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Journal of veterinary pharmacology and therapeutics2024; 47(3); 187-192; doi: 10.1111/jvp.13424

Effect of clodronate on gene expression in the peripheral blood of horses.

Abstract: There are two FDA-approved bisphosphonate products, clodronate (Osphos®) and tiludronate (Tildren®), for use in horses. It is hypothesized that bisphosphonates can produce analgesic effects and prevent proper healing of microcracks in bone. Therefore, bisphosphonate use is banned in racehorses. However, bisphosphonates have a short detection window in the blood before sequestration in the skeleton, making the reliability of current drug tests questionable. Seven exercising Thoroughbred horses were administered clodronate (1.8 mg/kg i.m.), and four were administered saline. RNA was isolated from peripheral blood mononuclear cells (PBMCs) collected immediately before a single dose of clodronate or saline and then on Days 1, 6, 28, 56 and 182 post-dose. mRNA was sequenced and analysed for differentially expressed transcripts. While no single transcripts were differentially expressed, pathway analysis revealed that p38 MAPK (p = .04) and Ras (p = .04) pathways were upregulated, and cadherin signalling (p = .02) was downregulated on Day 1. Previously investigated biomarkers, cathepsin K (CTSK) and type 5 acid phosphatase (ACP5), were analysed with RT-qPCR in a targeted gene approach, with no significant difference observed. A significant effect of time on gene expression for ACP5 (p = .03) and CTSK (p < .0001) was observed. Thus, these genes warrant further investigation for detecting clodronate use over time.
© 2024 The Authors. Journal of Veterinary Pharmacology and Therapeutics published by John Wiley & Sons Ltd.
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Publication Date: 2024-01-10 PubMed ID: 38197553PubMed Central: PMC11052667DOI: 10.1111/jvp.13424Google Scholar: Lookup
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  • Journal Article
  • Clinical Trial
  • Veterinary

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 explores the impact of administering the drug clodronate on gene expression levels in horses over time, with potential implications for drug detection methods in racehorses.

Introduction and Hypothesised Effects of Bisphosphonates

  • Clodronate and tiludronate are two bisphosphonate products approved by the FDA for use in horses. However, there has been speculation on the actual impact of these drugs, with suggestions that they could produce analgesic effects and even interfere with bone healing.
  • Because of these potential adverse effects, the use of bisphosphonates is banned in racehorses. Detecting their usage has proven challenging, however, as they rapidly sequestrate in the skeleton, leaving a short detection window in the blood; this hinders the reliability of most current drug tests.

Experimental Procedure and Findings

  • The study involved the administration of clodronate to seven thoroughbred horses, and a saline solution to four others as a control. Sequencing and analysis of RNA from peripheral blood mononuclear cells (PBMCs) determined any differentially expressed transcripts over a series of days following clodronate or saline administration.
  • The findings indicated that no single transcripts showed differential expression. However, pathway analysis revealed upregulation of p38 MAPK and Ras pathways, and downregulation of the cadherin signalling pathway on the first day after administration.
  • Additionally, the researchers also looked at the biomarkers cathepsin K (CTSK) and type 5 acid phosphatase (ACP5) through a targeted gene approach using RT-qPCR. No significant difference was observed.

Conclusions and Suggestions for Future Research

  • Beyond the primary findings, a significant effect of time on gene expression levels was also noted for ACP5 and CTSK. While these particular biomarkers did not show a significant initial change following clodronate administration, their expression levels appeared to fluctuate over time.
  • The researchers note that these genes may therefore warrant further investigation. This could create more reliable methods of detecting clodronate use over an extended time period, even after the drug has sequestrated in the skeleton and become undetectable in the blood.

Cite This Article

APA
Wilcox CV, Knych HK, Katzman SA, Arthur RM, Rodriguez V, Finno CJ. (2024). Effect of clodronate on gene expression in the peripheral blood of horses. J Vet Pharmacol Ther, 47(3), 187-192. https://doi.org/10.1111/jvp.13424

Publication

Journal of veterinary pharmacology and therapeutics
ISSN: 1365-2885
NlmUniqueID: 7910920
Country: England
Language: English
Volume: 47
Issue: 3
Pages: 187-192

Researcher Affiliations

Wilcox, Callie V
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, California, USA.
Knych, Heather K
  • K. L. Maddy Equine Analytical Pharmacology Laboratory, School of Veterinary Medicine, University of California, Davis, California, USA.
  • Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California, USA.
Katzman, Scott A
  • Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, California, USA.
Arthur, Rick M
  • School of Veterinary Medicine, University of California, Davis, California, USA.
Rodriguez, Veronika
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, California, USA.
Finno, Carrie J
  • Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, California, USA.

MeSH Terms

  • Animals
  • Horses / blood
  • Clodronic Acid / pharmacology
  • Bone Density Conservation Agents / pharmacology
  • Bone Density Conservation Agents / administration & dosage
  • Gene Expression Regulation / drug effects
  • Male
  • Female
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism

Grant Funding

  • L40 TR001136 / NCATS NIH HHS
  • T35 OD010956 / NIH HHS

Conflict of Interest Statement

CONFLICT OF INTEREST STATEMENT. The authors declare no conflict of interest.

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