Promoter methylation status of the TIMP2 and ADAMTS4 genes and patellar tendinopathy

Khoury, Louis El; Rickaby, Rebecca; Samiric, Tom; Raleigh, Stuart M

doi:10.1016/j.jsams.2017.08.016

Cited by 11 publications

(11 citation statements)

References 30 publications

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“…However, they did report an overrepresentation in the tendinopathy group of certain inferred pseudohaplotypes from the combination of these polymorphisms, as well as pseudohaplotypes of the collagen XI polymorphisms in combination with COL5A1 rs7174644 (-/AGGG) genotype 30 . Finally, a more recent line of investigation has been epigenetic risk factors for tendinopathy, particularly DNA methylation and its effects on expression levels of genes regulating collagen and other components of the ECM 31 .…”

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confidence: 99%

“…Considering the existing literature on the relationship between genetic factors and tendinopathy, this study aims to examine the association of different SNP genotypes with structural abnormalities indicative of elbow tendon pathology, namely COL5A1 rs12722, COL11A1 rs3753841, COL11A1 rs1676486 and COL11A2 rs1799907, selected in order to compare results with previous studies on patellar 24,31 , Achilles 13,25 and elbow tendinopathies 14 .…”

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confidence: 99%

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Influence of genetic factors in elbow tendon pathology: a case-control study

Alakhdar

Cook

Benítez-Martínez

et al. 2020

Sci Rep

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Elbow tendinopathy is a common pathology of the upper extremity that impacts both athletes and workers. Some research has examined the genetic component as a risk factor for tendinopathy, mainly in the lower limbs. A case-control study was designed to test for a relationship between certain collagen gene single nucleotide polymorphisms (SNPs) and elbow tendon pathology. A sample of 137 young adult athletes whose sports participation involves loading of the upper limb were examined for the presence of structural abnormalities indicative of pathology in the tendons of the lateral and medial elbow using ultrasound imaging and genotyped for the following SNPs: COL5A1 rs12722, COL11A1 rs3753841, COL11A1 rs1676486, and COL11A2 rs1799907. Anthropometric measurements and data on participants' elbow pain and dysfunction were collected using the Disabilities of the Arm, Shoulder and Hand and the Mayo Clinic Performance Index for the Elbow questionnaires. Results showed that participants in the structural abnormality group had significantly higher scores in pain and dysfunction. A significant relationship between COL11A1 rs3753841 genotype and elbow tendon pathology was found (p = 0.024), with the CT variant associated with increased risk of pathology.Tendinopathy is a common condition that affects a large portion of the population, making up 30% of all musculoskeletal injuries 1 and being the most prevalent tendon disorder 2 . It is generally defined as an overuse injury resulting in tendon degeneration after a failed early inflammatory healing response 3 , leading to collagen disorientation and disorganization in the absence of classic inflammatory changes, accompanied by pain and dysfunction 4,5 . Tendon homeostasis relies on a dynamic remodeling process influenced by tendon loading and cytokines, among other things. Evidence support the expression and functional involment of pro-inflammatory cytokines such as interleukin-1ß in tissues surrounding mechanically injured tendon 6 . Tendon inflammation and tendinopathy are possible manifestations of a disturbance of this homeostasis. The role of inflammation in tendon healing or failure to heal is complex and not fully understood, but it is known that an initial inflammatory response is required to begin the healing process. On the other hand, cytokines appear to be capable of inducing a failed healing response in several diseases of connective tissue (cartilage, bone, synovial joint) possibly by altering the expression of matrix metalloproteinases 7 . Probably the tendon is no exception, although there are no conclusive data at present on the role of these cytokines in the tendinopathy development 6,7 .The exact incidence of elbow tendinopathy is unknown, but it is estimated to affect 1-3% of adults each year in the lateral elbow 8 and 0.1-0.75% in the medial elbow 9 . It has been reported that the pathogenesis of the medial pathology parallels that of the lateral pathology, with similar patterns of angiofibroblastic degeneration 10 . In athletes, individuals who practice s...

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confidence: 99%

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Influence of genetic factors in elbow tendon pathology: a case-control study

Alakhdar

Cook

Benítez-Martínez

et al. 2020

Sci Rep

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“…Three studies identified used targeted approaches to identify DE methylated CpGs associated with genes of interest in patellar and the posterior, central and anterior cuff tendons. Two of the studies used diseased and healthy patellar tendon, from healthy Caucasian male patients aged 19–41, to identify changes in the epigenome in relation to tendinopathy 63 , 64 with each paper reporting a specific site; Adamts4 CpG—2995 upstream of promoter 64 and the CpG +61 upstream of MMP11 first exon, 63 these genes are known to translate to tendon specific proteases, involved in the maintenance of proteoglycans and the extracellular matrix. While these studies have shown that controlled analysis of the DNA sequence using a targeted approach revealed some changes in methylation at specific single CpG sites, functional significance remains to be verified, as no parallel gene expression analysis were undertaken.…”

Section: Resultsmentioning

confidence: 99%

Epigenetic mechanisms in Tendon Ageing

Riasat

Bardell

Goljanek‐Whysall

et al. 2020

British Medical Bulletin

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Introduction Tendon is a composite material with a well-ordered hierarchical structure exhibiting viscoelastic properties designed to transfer force. It is recognized that the incidence of tendon injury increases with age, suggesting a deterioration in homeostatic mechanisms or reparative processes. This review summarizes epigenetic mechanisms identified in ageing healthy tendon. Sources of data We searched multiple databases to produce a systematic review on the role of epigenetic mechanisms in tendon ageing. Areas of agreement Epigenetic mechanisms are important in predisposing ageing tendon to injury. Areas of controversy The relative importance of epigenetic mechanisms are unknown in terms of promoting healthy ageing. It is also unknown whether these changes represent protective mechanisms to function or predispose to pathology. Growing point Epigenetic markers in ageing tendon, which are under-researched including genome-wide chromatin accessibility, should be investigated. Areas timely for developing research Metanalysis through integration of multiple datasets and platforms will enable a holistic understanding of the epigenome in ageing and its relevance to disease.

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“…In turn of the hypermethylation of the MMP11 promotor, the authors speculated that MMP11 substrates would accumulate in the tendon matrix as the amount of the MMP11 enzyme available for catalysis would be limited. The misbalance of the protein composition of the tendon matrix will thereby lead to degenerative progression [29,30]. Altered methylation status of CpG islands upstream of the ADAMTS4 gene, but not the TIMP2 gene, was also associated with human patellar tendinopathy [29,30].…”

Section: Tissue Changes: Histopathological Structural Cellular Epimentioning

confidence: 99%

“…The misbalance of the protein composition of the tendon matrix will thereby lead to degenerative progression [29,30]. Altered methylation status of CpG islands upstream of the ADAMTS4 gene, but not the TIMP2 gene, was also associated with human patellar tendinopathy [29,30]. Review analysis of Vitamin C, a known critical cofactor of collagen synthesis, has also proposed that this vitamin can regulate epigenetic signatures by enhancing the activity of DNA and histone demethylases in the cell nucleus, thus steering a cell reprogramming towards more pluripotent state, which may influence the ECM/collagen homeostasis also in the tendon.…”

Section: Tissue Changes: Histopathological Structural Cellular Epimentioning

confidence: 99%

Spectrum of Tendon Pathologies: Triggers, Trails and End-State

Steinmann

Pfeifer

Brochhausen

et al. 2020

IJMS

102

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The biggest compartment of the musculoskeletal system is the tendons and ligaments. In particular, tendons are dense tissues connecting muscle to bone that are critical for the integrity, function and locomotion of this system. Due to the increasing age of our society and the overall rise in engagement in extreme and overuse sports, there is a growing prevalence of tendinopathies. Despite the recent advances in tendon research and due to difficult early diagnosis, a multitude of risk factors and vague understanding of the underlying biological mechanisms involved in the progression of tendon injuries, the toolbox of treatment strategies remains limited and non-satisfactory. This review is designed to summarize the current knowledge of triggers, trails and end state of tendinopathies.

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Promoter methylation status of the TIMP2 and ADAMTS4 genes and patellar tendinopathy

Cited by 11 publications

References 30 publications

Influence of genetic factors in elbow tendon pathology: a case-control study

Influence of genetic factors in elbow tendon pathology: a case-control study

Epigenetic mechanisms in Tendon Ageing

Spectrum of Tendon Pathologies: Triggers, Trails and End-State

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