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Animal genetics2025; 56(1); e13504; doi: 10.1111/age.13504

Identification of a global gene expression signature associated with the genetic risk of catastrophic fracture in iPSC-derived osteoblasts from Thoroughbred horses.

Abstract: Bone fractures are a significant problem in Thoroughbred racehorses. The risk of fracture is influenced by both genetic and environmental factors. To determine the biological processes that are affected in genetically susceptible horses, we utilised polygenic risk scoring to establish induced pluripotent stem cells (iPSCs) from horses at high and low genetic risk. RNA-sequencing on iPSC-derived osteoblasts revealed 112 genes that were significantly differentially expressed. Forty-three of these genes have known roles in bone, 27 are not yet annotated in the equine genome and 42 currently have no described role in bone. However, many of the proteins encoded by the known and unknown genes have reported interactions. Functional enrichment analyses revealed that the differentially expressed genes were overrepresented in processes regulating the extracellular matrix and pathways known to be involved in bone remodelling and bone diseases. Gene set enrichment analysis also detected numerous biological processes and pathways involved in glycolysis with the associated genes having a higher expression in the iPSC-osteoblasts from horses with low polygenic risk scores for fracture. Therefore, the differentially expressed genes may be relevant for maintaining bone homeostasis and contribute to fracture risk. A deeper understanding of the consequences of mis-regulation of these genes and the identification of the DNA variants which underpin their differential expression may reveal more about the molecular mechanisms which are involved in equine bone health and fracture risk.
© 2025 The Author(s). Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.
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Publication Date: 2025-01-13 PubMed ID: 39801206PubMed Central: PMC11726005DOI: 10.1111/age.13504Google Scholar: Lookup
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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.

This study uses gene profiling to understand the genetic factors contributing to bone fractures in Thoroughbred racehorses, and proposes potential molecular mechanisms linking genetic susceptibility and fracture risk.

Research Methodology

  • The research began by identifying the horses with a high genetic risk of fractures by using polygenic risk scoring. Polygenic risk scores are calculated from the sum of the effect of all risk genetic variants in an individual’s genome. In simpler terms, the researchers were able to use the genetic information of the horses to predict their risk of getting fractures.
  • Once the genetically susceptible horses were identified, the researchers established induced pluripotent stem cells (iPSCs) from these horses. iPSCs are derived from skin or blood cells that have been reprogrammed back into an embryonic-like pluripotent state, enabling the development of an unlimited source of any type of human cell needed for therapeutic purposes. In this study, the cells were grown into bone cells (osteoblasts).

Findings

  • The researchers analyzed the osteoblasts at the molecular level using a technique called RNA-sequencing. This allowed them to examine the expression of genes involved in bone health and fracture risk. They found 112 genes that were expressed differently, meaning these genes might be turned on or off or work at different speeds in horses at high risk for fractures.
  • Of these 112 genes, 43 are already known to be involved in bone health, 27 are not yet fully understood in the horse genome, and 42 have no known role in bone health. Observations suggest that these genes and the proteins they encode might interact in ways important to bone health.
  • The differential expression of these genes was observed to be involved mainly in the regulation of the extracellular matrix and other pathways that are known to be involved in bone remodeling and susceptibility to bone diseases. The extracellular matrix provides structural and biochemical support to the surrounding cells and is crucial in bone strength and integrity.
  • This study also suggested that the differentially expressed genes are involved in various biological processes and pathways relating to glycolysis (the process that converts glucose to energy), particularly in horses with lower polygenic risk scores. It suggests that energy metabolism might have a significant role in maintaining bone health.

Implication of Study

  • Understanding the genetical difference can provide insights into the molecular mechanisms involved in equine bone health and fracture risk. This could help in early diagnosis and development of better treatments or prevention strategies for bone fractures in Thoroughbred horses.
  • This study also set the stage for future research into identifying DNA variants that underpin the differential expression of these genes. By understanding how these genes and DNA variants interact and contribute to fractures, more effective therapeutic strategies may be developed.

Cite This Article

APA
Palomino Lago E, Ross AKC, McClellan A, Guest DJ. (2025). Identification of a global gene expression signature associated with the genetic risk of catastrophic fracture in iPSC-derived osteoblasts from Thoroughbred horses. Anim Genet, 56(1), e13504. https://doi.org/10.1111/age.13504

Publication

Animal genetics
ISSN: 1365-2052
NlmUniqueID: 8605704
Country: England
Language: English
Volume: 56
Issue: 1
Pages: e13504
PII: e13504

Researcher Affiliations

Palomino Lago, Esther
  • Department of Clinical Sciences and Services, Centre for Vaccinology and Regenerative Medicine, The Royal Veterinary College, Hatfield, Herts, UK.
Ross, Amy K C
  • Department of Clinical Sciences and Services, Centre for Vaccinology and Regenerative Medicine, The Royal Veterinary College, Hatfield, Herts, UK.
McClellan, Alyce
  • Animal Health Trust, Newmarket, UK.
  • Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
Guest, Deborah J
  • Department of Clinical Sciences and Services, Centre for Vaccinology and Regenerative Medicine, The Royal Veterinary College, Hatfield, Herts, UK.

MeSH Terms

  • Animals
  • Horses / genetics
  • Induced Pluripotent Stem Cells
  • Osteoblasts
  • Fractures, Bone / veterinary
  • Fractures, Bone / genetics
  • Transcriptome
  • Horse Diseases / genetics
  • Genetic Predisposition to Disease

Grant Funding

  • vet/prj/792 / Horserace Betting Levy Board
  • Alborada Trust

Conflict of Interest Statement

E. Palomino Lago, A.K.C. Ross and D.J. Guest are affiliated with The Royal Veterinary College, which holds patent WO 2015/019097 ‘Predictive Method for Bone Fracture Risk in Horses’ in relation to this work. This patent claims a method of predicting fracture risk in horses using one or more genetic variations from within the associated region on ECA18. A. McClellan has no competing interests to declare.

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