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Genome-wide analysis identifies differential promoter methylation of Leprel2, Foxf1, Mmp25, Igfbp6, and Peg12 in murine tendinopathy

Published on May 1, 2017in Journal of Orthopaedic Research3.043
· DOI :10.1002/jor.23393
Katie J. Trella3
Estimated H-index: 3
(UIC: University of Illinois at Chicago),
Jun Li18
Estimated H-index: 18
(Rush University Medical Center)
+ 6 AuthorsRobert W. Wysocki28
Estimated H-index: 28
(Rush University Medical Center)
Abstract
We have used a murine Achilles tendinopathy model to investigate whether tissue changes (such as collagen disorganization, chondroid metaplasia, and loss of tensile properties) which are broadly characteristic of human tendinopathies, are accompanied by changes in the expression of chromatin-modifying enzymes and the methylation status of promoter regions of tendon cell DNA. Tendinopathy was induced by two intra-tendinous TGF-β1 injections followed by cage activity or treadmill running for up to 28 days. Activation of DNA methyltransferases occurred at 3 days after the TGF-β1 injections and also at 14 days, but only with treadmill activity. Genome-wide Methyl Mini-Seq™ analysis identified 19 genes with differentially methylated promoters, five of which perform functions with an apparent direct relevance to tendinopathy (Leprel2, Foxf1, Mmp25, Igfbp6, and Peg12). The functions of the genes identified included collagen fiber assembly and pericellular interactions, therefore their perturbation could play a role in the characteristic disorganization of fibers in affected tendons. We postulate that a study of the functional genomics of these genes in animal and human tendon could further delineate the pathogenesis of this multi-factorial complex disease. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:947-955, 2017.
  • References (36)
  • Citations (7)
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References36
Newest
#1Ronald L. Wasserstein (American Statistical Association)H-Index: 3
#2Nicole A. Lazar (American Statistical Association)H-Index: 1
1,382 CitationsSource
Tendinopathy is a multifactorial syndrome characterised by tendon pain and thickening, and impaired performance during activity. Candidate gene association studies have identified genetic factors that contribute to intrinsic risk of developing tendinopathy upon exposure to extrinsic factors. Bioinformatics approaches that data-mine existing knowledge for biological relationships may assist with the identification of candidate genes. The aim of this study was to data-mine functional annotation of...
8 CitationsSource
#1Benjamin J F Dean (NOC: Nuffield Orthopaedic Centre)H-Index: 13
#2Peter Gettings (University of Essex)H-Index: 1
Last. Andrew Carr (NOC: Nuffield Orthopaedic Centre)H-Index: 93
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Background The role of inflammation in tendinopathy has historically been a subject of significant controversy. Our primary aim was to determine whether inflammatory cell numbers were increased in painful human tendinopathy versus healthy control tendons. Our secondary aim was to assess whether the inflammatory cells had been linked with symptoms or disease stage. Methods We conducted a systematic review of the scientific literature using the PRISMA and Cochrane guidelines of the Medline databas...
51 CitationsSource
#1Sujan Badal (Mayo Clinic)H-Index: 1
#2Yeng F. Her (Mayo Clinic)H-Index: 5
Last. L. James Maher (Mayo Clinic)H-Index: 27
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Abstract Fluoroquinolones (FQ) are powerful broad-spectrum antibiotics whose side effects include renal damage and, strangely, tendinopathies. The pathological mechanisms underlying these toxicities are poorly understood. Here, we show that the FQ drugs norfloxacin, ciprofloxacin, and enrofloxacin are powerful iron chelators comparable with deferoxamine, a clinically useful iron-chelating agent. We show that iron chelation by FQ leads to epigenetic effects through inhibition of α-ketoglutarate-d...
26 CitationsSource
#1Satoshi Wada (Tsurumi University)H-Index: 5
#2Hisashi Ideno (Tsurumi University)H-Index: 7
Last. Akira Nifuji (Tsurumi University)H-Index: 30
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Cell differentiation is controlled by specific transcription factors. The functions and expression levels of these transcription factors are regulated by epigenetic modifications, such as histone modifications and cytosine methylation of the genome. In tendon tissue, tendon-specific transcription factors have been shown to play functional roles in the regulation of tenocyte differentiation. However, the effects of epigenetic modifications on gene expression and differentiation in tenocytes are u...
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#1Chang Hun LeeH-Index: 21
#2Francis Y. LeeH-Index: 29
Last. Jeremy J. MaoH-Index: 48
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Current stem cell–based strategies for tissue regeneration involve ex vivo manipulation of these cells to confer features of the desired progenitor population. Recently, the concept that endogenous stem/progenitor cells could be used for regenerating tissues has emerged as a promising approach that potentially overcomes the obstacles related to cell transplantation. Here we applied this strategy for the regeneration of injured tendons in a rat model. First, we identified a rare fraction of tendo...
77 CitationsSource
#1Ewa M. Spiesz (QMUL: Queen Mary University of London)H-Index: 9
#2Chavaunne T. Thorpe (QMUL: Queen Mary University of London)H-Index: 16
Last. Hazel R. C. Screen (QMUL: Queen Mary University of London)H-Index: 28
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The role of inflammation in tendon injury is uncertain and a topic of current interest. In vitro studies of tendon accelerated overload damage can serve as a valuable source of information on the early stages of tendinopathy. Viable fascicle bundles from bovine flexor tendons were subjected to cyclic uniaxial loading from 1–10% strain. Immuno-staining for inflammatory markers and matrix degradation markers was performed on the samples after mechanical testing. Loaded samples exhibited visible ex...
41 CitationsSource
#2Tianyin ZhouH-Index: 12
Last. Remo Rohs (SC: University of Southern California)H-Index: 35
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Many anecdotal observations exist of a regulatory effect of DNA methylation on gene expression. However, in general, the underlying mechanisms of this effect are poorly understood. In this review, we summarize what is currently known about how this important, but mysterious, epigenetic mark impacts cellular functions. Cytosine methylation can abrogate or enhance interactions with DNA-binding proteins, or it may have no effect, depending on the context. Despite being only a small chemical change,...
45 CitationsSource
Cytosine methylation is a DNA modification generally associated with transcriptional silencing. Factors that regulate methylation have been linked to human disease, yet how they contribute to malignances remains largely unknown. Genomic maps of DNA methylation have revealed unexpected dynamics at gene regulatory regions, including active demethylation by TET proteins at binding sites for transcription factors. These observations indicate that the underlying DNA sequence largely accounts for loca...
699 CitationsSource
#1Bruno Magnan (University of Verona)H-Index: 18
#2Manuel Bondi (University of Verona)H-Index: 7
Last. Elena Manuela Samaila (University of Verona)H-Index: 9
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Abstract Achilles tendinopathy is a degenerative, not an inflammatory, condition. It is prevalent in athletes involved in running sports. A systematic literature review on Achilles tendon tendinopathy has been performed according to the intrinsic (age, sex, body weight, tendon temperature, systemic diseases, muscle strength, flexibility, previous injuries and anatomical variants, genetic predisposition and blood supply) and extrinsic risk factors (drugs and overuse), which can cause tendon suffe...
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#1Katie J. SikesH-Index: 2
#2Kristen RennerH-Index: 2
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#1Katie J. Sikes (UIC: University of Illinois at Chicago)H-Index: 2
#2Jun Li (Rush University Medical Center)H-Index: 18
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ABSTRACTPurpose/Aim of the study: Healthy tendons are maintained in homeostasis through controlled usage of glucose for energy and redox equilibrium. Tendon cell stress imposed by overuse injury or...
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#1Mor Grinstein (Harvard University)H-Index: 1
#2Heather L. Dingwall (Harvard University)H-Index: 7
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#1Louis El Khoury (University of Northampton)H-Index: 5
#2Rebecca Rickaby (University of Northampton)H-Index: 1
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Objectives Patellar tendinopathy (PT) is a debilitating and prevalent condition that tends to affect those who are physically active or engaged in jumping sports. Although tendinopathies are known to have a genetic basis, the role of DNA methylation as an epigenetic factor and risk determinant for human PT has never been described. We sought to determine whether differences existed between the methylation profiles of both the TIMP2 and ADAMTS4 gene promoter sequences in a cohort of males having ...
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