messer NT, Reed SK, Wilson DA, Kramer J. Effectiveness of administration of phenylbutazone alone or concurrent administration of phenylbutazone and flunixin meglumine to alleviate lameness in horses.. Am J Vet Res (2008) 69:167–73.
    doi: 10.2460/ajvr.69.2.167pubmed: 18241011google scholar: lookup
  52. Westacott CI, Barakat AF, Wood L, Perry MJ, Neison P, Bisbinas I. Tumor necrosis factor alpha can contribute to focal loss of cartilage in osteoarthritis.. Osteoarthritis Cartilage (2000) 8:213–21.
    doi: 10.1053/joca.1999.0292pubmed: 10806049google scholar: lookup
  53. Larsson S, Englund M, Struglics A, Lohmander LS. Interleukin-6 and tumor necrosis factor alpha in synovial fluid are associated with progression of radiographic knee osteoarthritis in subjects with previous meniscectomy.. Osteoarthritis Cartilage (2015) 23:1906–14.
    doi: 10.1016/j.joca.2015.05.035pubmed: 26521736google scholar: lookup
  54. Latourte A, Cherifi C, Maillet J, Ea HK, Bouaziz W, Funck-Brentano T. Systemic inhibition of IL-6/Stat3 signalling protects against experimental osteoarthritis.. Ann Rheum Dis (2017) 76:748–55.
    doi: 10.1136/annrheumdis-2016-209757pubmed: 27789465google scholar: lookup
  55. Wagner K, Lee KS, Yang J, Hammock BD. Epoxy fatty acids mediate analgesia in murine diabetic neuropathy.. Eur J Pain (2017) 21:456–65.
    doi: 10.1002/ejp.939pmc: PMC5300894pubmed: 27634339google scholar: lookup
  56. Terashvili M, Tseng LF, Wu HE, Narayanan J, Hart LM, Falck JR. Antinociception produced by 14,15-epoxyeicosatrienoic acid is mediated by the activation of beta-endorphin and met-enkephalin in the rat ventrolateral periaqueductal gray.. J Pharmacol Exp Ther (2008) 326:614–22.
    doi: 10.1124/jpet.108.136739pmc: PMC2567871pubmed: 18492947google scholar: lookup
  57. Li X, Ellman M, Muddasani P, Wang JHC, Cs-Szabo G, Van Wijnen AJ. Prostaglandin E2 and its cognate EP receptors control human adult articular cartilage homeostasis and are linked to the pathophysiology of osteoarthritis.. Arthritis Rheum (2009) 60:513–23.
    doi: 10.1002/art.24258pmc: PMC2659545pubmed: 19180509google scholar: lookup
  58. McIlwraith CW, Kawcak CE, Frisbie DD, Little CB, Clegg PD, Peffers MJ. Biomarkers for equine joint injury and osteoarthritis.. J Orthop Res (2018) 36:823–31.
    doi: 10.1002/jor.23738pubmed: 28921609google scholar: lookup
  59. Akeson G, Malemud C. A role for soluble IL-6 receptor in osteoarthritis.. J Funct Morphol Kinesiol (2017) 2:27.
    doi: 10.3390/jfmk2030027pmc: PMC5739325pubmed: 29276788google scholar: lookup
  60. Zhou Y-Q, Liu Z, Liu Z-H, Chen S-P, Li M, Shahveranov A. Interleukin-6: an emerging regulator of pathological pain.. J Neuroinflammation (2016) 13:141.
    doi: 10.1186/s12974-016-0607-6pmc: PMC4897919pubmed: 27267059google scholar: lookup
  61. Cibere J, Zhang H, Garnero P, Poole AR, Lobanok T, Saxne T. Association of biomarkers with pre-radiographically defined and radiographically defined knee osteoarthritis in a population-based study.. Arthritis Rheum (2009) 60:1372–80.
    doi: 10.1002/art.24473pmc: PMC4724193pubmed: 19404937google scholar: lookup
  62. Young DA, Barter MJ, Wilkinson DJ. Recent advances in understanding the regulation of metalloproteinases.. F1000Res (2019) 8:195.
    doi: 10.12688/f1000research.17471.1pmc: PMC6381797pubmed: 30828429google scholar: lookup
  63. Xu D, Li N, He Y, Timofeyev V, Lu L, Tsai HJ. Prevention and reversal of cardiac hypertrophy by soluble epoxide hydrolase inhibitors.. Proc Natl Acad Sci USA (2006) 103:18733–8.
    doi: 10.1073/pnas.0609158103pmc: PMC1693731pubmed: 17130447google scholar: lookup
  64. Cahue S, Sharma L, Dunlop D, Ionescu M, Song J, Lobanok T. The ratio of type II collagen breakdown to synthesis and its relationship with the progression of knee osteoarthritis.. Osteoarthritis Cartilage (2007) 15:819–23.
    doi: 10.1016/j.joca.2007.01.016pmc: PMC2139981pubmed: 17344068google scholar: lookup
  65. Notoya K, Jovanovic DV, Reboul P, Martel-Pelletier J, Mineau F, Pelletier JP. The induction of cell death in human osteoarthritis chondrocytes by nitric oxide is related to the production of prostaglandin E2 via the induction of cyclooxygenase-2.. J Immunol (2000) 165:3402–10.
    doi: 10.4049/jimmunol.165.6.3402pubmed: 10975859google scholar: lookup
  66. Charlier E, Relic B, Deroyer C, Malaise O, Neuville S, Collée J. Insights on molecular mechanisms of chondrocytes death in osteoarthritis.. Int J Mol Sci (2016) 17:2146.
    doi: 10.3390/ijms17122146pmc: PMC5187946pubmed: 27999417google scholar: lookup
  67. Fischer BA, Mundle S, Cole AA. Tumor necrosis factor-alpha induced DNA cleavage in human articular chondrocytes may involve multiple endonucleolytic activities during apoptosis.. Microsc Res Tech (2000) 50:236–42.
    doi: 10.1002/1097-0029(20000801)50:3<236::AID-JEMT7>3.0.CO;2-Epubmed: 10891889google scholar: lookup
  68. Linn S, Murtaugh B, Casey E. Role of sex hormones in the development of osteoarthritis.. PM R (2012) 4:S169–73.
    doi: 10.1016/j.pmrj.2012.01.013pubmed: 22632696google scholar: lookup
  69. Freedman LJ, Garcia MC, Ginther OJ. Influence of photoperiod and ovaries on seasonal reproductive activity in mares.. Biol Reprod (1979) 20:567–74.
    doi: 10.1095/biolreprod20.3.567pubmed: 572238google scholar: lookup
  70. Freystaetter G, Fischer K, Orav EJ, Egli A, Theiler R, Munzer T. Total serum testosterone and western Ontario and McMaster Universities osteoarthritis index pain and function among older men and women with severe knee osteoarthritis.. Arthritis Care Res (2020) 72:1511–8.
    doi: 10.1002/acr.24074pmc: PMC7702066pubmed: 31557423google scholar: lookup
  71. Huang ZY, Stabler T, Pei FX, Kraus VB. Both systemic and local lipopolysaccharide (LPS) burden are associated with knee OA severity and inflammation.. Osteoarthritis Cartilage (2016) 24:1769–75.
    doi: 10.1016/j.joca.2016.05.008pmc: PMC5026878pubmed: 27216281google scholar: lookup
Subscribe to our newsletter
Join 99,357 horse owners like you who receive our email updates on horse health and nutrition.