The Anti-Inflammatory Effects of Liraglutide in Equine Inflammatory Joint Models.
Abstract: This study investigates the anti-inflammatory properties of liraglutide, a glucagon-like peptide 1 receptor agonists, in equine in vitro models and in an in vivo acute synovitis model in Shetland ponies. The anti-inflammatory effect of liraglutide was assessed by measuring concentrations of inflammatory biomarker C-C Motif Chemokine Ligand 2 (CCL2) in culture media of equine whole blood, peripheral blood mononuclear cells (PBMCs), chondrocytes, and synoviocytes, with or without lipopolysaccharide (LPS) or interleukin-1β. In the in vivo experiment, acute synovitis was bilaterally induced with 0.25 ng LPS in the intercarpal joints of seven healthy Shetland ponies. The ponies were subsequently treated with either 6 mg liraglutide or a placebo as a paired control in each joint. The impact of liraglutide on biomarkers associated with inflammation (including white blood cell count, total protein, CCL2, and bradykinin) and cartilage metabolism (such as glycosaminoglycans, general matrix metalloproteinase activity, carboxypropeptide type II collagen, and collagen-cleavage neoepitope of type II collagen) was assessed across serial synovial fluid samples. Liraglutide was found to have an anti-inflammatory effect by reducing CCL2 concentrations in culture media of whole blood, PBMCs, chondrocytes, and synoviocytes. In contrast, no significant differences in synovial fluid inflammatory nor cartilage metabolism biomarker levels were found between joints treated with LPS and 6 mg liraglutide, versus LPS and placebo. In conclusion, liraglutide demonstrates the potential to attenuate inflammatory processes in joint cells. Additional research is necessary to validate its efficacy within the complex milieu of an inflamed joint.
© 2025 The Author(s). Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.
Publication Date: 2025-02-04 PubMed ID: 39904754PubMed Central: PMC11982606DOI: 10.1002/jor.26050Google Scholar: Lookup
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Summary
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Overview
- This study evaluated the anti-inflammatory effects of liraglutide, a glucagon-like peptide 1 receptor agonist, using laboratory models of horse joint cells and a live model of joint inflammation in Shetland ponies.
- While liraglutide reduced inflammatory markers in isolated cell cultures, it did not significantly alter inflammation or cartilage metabolism markers in the live pony joint inflammation model.
Background and Purpose
- Liraglutide is a drug known as a glucagon-like peptide 1 receptor agonist (GLP-1 RA), primarily used to regulate blood sugar, but it also has reported anti-inflammatory effects in other species.
- Inflammatory joint conditions in horses are common and can lead to pain and cartilage degradation. Targeting inflammation may help preserve joint health.
- This study aimed to test the anti-inflammatory potential of liraglutide in horse joint cells cultured in vitro and in a live equine joint inflammation model (acute synovitis in Shetland ponies).
Methods – In Vitro Component
- Various equine cell types relevant to joint inflammation were cultured: whole blood, peripheral blood mononuclear cells (PBMCs), chondrocytes (cartilage cells), and synoviocytes (cells lining the joint).
- Inflammation was induced in these cultures using either lipopolysaccharide (LPS) or interleukin-1β, both known stimulators of inflammatory responses.
- Liraglutide was applied to the cultures to see if it could reduce inflammation.
- The main marker measured was C-C Motif Chemokine Ligand 2 (CCL2), a protein involved in recruiting immune cells and promoting inflammation.
Results – In Vitro
- Liraglutide significantly reduced CCL2 levels in all cell cultures (whole blood, PBMCs, chondrocytes, synoviocytes), indicating an anti-inflammatory effect at the cellular level.
Methods – In Vivo Component
- An acute synovitis model was created in seven healthy Shetland ponies by injecting a small amount of LPS (0.25 ng) into the intercarpal joints of both forelimbs to induce joint inflammation.
- Each pony’s joints were treated differently in a paired design: one joint received 6 mg of liraglutide, the other a placebo.
- Synovial fluid samples were collected over time to measure markers related to inflammation and cartilage metabolism.
- Inflammation markers measured included white blood cell count, total protein, CCL2, and bradykinin.
- Cartilage metabolism markers measured included glycosaminoglycans, matrix metalloproteinase activity, and collagen-related peptides indicating cartilage breakdown or repair.
Results – In Vivo
- No significant differences were found between liraglutide-treated joints and placebo-treated joints in any of the inflammatory or cartilage metabolism biomarkers.
- This suggests that liraglutide at the tested dose did not produce a measurable anti-inflammatory or cartilage-protective effect in the acute inflamed joint environment in live ponies.
Conclusions and Implications
- Liraglutide demonstrated clear anti-inflammatory effects by reducing CCL2 secretion in isolated equine joint cells and blood cells.
- However, the complexity of joint inflammation in living animals, involving multiple cell types, signaling molecules, and tissue interactions, may limit liraglutide’s efficacy in vivo at the tested dose.
- Further research is needed to explore whether different dosing, timing, or combination therapies might enhance liraglutide’s anti-inflammatory effects in equine joints.
- This study suggests potential but highlights challenges in translating cell culture findings into effective treatments for joint inflammation in horses.
Cite This Article
APA
Scheike AS, Plomp S, Fugazzola MC, Meurot C, Berenbaum F, van Weeren PR, Tryfonidou MA, von Hegedus JH.
(2025).
The Anti-Inflammatory Effects of Liraglutide in Equine Inflammatory Joint Models.
J Orthop Res, 43(5), 893-903.
https://doi.org/10.1002/jor.26050 Publication
Researcher Affiliations
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
- 4Moving Biotech, Lille, France.
- 4Moving Biotech, Lille, France.
- INSERM CRSA, AP-HP Saint-Antoine Hospital, Sorbonne University, Paris, France.
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
MeSH Terms
- Animals
- Horses
- Liraglutide / therapeutic use
- Liraglutide / pharmacology
- Synovitis / drug therapy
- Synovitis / veterinary
- Synovitis / chemically induced
- Anti-Inflammatory Agents / therapeutic use
- Anti-Inflammatory Agents / pharmacology
- Synovial Fluid
- Horse Diseases / drug therapy
- Chondrocytes / metabolism
- Chondrocytes / drug effects
- Chemokine CCL2 / metabolism
- Leukocytes, Mononuclear / metabolism
- Leukocytes, Mononuclear / drug effects
- Male
- Lipopolysaccharides
- Biomarkers / metabolism
- Cells, Cultured
- Disease Models, Animal
Grant Funding
- This project has received funding from the Eurostars-2 joint program with co-funding from the European Union Horizon 2020 research and innovation program.
Conflict of Interest Statement
Co‐author Dr. Francis Berenbaum is the CEO of 4Moving Biotech and chair of the scientific advisory board of 4P Pharma. 4Moving Biotech and Sorbonne University own two patents for the method of use of GLP1 analogs in the treatment of osteoarthritis (PCT/FR2013/051998 and PCT/IB2018//059100). The other authors declare no conflicts of interest.
References
This article includes 43 references
- . Global Burden of Disease Study 2019 (GBD 2019) Results. Osteoarthritis‐Level 3 Cause. .
- Baccarin RYA, Seidel SRT, Michelacci YM, Tokawa P, Oliveira TM. Osteoarthritis: A Common Disease That Should Be Avoided in the Athletic Horse's Life. Animal Frontiers 12, no. 3 (2022): 25–36.
- Steinmetz JD, Culbreth GT, Haile LM. Global, Regional, and National Burden of Osteoarthritis, 1990–2020 and Projections to 2050: A Systematic Analysis for the Global Burden of Disease Study 2021. Lancet Rheumatology 5, no. 9 (2023): e508–e522.
- Hunter DJ, Bierma‐Zeinstra S. Osteoarthritis. Lancet 393, no. 10182 (2019): 1745–1759.
- Stone S, Malanga GA, Capella T. Corticosteroids: Review of the History, the Effectiveness, and Adverse Effects in the Treatment of Joint Pain. Pain Physician 24, no. S1 (2021): 233.
- Wernecke C, Braun HJ, Dragoo JL. The Effect of Intra‐Articular Corticosteroids on Articular Cartilage: A Systematic Review. Orthopaedic Journal of Sports Medicine 3, no. 5 (2015): 2325967115581163.
- Wijn SR, Rovers MM, van Tienen TG, Hannink G. Intra‐Articular Corticosteroid Injections Increase the Risk of Requiring Knee Arthroplasty: A Multicentre Longitudinal Observational Study Using Data From the Osteoarthritis Initiative. Bone & Joint Journal 102, no. 5 (2020): 586–592.
- Baggio LL, Drucker DJ. Glucagon‐Like Peptide‐1 Receptors in the Brain: Controlling Food Intake and Body Weight. Journal of Clinical Investigation 124, no. 10 (2014): 4223–4226.
- Meurot C, Martin C, Sudre L. Liraglutide, a Glucagon‐Like Peptide 1 Receptor Agonist, Exerts Analgesic, Anti‐Inflammatory and Anti‐Degradative Actions in Osteoarthritis. Scientific Reports 12, no. 1 (2022): 1567.
- Chen J, Xie JJ, Shi KS. Glucagon‐Like Peptide‐1 Receptor Regulates Endoplasmic Reticulum Stress‐Induced Apoptosis and the Associated Inflammatory Response in Chondrocytes and the Progression of Osteoarthritis in Rat. Cell Death & Disease 9, no. 2 (2018): 212.
- Que Q, Guo X, Zhan L. The GLP‐1 Agonist, Liraglutide, Ameliorates Inflammation Through the Activation of the PKA/CREB Pathway in a Rat Model of Knee Osteoarthritis. Journal of Inflammation 16 (2019): 13.
- Gudbergsen H, Overgaard A, Henriksen M. Liraglutide After Diet‐Induced Weight Loss for Pain and Weight Control in Knee Osteoarthritis: A Randomized Controlled Trial. American Journal of Clinical Nutrition 113, no. 2 (2021): 314–323.
- Zhu H, Zhou L, Wang Q. Glucagon‐Like Peptide‐1 Receptor Agonists as a Disease‐Modifying Therapy for Knee Osteoarthritis Mediated by Weight Loss: Findings From the Shanghai Osteoarthritis Cohort. Annals of the Rheumatic Diseases 82 (2023): 1218–1226.
- Bliddal H, Bays H, Czernichow S. Semaglutide 2.4 mg Efficacy and Safety in People With Obesity and Knee Osteoarthritis: Results: From the STEP 9 Randomised Clinical Trial. Osteoarthritis and Cartilage 32, no. 6 (2024): 745–746.
- Malda J, Benders KEM, Klein TJ. Comparative Study of Depth‐Dependent Characteristics of Equine and Human Osteochondral Tissue From the Medial and Lateral Femoral Condyles. Osteoarthritis and Cartilage 20, no. 10 (2012): 1147–1151.
- McCoy AM. Animal Models of Osteoarthritis: Comparisons and Key Considerations. Veterinary Pathology 52, no. 5 (2015): 803–818.
- Zanotto GM, Frisbie DD. Current Joint Therapy Usage in Equine Practice: Changes in the Last 10 Years. Equine Veterinary Journal 54, no. 4 (2022): 750–756.
- Cokelaere SM, Plomp SGM, de Boef E. Sustained Intra‐Articular Release of Celecoxib in an Equine Repeated LPS Synovitis Model. European Journal of Pharmaceutics and Biopharmaceutics 128 (2018): 327–336.
- De Grauw JC, Van Loon JPAM, Van de Lest CHA, Brunott A, van Weeren PR. In Vivo Effects of Phenylbutazone on Inflammation and Cartilage‐Derived Biomarkers in Equine Joints With Acute Synovitis. Veterinary Journal 201, no. 1 (2014): 51–56.
- Kearney CM, Korthagen NM, Plomp SGM. Treatment Effects of Intra‐Articular Triamcinolone Acetonide in an Equine Model of Recurrent Joint Inflammation. Equine Veterinary Journal 53, no. 6 (2021): 1277–1286.
- Papadopoulos JS, Agarwala R. COBALT: Constraint‐Based Alignment Tool for Multiple Protein Sequences. Bioinformatics 23, no. 9 (2007): 1073–1079.
- Xu Y, Ke Y, Wang B, Lin J. The Role of MCP‐1‐CCR2 Ligand‐Receptor Axis in Chondrocyte Degradation and Disease Progress in Knee Osteoarthritis. Biological Research 48 (2015): 64.
- Raghu H, Lepus CM, Wang Q. CCL2/CCR2, but Not CCL5/CCR5, Mediates Monocyte Recruitment, Inflammation and Cartilage Destruction in Osteoarthritis. Annals of the Rheumatic Diseases 76, no. 5 (2017): 914–922.
- Farndale R, Buttle D, Barrett A. Improved Quantitation and Discrimination of Sulphated Glycosaminoglycans by Use of Dimethylmethylene Blue. Biochimica et Biophysica Acta (BBA) – General Subjects 883, no. 2 (1986): 173–177.
- Van Loon JPAM, Van Dierendonck MC. Pain Assessment in Horses After Orthopaedic Surgery and With Orthopaedic Trauma. Veterinary Journal 246 (2019): 85–91.
- Posit team PS PBC. RStudio: Integrated Development Environment for R. 2022.
- . GraphPad Prism Version 9.3.1 (471) for Windows. 2021.
- Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: A Flexible Statistical Power Analysis Program for the Social, Behavioral, and Biomedical Sciences. Behavior Research Methods 39 (2007): 175–191.
- De Grauw JC, Van de Lest CHA, Brama PAJ, Rambags B, van Weeren PR. In Vivo Effects of Meloxicam on Inflammatory Mediators, MMP Activity and Cartilage Biomarkers in Equine Joints With Acute Synovitis. Equine Veterinary Journal 41, no. 7 (2009): 693–699.
- Meurot C, Jacques C, Martin C. Targeting the GLP‐1/GLP‐1R Axis to Treat Osteoarthritis: A New Opportunity?. Journal of Orthopaedic Translation 32 (2022): 121–129.
- Huang J, Yi H, Zhao C. Glucagon‐Like Peptide‐1 Receptor (GLP‐1R) Signaling Ameliorates Dysfunctional Immunity in COPD Patients. International Journal of Chronic Obstructive Pulmonary Disease 13 (2018): 3191–3202.
- Rode A K O, Buus T B, Mraz V. Induced Human Regulatory T Cells Express the Glucagon‐Like Peptide‐1 Receptor. Cells 11, no. 16 (2022): 2587.
- Zobel E H, Ripa R S, von Scholten B J. Effect of Liraglutide on Expression of Inflammatory Genes in Type 2 Diabetes. Scientific Reports 11, no. 1 (2021): 18522.
- Scanzello C R. Role of Low‐Grade Inflammation in Osteoarthritis. Current Opinion in Rheumatology 29, no. 1 (2017): 79–85.
- Mei J, Sun J, Wu J, Zheng X. Liraglutide Suppresses TNF‐α‐Induced Degradation of Extracellular Matrix in Human Chondrocytes: A Therapeutic Implication in Osteoarthritis. American Journal of Translational Research 11, no. 8 (2019): 4800–4808.
- Kumar P, Kumar A, Song Z H. Structure‐Activity Relationships of Fatty Acid Amide Ligands in Activating and Desensitizing G Protein‐Coupled Receptor 119. European Journal of Pharmacology 723 (2014): 465–472.
- Van Loon J P A M, De Grauw J C, van Dierendonck M, L'ami J J, Back W, Van Weeren P R. Intra‐Articular Opioid Analgesia Is Effective in Reducing Pain and Inflammation in an Equine LPS Induced Synovitis Model. Equine Veterinary Journal 42, no. 5 (2010): 412–419.
- de Grauw J C, van de Lest C H, van Weeren P R. Inflammatory Mediators and Cartilage Biomarkers in Synovial Fluid After a Single Inflammatory Insult: A Longitudinal Experimental Study. Arthritis Research & Therapy 11 (2009): 1–8.
- Udo M, Muneta T, Tsuji K. Monoiodoacetic Acid Induces Arthritis and Synovitis in Rats in a Dose‐ and Time‐Dependent Manner: Proposed Model‐Specific Scoring Systems. Osteoarthritis and Cartilage 24, no. 7 (2016): 1284–1291.
- Smit I H, Hernlund E, Brommer H, van Weeren P R, Rhodin M, Serra Bragança F M. Continuous Versus Discrete Data Analysis for Gait Evaluation of Horses With Induced Bilateral Hindlimb Lameness. Equine Veterinary Journal 54, no. 3 (2022): 626–633.
- Frisbie D D, Al‐Sobayil F, Billinghurst R C, Kawcak C E, McIlwraith C W. Changes in Synovial Fluid and Serum Biomarkers With Exercise and Early Osteoarthritis in Horses. Osteoarthritis and Cartilage 16, no. 10 (2008): 1196–1204.
- Te Moller N C R, Mohammadi A, Plomp S. Structural, Compositional, and Functional Effects of Blunt and Sharp Cartilage Damage on the Joint: A 9‐Month Equine Groove Model Study. Journal of Orthopaedic Research 39, no. 11 (2021): 2363–2375.
- Kuyinu E L, Narayanan G, Nair L S, Laurencin C T. Animal Models of Osteoarthritis: Classification, Update, and Measurement of Outcomes. Journal of Orthopaedic Surgery and Research 11 (2016): 19.
Citations
This article has been cited 2 times.- Korac L, St George L, MacNicol J, McCrae P, Jung L, Golestani N, Karrow N, Cánovas A, Pearson W. Functional and biochemical inflammatory responses to low-dose intra-articular recombinant equine IL-1β: a pilot study. Front Vet Sci 2025;12:1746738.
- Zheng M, Zhao J, Wang Y, Cui Z, Qiao Z, Wu H, Shi C, Wang X. Exploring new therapeutic drugs for osteoarthritis and osteoporosis: Glucagon-like peptide-1 receptor agonists: A review. Medicine (Baltimore) 2025 Jul 18;104(29):e43239.
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