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Purpose: There is an increase in the incidence of Achilles tendon injuries as a result of the participation in physical activity. It has been suggested that some individuals have a genetic predisposition to Achilles tendon pathology (ATP). The aim of this study was to determine whether the alpha 1 type V collagen (COL5A1) gene, which encodes for a tendon protein, is associated with the symptoms of ATP.
Methods: One-hundred and eleven Caucasian subjects diagnosed with ATP and 129 Caucasian control (CON) subjects were genotyped for the BstUI and DpnII restriction fragment length polymorphisms (RFLPs) within the COL5A1 gene.
Results: There was a significant difference in the allele frequencies of the COL5A1 BstUI RFLP between the ATP and CON subjects (P=0.006). The frequency of the A2 allele was significantly higher in the CON group (29.8%) than in the ATP group (18.0%) (odds ratio of 1.9; 95% confidence interval (CI) 1.3-3.0; P=0.004). This allele had a stronger protective role when only the 72 patients diagnosed with chronic Achilles tendinopathy were analyzed (odds ratio of 2.6; 95% CI 1.5-4.5).
Conclusions: The COL5A1 BstUI RFLP is associated with ATP and more specifically, chronic Achilles tendinopathy. Individuals with an A2 allele of this gene are less likely of developing symptoms of chronic Achilles tendinopathy.
Last edited by NewsBot : 20th November 2012 at 02:37 PM.
Objectives. To determine the expression of mRNA encoding the proteoglycans aggrecan, versican, biglycan and decorin in mid-tendon samples of chronic painful Achilles tendinopathy and ruptured Achilles tendons, compared with normal tendons.
Methods. Total RNA isolated from frozen tendon samples (14 normal, 13 painful, 14 ruptured) was assayed by relative quantitative reverse transcription polymerase chain reaction for aggrecan, versican, biglycan and decorin mRNA, normalized using 18S rRNA. Differences between sample groups were tested by univariate analysis of variance with age as co-variate.
Results. In normal tendon samples expression of each of the proteoglycan mRNA decreased with increasing age. Decorin mRNA was the most highly-expressed of the proteoglycan mRNA, while versican mRNA expression was higher (3.8-fold) than that of aggrecan. In painful tendinopathy both aggrecan and biglycan mRNA expression increased (more than 10-fold and 5-fold, respectively) compared with normal tendon samples, but levels of versican and decorin mRNA were not significantly changed. In ruptured tendons the levels of aggrecan, biglycan and versican mRNA were not changed compared with normal tendon samples, but decorin mRNA decreased markedly.
Conclusions. Increased aggrecan and biglycan mRNA expression in painful tendinopathy resembles the pattern in fibrocartilaginous regions of tendon, and may reflect an altered mechanical environment at the site of the lesion. Increased aggrecan mRNA expression may underlie the increase in glycosaminoglycan observed in painful tendinopathy.
Re: Genetic component to achilles tendon pathology
From the ACSM Mtg: Structural And Physiological Changes In Chronically overused Achilles tendons
Henning Langberg, Jessica Pingel, Ulrich Fredberg, Klaus Qvortrup, Jytte Overgaard, Michael Kjaer
PURPOSE: The aim was to elucidate to what extent tendinopathy initiates focal physiological and structural changes.
METHODS: Geneexpression and structural parameters were analysed in Achilles tendon biopsies. Eighteen (expression-study) and fourteen (structural-study) Achilles Tendinopathy patients respectively with chronic tendinopathy (> 6 mth of symptoms) of the Achilles tendon were included. Biopsies from the symptomatic Achilles tendon were taken, one from the area related to the pathology based on clinical examination and ultrasound diagnostics and one from the healthy area 4 cm away from the injury respectively. Structural parameters e.g. fibril density, fibril size, cell number and cellular faction were measured using TEM. Gene expression (mRNA levels) of growth factors and structural elements were determined.
RESULTS: Collagen 1, Collagen 3, Fibronectin, Tenascin C, TGF-b and Fibromodulin was significantly increased in the tendinopathic area of the Achilles tendon. Decorin showed a tendency of decrease in the tendinopathic tissue. This indicates a higher collagen synthesis in tendinopathy. Additionally MMP-2, MMP-9 and TIMP 2 were significantly increased in the tendinopathic tissue with no changes observed in TIMP-1, indicating a higher collagen breakdown in tendinopathy. Fibrillogenesis is not present in tendinopathy scleraxis, lysyl oxidase and tenomodulin were not significantly different. Furthermore bFGF, cmet and ki67 were significantly decreased whereas CTGF, HGF, VEGF, IGF showed no significant, indicating that wound healing was not taking place in the chronic tendons. Likewise the inflammatory factors COX-1, IL-1 and IL-6 showed no significant changes. The density and Mean area of collagen fibrils were significant different with the tendinopathic part of the tendons showing significant more fibrils per uM2 with a small diameter and mean area.
CONCLUSIONS: In summery several gene expressions changed with tendinopathy indicating an increased collagen turnover in tendinopathy. Further theses changes in gene expression might have promoted the structural changes of the collagen fibrils taking place in tendinopathy. Since no signs of fibrillogenesis, inflammation or wound healing could be detected, these study supports that tendinopathy is an ongoing degenerative process.
The causation of tendinopathy is multifactorial and there is increasing evidence that genetic factors play an important role in its aetiology. Some of the genes implicated encode: (i) structural components of connective tissue (collagens and glycoproteins); (ii) extracellular matrix (ECM) proteinases (MMPs); and (iii) cytokines and growth factors [1-2]. Although several genes have been implicated to date, variants within the 3’-untranslated region (UTR) of COL5A1 were shown to associate with chronic Achilles tendinopathy [3-4] and lower limb range of motion measurements [5-6], an additional intrinsic risk factor for chronic Achilles tendinopathy. COL5A1 encodes the α1 chain of type V collagen, a quantitatively minor fibrillar collagen that regulates type I fibrillogenesis.
We have recently described two major functional forms of the COL5A1 3’-UTR, namely the C- and T-forms, which contained a set of seven strongly linked sequence variants that showed significant differences in mRNA stability . Four of these COL5A1 variants are associated with Achilles tendinopathy and appear to alter the predicted mRNA secondary structure of the 3’-UTR. We propose that this change in secondary structure causes the altered COL5A1 mRNA stability and, by implication, type V collagen production.
In addition the COL5A1 3’-UTR contains several putative cis-acting elements including a functional microRNA binding site for Hsa-miR-608 . Two forms of the mature Hsa-miR-608, which are produced by the polymorphic MIR608 gene, can potentially bind this miRNA binding site [www.ncbi.nlm.nih.gov]. This variant within the MIR608 gene is also independently associated with chronic Achilles tendinopathy. These genetic association studies of the COL5A1 and MIR608 genes, together with the functional studies of the COL5A1 3’-UTR, suggest that type V collagen synthesis is involved in the molecular mechanisms of, at least, chronic Achilles tendinopathy.
We hypothesize that the T-functional form of the COL5A1 3’-UTR, which is associated with chronic Achilles tendinopathy, results in increased type V collagen production, decreased mean fibril diameter, and increased fibril density. These structural changes in the fibril result in changes to the mechanical properties of tendons. More specifically, we hypothesize that the changes in mechanical properties associated with the T-functional form result in (i) a reduced tensile strength and (ii) increased creep inhibition and/or stiffness. However, future work is required to test this hypothesis .
1. Collins M and Raleigh SM: (2009) Genetic risk factors for musculoskeletal soft tissue injuries. Med Sport Sci 54:136–149.
2. Raleigh SM and Collins, M: (2012) Gene Variants that Predispose to Achilles Tendon Injuries: An Update on Recent Advances. In A. Čretnik (Ed.), Achilles Tendon (pp. 25–40). InTech. Retrieved from http://www.intechopen.com
3. Mokone GG et al: (2006) The COL5A1 gene and Achilles tendon pathology. Scand J Med Sci Sports 16(1):19–26.
4. September AV et al: (2009) Variants within the COL5A1 gene are associated with Achilles tendinopathy in two populations. Br J Sports Med 43(5):357–365.
5. Collins M et al: (2009) The COL5A1 genotype is associated with range of motion measurements. Scand J Med Sci Sports 19(6):803–810.
6. Brown JC et al: (2011) Range of motion measurements diverge with increasing age for COL5A1 genotypes. Scand J Med Sci Sports 21(6):e266-e272.
7. Laguette MJ et al: (2011). Sequence variants within the 3'-UTR of the COL5A1 gene alters mRNA stability: Implications for musculoskeletal soft tissue injuries. Matrix Biol 30(5-6):338–345.
Achilles tendinopathy is a degenerative condition for which several risk factors have been implicated including components of the inflammatory pathway. The aims of this study was to evaluate (i) several functional variants within genes encoding components of the apoptosis signaling cascade and (ii) the effectiveness of a polygenic apoptosis profile to capture Achilles tendinopathy (TEN) risk.
A total of 358 unaffected control (CON) participants [159 South Africa (SA CON) and 199 Australia (AUS CON)] and 166 affected TEN participants (87 SA TEN and 79 AUS TEN) were genotyped for four variants [CASP8 (rs384129), CASP8 (rs1045485), NOS3 (rs1799983) and NOS2 (rs2779249)]. Logistic regression was used to derive risk models for TEN and a receiver operator characteristic (ROC) curve was plotted to determine the effectiveness of the models to capture TEN risk.
An independent association of CASP8_rs1045485 and CASP8_rs3834129, together with their haplotype was observed with TEN risk. The optimal risk model identified from the study included the two CASP8 genetic loci investigated (CASP8_rs384129 and CASP8_rs1045485) together with sex to capture TEN risk in both SA and AUS participants collectively.
These findings further implicate the apoptosis signalling cascade as one of the important biological pathways involved in the development of Achilles tendinopathy.
In Achilles tendon injuries, it is suggested that a pathological continuum might be evident from the healthy Achilles tendon to Achilles tendinopathy to Achilles tendon rupture. As such, risk factors for both tendinopathy and rupture should be the same.
Hereditary and medical risk factors for Achilles tendinopathy and Achilles tendon rupture are the same to a similar extent in a matched pair analysis.
Matched pair study; level of evidence: 3.
Recreational sportsmen as well as athletes on national level.
566 questionnaires were analysed. 310 subjects were allocated to 3 groups (A, B, C) after matching the pairs for age, weight, height and gender: (A) healthy Achilles tendons (n = 89, age 39 ± 11 years, BMI 25.1 ± 3.9, females 36%), (B) chronic Achilles tendinopathy (n = 161, age 41 ± 11 years, BMI 24.4 ± 3.7, females 34%), (C) acute Achilles tendon rupture (n = 60, age 40 ± 9 years, BMI 25.2 ± 3.2, females 27%).
We found a positive family history of Achilles tendinopathy as a risk factor for Achilles tendinopathy (OR: 4.8, 95% CI: 1.1–21.4; p = 0.023), but not for Achilles tendon rupture (OR: 4.0, 95% CI 0.7–21.1, p = 0.118). Smoking and cardiac diseases had a lower incidence in Achilles tendinopathy than in healthy subjects (both p = 0.001), while cardiovascular medication did not change the risk profile.
Identifying risk factors associated with Achilles tendon disorders has a high clinical relevance regarding the development and implementation of prevention strategies and programs. This cross-sectional study identified a positive family history as a significant solitary risk factor for Achilles tendinopathy, increasing the risk fivefold. However, in this matched pair analysis excluding age, weight, height and gender as risk factors no further factor necessarily increases the risk for either Achilles tendinopathy or Achilles tendon rupture.
The TNC gene has previously been associated with Achilles tendinopathy (AT) in a South African population. The aims of this study were (i) to investigate the association of single nucleotide polymorphisms within the TNC gene, and the additional candidate gene, COL27A1, with AT in two populations, and (ii) to identify if there is a risk haplotype for AT in both populations. Three hundred and thirty nine healthy control participants (CON) and 179 participants clinically diagnosed with AT (TEN) from South Africa and Australia, were genotyped for variants: rs4143245, rs1249744, rs753085, rs946053 (COL27A1) and rs13321, rs2104772, rs1330363 (TNC). Haplotypes were inferred using the genotype data. The rs2104772 (p = 0.017) and rs1330363 (p = 0.020) variants within TNC showed a significant allele association with AT. The GCA haplotype (rs946053-rs13321-rs2104772) occurred significantly more frequently in TEN participants compared to CON (27% vs. 18%; p = 0.019). This study further implicates the genomic region containing the TNC and COL27A1 genes in influencing risk of AT, and maps the potential risk allele to a genetic interval flanked by rs946053 and rs2104772. This region may have functional effects on the transcription, structure and properties of tenascin-C and the alpha-1 chain of type XXVII collagen
Re: Genetic component to achilles tendon pathology
Polymorphisms within the COL5A1 3′-UTR That Alters mRNA Structure and the MIR608 Gene are Associated with Achilles Tendinopathy
Yoonus Abrahams, Mary-Jessica Laguette, Sharon Prince, Malcolm Collins Annals of Human Genetics (online first)
COL5A1 encodes for the α1 chain of type V collagen, an important regulator of fibril assembly in tendons, ligaments and other connective tissues. A polymorphism (rs12722) within the functional COL5A1 3′-untranslated region (UTR) has been shown to associate with chronic Achilles tendinopathy and other exercise-related phenotypes. The COL5A1 3′-UTR contains several putative cis-acting elements including a functional Hsa-miR-608 binding site. The aim of this study was to determine whether previously uncharacterized polymorphisms within a functional region of the COL5A1 3′-UTR or the MIR608 gene are associated with chronic Achilles tendinopathy. The effect of these COL5A1 3′-UTR polymorphisms on the 3′-UTR predicted mRNA secondary structure was also investigated. One hundred and sixty Caucasian chronic Achilles tendinopathic and 342 control participants were genotyped for the COL5A1 3′-UTR markers rs71746744, rs16399 and rs1134170, as well as marker rs4919510 within MIR608. All four genetic markers were independently associated with chronic Achilles tendinopathy. The COL5A1 polymorphisms appear to alter the predicted secondary structure of the 3′-UTR. We propose that the secondary structure plays a role in the regulation of the COL5A1 mRNA stability and by implication type V collagen production.
The incidence of acute and chronic conditions of the tendo Achillis appear to be increasing. Causation is multifactorial but the role of inherited genetic elements and the influence of environmental factors altering gene expression are increasingly being recognised. Certain individuals’ tendons carry specific variations of genetic sequence that may make them more susceptible to injury. Alterations in the structure or relative amounts of the components of tendon and fine control of activity within the extracellular matrix affect the response of the tendon to loading with failure in certain cases.
This review summarises present knowledge of the influence of genetic patterns on the pathology of the tendo Achillis, with a focus on the possible biological mechanisms by which genetic factors are involved in the aetiology of tendon pathology. Finally, we assess potential future developments with both the opportunities and risks that they may carry.
The pathogenesis of tendinopathy is complex and incompletely understood. Although significant advances have been made in terms of understanding the pathological changes in both the extracellular matrix and the cells involved, relatively little is known about the role of neuronal regulation in tendinopathy. The frequent mismatch between tendon pathology and pain may be explained, in part, by differences in the peripheral neuronal phenotype of patients.
The primary purpose of this review was to determine whether evidence exists of changes in the peripheral neuronal phenotype in painful human tendinopathy and, if so, to identify the associated histological and molecular changes. The secondary purpose was to determine if any changes in the peripheral neuronal phenotype reported correlate with pain symptoms.
We conducted a systematic review of the scientific literature using the PRISMA and Cochrane guidelines. The Medline and Embase databases were searched using specific search criteria. Only studies analyzing the peripheral tissue of patients with the clinical diagnosis of tendinopathy were included. Inclusion was agreed on by two independent researchers on review of abstracts or full text.
Overall in the 27 included studies, there was clear evidence of changes in the peripheral neuronal phenotype in painful human tendinopathy. The excitatory glutaminergic system was significantly upregulated in seven studies, there was a significant increase in sensory neuropeptide expression in four studies, and there were significant changes in the molecular morphology of tenocytes, blood vessels, and nerves. In rotator cuff tendinopathy, substance P has been shown to correlate with pain and the neural density in the subacromial bursa has been shown to correlate with rest pain.
The peripheral neuronal phenotype is an important factor in the pathogenesis of painful human tendinopathy. Further research in this area specifically correlating tissue changes to clinical scores has great potential in further developing our understanding of the disease process.
Re: Genetic component to achilles tendon pathology
Association of type XI collagen genes with chronic Achilles tendinopathy in independent populations from South Africa and Australia
Melanie Hay, Jon Patricios, Robert Collins, Andy Branfield, Jill Cook, Christopher J Handley, Alison V September, Michael Posthumus, Malcolm Collins Br J Sports Med doi:10.1136/bjsports-2013-092379
Background Type XI collagen, which is expressed in developing tendons and is encoded by the COL11A1, COL11A2 and COL2A1 genes, shares structural and functional homology with type V collagen, which plays an important role in collagen fibril assembly. We investigated the association of these three polymorphisms with Achilles tendinopathy (AT) and whether these polymorphisms interact with COL5A1 to modulate the risk of AT.
Methods 184 participants diagnosed with chronic AT (TEN) and 338 appropriately matched asymptomatic controls (CON) were genotyped for the three polymorphisms.
Results Although there were no independent associations with AT, the TCT pseudohaplotype constructed from rs3753841 (T/C), rs1676486 (C/T) and rs1799907 (T/A) was significantly over-represented (p=0.006) in the TEN (25.9%) compared with the CON (17.1%) group. The TCT(AGGG) pseudohaplotypes constructed using these type XI collagen polymorphisms and the functional COL5A1 rs71746744 (-/AGGG) polymorphism were also significantly over-represented (p<0.001) in the TEN (25.2%) compared with the CON (9.1%) group.
Discussion The genes encoding structural and functionally related type XI (COL11A1 and COL11A2) and type V (COL5A1) collagens interact with one another to collectively modulate the risk for AT. Although there are no immediate clinical applications, the results of this study provide additional evidence that interindividual variations in collagen fibril assembly might be an important molecular mechanism in the aetiology of chronic AT.