{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T13:46:49Z","timestamp":1789480009011,"version":"build-2803163510"},"reference-count":48,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T00:00:00Z","timestamp":1755820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UCD Seed Funding Grant","award":["SF1592"],"award-info":[{"award-number":["SF1592"]}]},{"name":"UCD Seed Funding Grant","award":["R21299"],"award-info":[{"award-number":["R21299"]}]},{"name":"UCD In House Schemes Grant: Optimisation Of Translational Large Animal Models","award":["SF1592"],"award-info":[{"award-number":["SF1592"]}]},{"name":"UCD In House Schemes Grant: Optimisation Of Translational Large Animal Models","award":["R21299"],"award-info":[{"award-number":["R21299"]}]},{"name":"UCD Lyons Translational Research Unit","award":["SF1592"],"award-info":[{"award-number":["SF1592"]}]},{"name":"UCD Lyons Translational Research Unit","award":["R21299"],"award-info":[{"award-number":["R21299"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Animals"],"abstract":"<jats:p>The aim of this study was to refine the lipopolysaccharide (LPS)-induced synovitis model in normal carpal joints of Thoroughbred horses by comparing two low LPS doses. A further aim was to investigate the relationship between the induced synovitis and lameness. The study design consisted of two phases using nine horses with a unilateral crossover design and a within-animal saline control. Synoviocentesis was performed at post-injection hour (PIH) 0, 8, 24, 72 and 168, allowing for synovial fluid cytology and biomarker analysis. Objective gait and thermographic analysis were used to objectively measure clinical effects. The results demonstrate that injection of either a 0.125 ng or 0.25 ng dose of LPS induces a comparable degree of synovitis in terms of TP, WBC, PGE2 and MMP activity at peak values. Statistically significant changes in baseline lameness values were not detected with the 0.125 ng dose, a novel and valuable finding suggesting a comparable degree of synovitis is achieved without significant lameness. All measured parameters had returned to baseline by PIH 168. In conclusion, the findings of this study confirm that this LPS model produces a consistent and reliable synovitis at 0.25 ng and 0.125 ng doses. The reduction in lameness evident at the 0.125 ng dose offers enhanced animal welfare while delivering measurable synovitis. The authors believe that a further reduction in the LPS dose is possible with continued development of a repeated low-dose\/slow-release model to better mimic clinical disease.<\/jats:p>","DOI":"10.3390\/ani15172474","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T15:57:47Z","timestamp":1755878267000},"page":"2474","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Refinement of the Lipopolysaccharide-Induced Synovitis Model in Equine Middle Carpal Joints"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3893-2041","authenticated-orcid":false,"given":"Michael J. S.","family":"Duggan","sequence":"first","affiliation":[{"name":"School of Veterinary Medicine, UCD Veterinary Hospital, University College Dublin, D04 W6F6 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1518-5151","authenticated-orcid":false,"given":"Clodagh","family":"Kearney","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine, UCD Veterinary Hospital, University College Dublin, D04 W6F6 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7641-3741","authenticated-orcid":false,"given":"Milda","family":"Baltrimaite","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine, UCD Veterinary Hospital, University College Dublin, D04 W6F6 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9812-2123","authenticated-orcid":false,"given":"Margot C.","family":"Labbert\u00e9","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine, UCD Veterinary Hospital, University College Dublin, D04 W6F6 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1670-155X","authenticated-orcid":false,"given":"Rory","family":"Gibney","sequence":"additional","affiliation":[{"name":"Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 R590 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3405-0551","authenticated-orcid":false,"given":"Pieter A. 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J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.2460\/ajvr.69.12.1646","article-title":"Anti-Inflammatory and Analgesic Effects of Intra-Articular Injection of Triamcinolone Acetonide, Mepivacaine Hydrochloride, or Both on Lipopolysaccharide-Induced Lameness in Horses","volume":"69","author":"Kay","year":"2008","journal-title":"Am. J. Vet. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"693","DOI":"10.2746\/042516409X436286","article-title":"In Vivo Effects of Meloxicam on Inflammatory Mediators, MMP Activity and Cartilage Biomarkers in Equine Joints with Acute Synovitis","volume":"41","author":"Brama","year":"2009","journal-title":"Equine Vet. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1016\/j.joca.2012.08.008","article-title":"Evaluation of the Inflammatory Response in Experimentally Induced Synovitis in the Horse: A Comparison of Recombinant Equine Interleukin 1 Beta and Lipopolysaccharide","volume":"20","author":"Ross","year":"2012","journal-title":"Osteoarthr. Cartil."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1007\/s13346-018-0557-x","article-title":"Intra-Articular Delivery of a Nanocomplex Comprising Salmon Calcitonin, Hyaluronic Acid, and Chitosan Using an Equine Model of Joint Inflammation","volume":"8","author":"Sladek","year":"2018","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1111\/evj.13260","article-title":"Pharmacokinetics and Anti-Inflammatory Effects of Flunixin Meglumine as a Sole Agent and in Combination with Phenylbutazone in Exercised Thoroughbred Horses","volume":"53","author":"Knych","year":"2021","journal-title":"Equine Vet. J."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Van de Water, E., Oosterlinck, M., Korthagen, N.M., Duchateau, L., Dumoulin, M., van Weeren, P.R., Olijve, J., van Doorn, D.A., and Pille, F. (2021). The Lipopolysaccharide Model for the Experimental Induction of Transient Lameness and Synovitis in Standardbred Horses. Vet. J., 270.","DOI":"10.1016\/j.tvjl.2021.105626"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Castro-Cuellar, G., Cremer, J., Queiroz-Williams, P., Knych, H.K., and Leise, B.S. (2023). Pharmacokinetics of Intra-articular Buprenorphine in Horses with Lipopolysaccharide-induced Synovitis. J. Vet. Pharmacol. Ther., 46.","DOI":"10.1111\/jvp.13119"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1177\/0300985815588611","article-title":"Animal Models of Osteoarthritis: Comparisons and Key Considerations","volume":"52","author":"McCoy","year":"2015","journal-title":"Vet. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Bertoni, L., Jacquet-Guibon, S., Branly, T., Legendre, F., Desanc\u00e9, M., Mespoulhes, C., Melin, M., Hartmann, D.-J., Schmutz, A., and Denoix, J.-M. (2020). An Experimentally Induced Osteoarthritis Model in Horses Performed on Both Metacarpophalangeal and Metatarsophalangeal Joints: Technical, Clinical, Imaging, Biochemical, Macroscopic and Microscopic Characterization. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0235251"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Manivong, S., Cullier, A., Audigi\u00e9, F., Banquy, X., Moldovan, F., Demoor, M., and Roullin, V.G. (2023). New Trends for Osteoarthritis: Biomaterials, Models and Modeling. Drug Discov. Today, 28.","DOI":"10.1016\/j.drudis.2023.103488"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1177\/096805199700400308","article-title":"Second International Standard for Endotoxin: Calibration in an International Collaborative Study","volume":"4","author":"Poole","year":"1997","journal-title":"J. Endotoxin Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"379","DOI":"10.2460\/ajvr.1993.54.03.379","article-title":"Effects of Intra-Articularly Administered Endotoxin on Clinical Signs of Disease and Synovial Fluid Tumor Necrosis Factor, Interleukin 6, and Prostaglandin E2 Values in Horses","volume":"54","author":"Hawkins","year":"1993","journal-title":"Am. J. Vet. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1111\/evj.13396","article-title":"Treatment Effects of Intra-Articular Triamcinolone Acetonide in an Equine Model of Recurrent Joint Inflammation","volume":"53","author":"Kearney","year":"2021","journal-title":"Equine Vet. J."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Kearney, C.M., Khatab, S., van Buul, G.M., Plomp, S.G.M., Korthagen, N.M., Labbert\u00e9, M.C., Goodrich, L.R., Kisiday, J.D., Van Weeren, P.R., and van Osch, G.J.V.M. (2022). Treatment Effects of Intra-Articular Allogenic Mesenchymal Stem Cell Secretome in an Equine Model of Joint Inflammation. Front. Vet. Sci., 9.","DOI":"10.3389\/fvets.2022.907616"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"866","DOI":"10.2460\/ajvr.1996.57.06.866","article-title":"Effects of Pretreatment with Ketoprofen and Phenylbutazone on Experimentally Induced Synovitis in Horses","volume":"57","author":"Owens","year":"1996","journal-title":"Am. J. Vet. Res."},{"key":"ref_18","unstructured":"Pfau, T. (2018). EquiGait Wireless: Instruction Manual, EquiGait Ltd."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1111\/j.2042-3306.2012.00571.x","article-title":"Comparison of an Inertial Sensor System of Lameness Quantification with Subjective Lameness Evaluation","volume":"44","author":"McCracken","year":"2012","journal-title":"Equine Vet. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.ab.2003.12.035","article-title":"Characterization of Mca-Lys-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2, a Fluorogenic Substrate with Increased Specificity Constants for Collagenases and Tumor Necrosis Factor Converting Enzyme","volume":"328","author":"Neumann","year":"2004","journal-title":"Anal. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"224","DOI":"10.22203\/eCM.v029a17","article-title":"Fact versus Artifact: Avoiding Erroneous Estimates of Sulfated Glycosaminoglycan Content Using the Dimethylmethylene Blue Colorimetric Assay for Tissue-Engineered Constructs","volume":"29","author":"Levenston","year":"2015","journal-title":"Eur. Cell. Mater."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/0304-4165(86)90306-5","article-title":"Improved Quantitation and Discrimination of Sulphated Glycosaminoglycans by Use of Dimethylmethylene Blue","volume":"883","author":"Farndale","year":"1986","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.tvjl.2014.03.030","article-title":"In Vivo Effects of Phenylbutazone on Inflammation and Cartilage-Derived Biomarkers in Equine Joints with Acute Synovitis","volume":"201","author":"Brunott","year":"2014","journal-title":"Vet. J."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kearney, C.M., Korthagen, N.M., Plomp, S.G.M., Labbert\u00e9, M.C., de Grauw, J.C., van Weeren, P.R., and Brama, P.A.J. (2023). A Translational Model for Repeated Episodes of Joint Inflammation: Welfare, Clinical and Synovial Fluid Biomarker Assessment. Animals, 13.","DOI":"10.3390\/ani13203190"},{"key":"ref_25","unstructured":"R Core Team (2023). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.2460\/ajvr.2003.64.1491","article-title":"Effect of Induced Unilateral Synovitis of Distal Intertarsal and Tarsometatarsal Joints on Sagittal Plane Kinematics and Kinetics of Trotting Horses","volume":"64","author":"Khumsap","year":"2003","journal-title":"Am. J. Vet. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1111\/j.2042-3306.2010.00077.x","article-title":"Intra-Articular Opioid Analgesia Is Effective in Reducing Pain and Inflammation in an Equine LPS Induced Synovitis Model","volume":"42","author":"Back","year":"2010","journal-title":"Equine Vet. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.tvjl.2012.01.015","article-title":"Analgesic and Anti-Hyperalgesic Effects of Epidural Morphine in an Equine LPS-Induced Acute Synovitis Model","volume":"193","author":"Menke","year":"2012","journal-title":"Vet. J."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Andreassen, S.M., Vinther, A.M.L., Nielsen, S.S., Andersen, P.H., Tnibar, A., Kristensen, A.T., and Jacobsen, S. (2017). Changes in Concentrations of Haemostatic and Inflammatory Biomarkers in Synovial Fluid after Intra-Articular Injection of Lipopolysaccharide in Horses. BMC Vet. Res., 13.","DOI":"10.1186\/s12917-017-1089-1"},{"key":"ref_30","first-page":"305","article-title":"Arthrogenic Lameness of the Fetlock: Synovial Fluid Markers of Inflammation and Cartilage Turnover in Relation to Clinical Joint Pain","volume":"38","author":"Brommer","year":"2006","journal-title":"Equine Vet. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1053\/jvet.2001.28430","article-title":"Synovial Fluid Cytokines and Eicosanoids as Markers of Joint Disease in Horses","volume":"30","author":"Bertone","year":"2001","journal-title":"Vet. Surg."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1093\/af\/vfac026","article-title":"Osteoarthritis: A Common Disease That Should Be Avoided in the Athletic Horse\u2019s Life","volume":"12","author":"Baccarin","year":"2022","journal-title":"Anim. Front. Rev. Mag. Anim. Agric."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.ejpb.2018.05.001","article-title":"Sustained Intra-Articular Release of Celecoxib in an Equine Repeated LPS Synovitis Model","volume":"128","author":"Cokelaere","year":"2018","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_34","first-page":"2693","article-title":"Influence of an Intra-Articular Lipopolysaccharide Challenge on Markers of Inflammation and Cartilage Metabolism in Young Horses","volume":"91","author":"Lucia","year":"2013","journal-title":"Am. Soc. Anim. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1093\/jas\/sky423","article-title":"Effects of Repeated Arthrocentesis on Systemic Cytokine Expression and Leukocyte Population in Young Horses Challenged with Intra-Articular Lipopolysaccharide","volume":"97","author":"Hunt","year":"2019","journal-title":"J. Anim. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S0749-0739(17)30077-9","article-title":"Diagnostic Thermography","volume":"17","author":"Turner","year":"2001","journal-title":"Vet. Clin. North Am. Equine Pract."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.jevs.2012.07.003","article-title":"Use of Infrared Thermography to Detect Intrasynovial Injections in Horses","volume":"33","author":"Figueiredo","year":"2013","journal-title":"J. Equine Vet. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.jevs.2016.11.002","article-title":"Infrared Thermography: Current Applications in Equine Medicine","volume":"60","author":"Soroko","year":"2018","journal-title":"J. Equine Vet. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1136\/vr.158.25.852","article-title":"Investigations of the Reliability of Observational Gait Analysis for the Assessment of Lameness in Horses","volume":"158","author":"Hewetson","year":"2006","journal-title":"Vet. Rec."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"de Grauw, J.C., van de Lest, C.H., and van Weeren, P.R. (2009). Inflammatory Mediators and Cartilage Biomarkers in Synovial Fluid after a Single Inflammatory Insult: A Longitudinal Experimental Study. Arthritis Res. Ther., 11.","DOI":"10.1186\/ar2640"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1111\/evj.13899","article-title":"Residual Effects of Intra-Articular Betamethasone and Triamcinolone Acetonide in an Equine Acute Synovitis Model","volume":"55","author":"Partridge","year":"2023","journal-title":"Equine Vet. J."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Knych, H.K., Weiner, D., Harrison, L., and McKemie, D.S. (2022). Pharmacokinetics and Pharmacodynamics of Intra-Articular Isoflupredone Following Administration to Horses with Lipopolysaccharide-Induced Synovitis. BMC Vet. Res., 18.","DOI":"10.1186\/s12917-022-03537-5"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Urayama, S., Tanaka, A., Kusano, K., Sato, H., Muranaka, M., Mita, H., Nagashima, T., and Matsuda, H. (2023). Oral Administration of Meloxicam and Flunixin Meglumine Have Similar Analgesic Effects After Lipopolysaccharide-Induced Inflammatory Response in Thoroughbred Horses. J. Equine Vet. Sci., 121.","DOI":"10.1016\/j.jevs.2022.104205"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ekstrand, C., Bondesson, U., Giving, E., Hedeland, M., Ingvast-Larsson, C., Jacobsen, S., L\u00f6fgren, M., Moen, L., Rhodin, M., and Saetra, T. (2019). Disposition and Effect of Intra-Articularly Administered Dexamethasone on Lipopolysaccharide Induced Equine Synovitis. Acta Vet. Scand., 61.","DOI":"10.1186\/s13028-019-0464-2"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1002\/jps.21152","article-title":"Endotoxin Limits in Formulations for Preclinical Research","volume":"97","author":"Malyala","year":"2008","journal-title":"J. Pharm. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1111\/evj.12629","article-title":"The Preventive Effects of Two Nutraceuticals on Experimentally Induced Acute Synovitis","volume":"49","author":"Oosterlinck","year":"2017","journal-title":"Equine Vet. J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"16","DOI":"10.2174\/1874312901711010016","article-title":"Use of Saline as a Placebo in Intra-Articular Injections in Osteoarthritis: Potential Contributions to Nociceptive Pain Relief","volume":"11","author":"Rael","year":"2017","journal-title":"Open Rheumatol. J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1002\/ejp.584","article-title":"Repeated Intra-Articular Injections of Acidic Saline Produce Long-Lasting Joint Pain and Widespread Hyperalgesia","volume":"19","author":"Sugimura","year":"2015","journal-title":"Eur. J. Pain"}],"container-title":["Animals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2615\/15\/17\/2474\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:34:17Z","timestamp":1760034857000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2615\/15\/17\/2474"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,22]]},"references-count":48,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ani15172474"],"URL":"https:\/\/doi.org\/10.3390\/ani15172474","relation":{},"ISSN":["2076-2615"],"issn-type":[{"value":"2076-2615","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,22]]}}}