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Harnessing the Horse for Human Osteoarthritis: microRNA-181a-5p Antisense Oligonucleotides in Clinically Normal Equine Fetlock Joints Are Safe and Well Tolerated.
Abstract: Horses serve as a translational model for human osteoarthritis (OA) due to their comparable joint size, cartilage thickness, and incidence of naturally occurring disease. Overexpression of microRNA-181a-5p has been implicated in cartilage degradation in OA, and its inhibition using locked nucleic acid antisense oligonucleotides (LNA-miR-181a-5p ASOs) represents a potential therapeutic strategy. This study evaluated the safety of intraarticular (IA) LNA-miR-181a-5p ASO injection in clinically normal horse fetlock joints. Twelve horses were randomized to receive two IA injections, 28 days apart, of either low-dose [2000 µg (n = 6)] or high-dose [4000 µg (n = 6)] LNA-miR-181a-5p ASO. Over 56 days, variables assessed included physical examinations, joint assessments (effusion, circumference, temperature), lameness scores, and biofluid analyses. Physical and lameness evaluation variables remained similar to baseline and did not differ by dose (p > 0.05). Joint effusion was mildly increased in high-dose joints at Day 3 post-injection (p 0.05). A transient, dose-independent increase (p 0.05). Although TNF-α concentrations were greater in the high-dose group (p < 0.05), values were variable across horses, even prior to treatment. Overall, IA LNA-miR-181a-5p ASO was well tolerated in clinically normal horse fetlocks, with only transient inflammatory changes, supporting its evaluation as a potential OA therapy.
© 2026 The Author(s). Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.
Publication Date: 2026-10-25 PubMed ID: 42926329PubMed Central: PMC13695786DOI: 10.1002/jor.70298Google 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.
- Journal Article
Summary
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Research Overview
- This study tested the safety of injecting a novel microRNA-targeting drug into healthy horse joints to assess its potential as a treatment for osteoarthritis.
- The drug, antisense oligonucleotides against microRNA-181a-5p, was well tolerated with minimal and temporary joint inflammation observed.
Background and Purpose
- Osteoarthritis (OA) is a joint disease involving cartilage breakdown and inflammation.
- Horses are good models for human OA because their joint anatomy and disease development are similar.
- MicroRNA-181a-5p is implicated in cartilage degradation in OA.
- Inhibiting this microRNA with locked nucleic acid antisense oligonucleotides (LNA-miR-181a-5p ASOs) could be a novel therapeutic approach.
- The main goal was to determine if injecting this ASO drug into healthy horse fetlock joints is safe and well tolerated.
Study Design
- Twelve clinically normal horses were randomly assigned to two groups (6 horses each).
- Each group received two intraarticular (IA) injections of either low dose (2000 µg) or high dose (4000 µg) ASO, 28 days apart.
- The fetlock joint was chosen for injection and observation.
- Follow-up lasted 56 days, including comprehensive clinical and laboratory assessments at multiple timepoints.
Assessments and Measurements
- Physical examinations included monitoring for general health and signs of adverse effects.
- Joint-specific parameters measured were effusion (fluid accumulation/swelling), joint circumference, and temperature.
- Lameness scoring was used to detect functional impairment or discomfort in the horse.
- Synovial fluid and blood samples were analyzed for inflammatory markers and cell counts.
- Key inflammatory mediators included IL-1β, prostaglandin E (PGE), and tumor necrosis factor-alpha (TNF-α).
Results
- Physical exams and lameness scores remained unchanged from baseline, indicating no significant adverse effects on general well-being or joint function.
- Minor joint effusion increase was observed only in the high-dose group at 3 days after injection, suggesting mild, transient joint swelling.
- Joint circumference and temperature did not change significantly in either dose group.
- There was a transient, dose-independent rise in nucleated cell count in synovial fluid at day 3 post-injection, consistent with mild inflammation related to the injection process (arthrocentesis), not the drug itself.
- Concentrations of IL-1β and PGE remained stable across doses and over time, indicating no significant inflammatory response.
- TNF-α was slightly higher in the high-dose group but showed high variability even before treatment, limiting interpretation of this finding as an adverse drug effect.
- Hematologic and biochemical parameters remained stable, demonstrating systemic safety.
Conclusions and Implications
- Intraarticular administration of LNA-miR-181a-5p ASOs was safe and well tolerated in healthy horse fetlock joints.
- Observed inflammatory changes were transient, mild, and likely related to injection trauma rather than the ASO drug itself.
- This supports further investigation of this microRNA-targeting approach as a potential disease-modifying therapy for OA.
- Using the horse model provides translational relevance due to similar joint characteristics with humans.
- Future studies may assess efficacy in OA-affected joints and long-term safety.
Cite This Article
APA
Connor McCorkell T, Mortagy N, Luque RM, Koch TG, Beeler-Marfisi J, Raja Rampersaud Y, Lamarre J, Kapoor M, Koenig JB.
(2026).
Harnessing the Horse for Human Osteoarthritis: microRNA-181a-5p Antisense Oligonucleotides in Clinically Normal Equine Fetlock Joints Are Safe and Well Tolerated.
J Orthop Res, 44(11), e70298.
https://doi.org/10.1002/jor.70298 Publication
Researcher Affiliations
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.
- Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada.
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.
- Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada.
- Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.
MeSH Terms
- Animals
- Horses
- Osteoarthritis / veterinary
- Osteoarthritis / therapy
- Osteoarthritis / drug therapy
- MicroRNAs
- Oligonucleotides, Antisense / therapeutic use
- Oligonucleotides, Antisense / administration & dosage
- Injections, Intra-Articular
- Male
- Female
Grant Funding
- 540277 / CIHR
- Krembil Foundation
- Tony and Shari Fell Platinum Chair in Arthritis Research
Conflict of Interest Statement
M.K. and Y.R.R. hold a patent “MiRNA biomarkers for cartilage degeneration: Patent number: 10888577”. All other authors declare no conflicts of interest.
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