Abstract
Equine degenerative suspensory ligament desmitis (DSLD) in Peruvian Paso horses typically presents at 7-15 years and is characterized by lameness, focal disorganization of collagen fibrils, and chondroid deposition in the body of the ligament. With the aim of developing a test for disease risk (that can be used to screen horses before breeding) we have quantified the expression of 76 TGFβ-signaling target genes in adipose-derived stromal fibroblasts (ADSCs) from six DSLD-affected and five unaffected Paso horses. Remarkably, 35 of the genes showed lower expression (p<0.05) in cells from DSLD-affected animals and this differential was largely eliminated by addition of exogenous TGFβ1. Moreover, TGFβ1-mediated effects on expression were prevented by the TGFβR1/2 inhibitor LY2109761, showing that the signaling was via a TGFβR1/2 complex. The genes affected by the pathology indicate that it is associated with a generalized metabolic disturbance, since some of those most markedly altered in DSLD cells (ATF3, MAPK14, ACVRL1 (ALK1), SMAD6, FOS, CREBBP, NFKBIA, and TGFBR2) represent master-regulators in a wide range of cellular metabolic responses.
MeSH terms
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Adipose Tissue / pathology*
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Animals
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Chromatin / metabolism
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Fibroblasts / drug effects
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Fibroblasts / pathology*
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Gene Expression Regulation* / drug effects
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Horse Diseases / pathology*
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Horses
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Ligaments*
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Male
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Pyrazoles / pharmacology
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Pyrroles / pharmacology
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / antagonists & inhibitors
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Signal Transduction / drug effects
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Stromal Cells / pathology*
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Transforming Growth Factor beta / metabolism*
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Transforming Growth Factor beta1 / pharmacology
Substances
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Chromatin
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LY2109761
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Pyrazoles
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Pyrroles
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Receptors, Transforming Growth Factor beta
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II
Grants and funding
This study received funding from the Rush Arthritis Institute and the Katz/Rubschlager Endowed Chair. Funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.