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Journal of orthopaedic surgery and research2020; 15(1); 460; doi: 10.1186/s13018-020-01994-y

Differential gene expression in skin RNA of horses affected with degenerative suspensory ligament desmitis.

Abstract: Equine degenerative suspensory ligament desmitis (DSLD) is a systemic connective tissue disorder first identified in Peruvian Paso horses but afflicting other horse breeds as well. Inappropriate accumulation of proteoglycans in connective tissues, most prominently in tendons and ligaments, leads to progressive and debilitating lameness and pain. It is largely unknown what drives the overproduction of proteoglycans, but our previous studies suggest involvement of bone morphogenetic protein 2 (BMP2), a member of the transforming growth factor-β (TGFβ) family, impacting synthesis of proteoglycans. To identify potential players in pathogenesis of DSLD a new approach utilizing next generation sequencing was undertaken. Methods: Next generation sequencing was performed using RNA extracted from skin biopsies of six control Peruvian Pasos and six horses with DSLD (4 Peruvian Pasos and 2 warmbloods). The CuffDiff result sets were validated with algorithms used to run them. This was based on the determined false discovery rates derived from the P values adjusted for multiple testing for any given result. Results: Bioinformatics analysis of transcriptomes revealed differential expression of over 1500 genes, including increased expression of genes for several growth factors (most prominently BMP2, FGF5, CTGF, many members of the EGF family), and mediators of signaling (Fos, Myc, MAPK system), and keratins. Two genes encoding for enzymes involved in synthesis of hyaluronan were also overexpressed. Gene expression was decreased for protein cores of many proteoglycans, several growth factors, most collagens, and many peptides with immune function. Conclusions: The overexpression of BMP2 correlates well with our previous data. However, the decrease in expression of numerous proteoglycans was unexpected. A mutation in a gene of a less characterized proteoglycan and/or glycosyltransferase with subsequent increased production of hyaluronan and/or a proteoglycan(s) undetected in our study could account for the systemic proteoglycan deposition. Decreased collagen gene expression indicates abnormal connective tissue metabolism. The increased expression of keratin genes and FGF5 supports reports of skin abnormalities in DSLD. Underexpression of immune function genes corresponds with lack of inflammation in DSLD tissues. Finally, though the proteoglycan and/or glycosaminoglycan abundant in DSLD has not been identified, we validated our previous data, including overexpression of BMP2, and systemic nature of DSLD due to disturbed metabolism of the extracellular matrix.
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Publication Date: 2020-10-07 PubMed ID: 33028365PubMed Central: PMC7541307DOI: 10.1186/s13018-020-01994-yGoogle Scholar: Lookup
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  • Journal Article

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 research article focuses on the investigation of genes involved in Equine Degenerative Suspensory Ligament Desmitis (DSLD) – a serious hoof condition in horses – through the use of next-generation sequencing of skin RNA. The study identified over 1500 genes with different expression levels in affected horses, suggesting a deeper level of complexity in the pathogenesis of this disease.

Methodology

  • The researchers utilised next-generation sequencing to study the RNA extracted from skin biopsies of 12 horses. Six of these were control Peruvian Pasos while the other six were affected by DSLD.
  • The team carefully validated the CuffDiff result sets with algorithms used to run them, based on false discovery rates for increased accuracy and reliability of the results.

Results

  • The team found differential expression in over 1500 genes. This included increased expression of genes for several growth factors (notably BMP2, FGF5, CTGF), numerous members of the EGF family, mediators of signaling (Fos, Myc, MAPK system), and keratins.
  • They also identified two genes for enzymes involved in hyaluronan synthesis were overexpressed.
  • On the other hand, gene expression was decreased for protein cores of many proteoglycans, additional growth factors, most collagens, and a number of peptides with immune function.

Conclusions

  • The overexpression of the BMP2 gene aligns well with the team’s previous data. However, the decrease in the expression of numerous proteoglycans was unexpected.
  • The authors proposed that a mutation in a less characterized proteoglycan and/or glycosyltransferase could lead to increased production of hyaluronan or a proteoglycan(s) that was undetected in their study.
  • They also suggested that the decrease in collagen gene expression shows abnormal connective tissue metabolism, which could contribute to the condition.
  • The enhanced expression of keratin genes with FGF5 may support the incidence of skin abnormalities in DSLD.
  • The underexpression of immune function genes corresponds with the lack of inflammation commonly found in DSLD tissues, which may play a role in the disease’s development and progression.
  • In conclusion, while the proteoglycan and/or glycosaminoglycan that appear in high amounts in DSLD have not yet been identified, the study advances our understanding in that it confirms earlier data, including the overexpression of the BMP2 gene, and strengthens the idea that DSLD is a systemic condition resulting from disturbed extracellular matrix metabolism.

Cite This Article

APA
Haythorn A, Young M, Stanton J, Zhang J, Mueller POE, Halper J. (2020). Differential gene expression in skin RNA of horses affected with degenerative suspensory ligament desmitis. J Orthop Surg Res, 15(1), 460. https://doi.org/10.1186/s13018-020-01994-y

Publication

Journal of orthopaedic surgery and research
ISSN: 1749-799X
NlmUniqueID: 101265112
Country: England
Language: English
Volume: 15
Issue: 1
Pages: 460
PII: 460

Researcher Affiliations

Haythorn, Abigail
  • Department of Pathology, College of Veterinary Medicine, The University of Georgia, Athens, GA, 30602, USA.
Young, Madeline
  • Department of Pathology, College of Veterinary Medicine, The University of Georgia, Athens, GA, 30602, USA.
Stanton, James
  • Department of Pathology, College of Veterinary Medicine, The University of Georgia, Athens, GA, 30602, USA.
Zhang, Jian
  • Department of Pathology, College of Veterinary Medicine, The University of Georgia, Athens, GA, 30602, USA.
Mueller, P O E
  • Department of Large Animal Medicine, College of Veterinary Medicine, The University of Georgia, Athens, GA, 30602, USA.
Halper, Jaroslava
  • Department of Pathology, College of Veterinary Medicine, The University of Georgia, Athens, GA, 30602, USA. jhalper@uga.edu.
  • AU/UGA Medical Partnership, The University of Georgia, Athens, GA, 30602, USA. jhalper@uga.edu.

MeSH Terms

  • Animals
  • Bone Morphogenetic Protein 2 / metabolism
  • Collagen / metabolism
  • Connective Tissue Diseases / complications
  • Connective Tissue Diseases / genetics
  • Connective Tissue Diseases / veterinary
  • Disease Progression
  • Gene Expression
  • High-Throughput Nucleotide Sequencing / methods
  • Horse Diseases / genetics
  • Horse Diseases / metabolism
  • Horses
  • Hyaluronic Acid / metabolism
  • Lameness, Animal / etiology
  • Ligaments / metabolism
  • Pain / etiology
  • Pain / veterinary
  • Proteoglycans / metabolism
  • RNA / genetics
  • RNA / metabolism
  • Skin / metabolism
  • Tendons / metabolism

Conflict of Interest Statement

None of the authors has a competing financial or other conflict of interest in this study. However, Dr. Jaroslava Halper is an associate editor of this journal.

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Citations

This article has been cited 7 times.
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