DEGRADOME EXPRESSION PROFILING IN STRAINED AND PATHOLOGICAL TENDON: FINDING NEW TARGETS FOR TENDINOPATHY RESEARCH
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IntroductionThe exact mechanisms leading to tendinopathies and tendon ruptures remain poorly understood while their occurrence is clearly associated with exercise. Overloading is thought to be a major factor contributing to the development of tendon pathologies. However, as animal studies have shown, heavy loading alone won't cause tendinopathies. It has been speculated, that malfunctioning adaptation or healing processes might be involved, triggering tendon tissue degeneration. By analysing the expression of the entirety of degrading enzymes (degradome) in pathological and non-pathological, strained and non-strained tendon tissue, the aim of this study was to identify common or opposite patterns in gene regulation. This approach may generate new targets for future studies.Materials and MethodsRNA was extracted from different tendon tissues: normal (n=7), tendinopathic (n=4) and ruptured (n=4) Achilles tendon; normal (n=4) and tendinopathic (n=4) posterior tibialis tendon; normal hamstrings tendon with or...Cite
Tendons are complex connective tissues that transmit tensile forces between muscles and tendons. Tendon injuries are among the most common orthopedic problems with long-term disability as a frequent consequence due to prolonged healing time. Furthermore, the repair tissue is of inferior quality, predisposing patients to high rates of recurrence following initial injury. Coordinated cellular processes and biological factors under the influence of mechanical loading are involved in tendon healing and our understanding of these events lags behind other musculoskeletal tissues. Tendons are relatively hypocellular and hypovascular, with little or no intrinsic regenerative capacity. Studies have documented fatty degeneration, chondrogenic dysplasia, and ectopic ossification within tendon repair tissue. The underlying pathogenesis for these metaplastic changes that compromise the quality of tendon repair tissue is poorly understood. The purpose of this review is to compile literature reporting molecular processes that regulate/control the phenotype of cells responsible for abnormal matrix deposition at repair site. In addition, recent studies reporting the interplay of mechanotransduction and cellular responses during tendon repair are summarized. Identifying the links between cellular, biological, and mechanical parameters involved in tendon repair is paramount to develop successful therapies for tendon healing.
Mechanotransduction
Degeneration (medical)
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Tendon problems are frequent among horses and humans as both species face athletic challenges. Repetitive exercise often leads to overuse injuries in tendons and the number of reported cases of tendon injuries has increased enormously during the last decades, due to changes in demographics and lifestyle. Of the many existing treatment options none can be classified as sufficiently effective. In this thesis, the subject of tendon injuries is approached from various angles. The first study describes a model for tendinopathy in the equine superficial digital flexor tendon; a tendon which is often injured in horses and is comparable to the human Achilles tendon. For testing the efficacy of different treatments it is crucial to have a well-characterized model which mimics the clinical signs of naturally occurring tendinopathy. This equine model met all the important criteria and therefore has interesting potential for further studies. The second study investigates whether casting of the limb, thereby preventing loading of an injured tendon, would be beneficial. After casting one of two front legs of horses having similar tendon injuries in both front legs lesion propagation was monitored. The lesion in the cast-protected leg remained significantly smaller. This result may influence standing veterinary practice for the treatment of acute tendon injuries in the horse. In the third study the model described above was used to test the efficacy of platelet rich plasma (PRP) a new and popular treatment made directly from the patient’s own blood . . The repair tissue from the PRP-treated tendon had a better structure and better mechanical properties than from its placebo-treated counterpart. The fourth study focuses on genipin, a drug from traditional Chinese medicine, which is a strong cross-linker and hence might improve the quality of the repair tissue. Unfortunately, cell survival was insufficient at effective concentrations. In the fifth study the healing potential of two cell populations, one from the tendon core and one from the sheaths surrounding the tendons (the peritenon) was studied. Peritenon-derived cells showed in vitro a higher reactive potential for healing than cells from the tendon core, but showed also increased propensity to differentiate towards bone cells or myofibroblasts; cells that are associated with permanent scarring. The last study looks in closer detail into the differentiation of tendon cells into myofibroblasts and their subsequent contraction. Differentiation into myofibroblasts was influenced by matrix stiffness and by the tethering of the collagen ligands on the matrix. The different contraction assays also revealed the stimulating effect of transforming growth factor beta 1 on cell contraction. In summary, this thesis addresses then problem of tendon healing from various angles (immobilization, PRP and Genipin) and contributes to the understanding of the etiopathogenesis of defective healing.
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ABSTRACT Tendon disorders are common and lead to significant disability, pain, healthcare cost, and lost productivity. A wide range of injury mechanisms exist leading to tendinopathy or tendon rupture. Tears can occur in healthy tendons that are acutely overloaded (e.g., during a high speed or high impact event) or lacerated (e.g., a knife injury). Tendinitis or tendinosis can occur in tendons exposed to overuse conditions (e.g., an elite swimmer's training regimen) or intrinsic tissue degeneration (e.g., age‐related degeneration). The healing potential of a torn or pathologic tendon varies depending on anatomic location (e.g., Achilles vs. rotator cuff) and local environment (e.g., intrasynovial vs. extrasynovial). Although healing occurs to varying degrees, in general healing of repaired tendons follows the typical wound healing course, including an early inflammatory phase, followed by proliferative and remodeling phases. Numerous treatment approaches have been attempted to improve tendon healing, including growth factor‐ and cell‐based therapies and rehabilitation protocols. This review will describe the current state of knowledge of injury and repair of the three most common tendinopathies—flexor tendon lacerations, Achilles tendon rupture, and rotator cuff disorders—with a particular focus on the use of animal models for understanding tendon healing. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:832–839, 2015.
Tendinitis
Tendinosis
Degeneration (medical)
Rotator cuff injury
Microtrauma
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Tendinopathy is the clinical presentation of pain and dysfunction resulting in prolonged periods of reduced activity. While not directly related, tendon pain is associated with structural pathology. However, the primary histopathological event and the pathogenesis of tendon pathology is not fully understood, with numerous theoretical models proposed. Consistent within all these models is that loading the tendon beyond its capacity (overload) is critical in the development of pathology and possibly pain. Our understanding of how load affects the structural integrity of the tendon and contributes to the pathogenesis is poor due to limitations associated with conventional imaging modalities (ultrasound and magnetic resonance imaging). Ultrasound tissue characterisation (UTC) is a novel imaging modality that captures a three-dimensional ultrasound image, allowing for the quantification of tendon structure based on the stability of pixels brightness over contiguous transverse images. Four echo-types are discriminated that have been validated against histopathological specimens in horses. Quantification of these echo-types have been used to test the efficacy of various treatments in horses and humans, and test the diagnostic accuracy in detecting Achilles tendinopathy in humans. Little research has been performed using UTC to understand how tendons respond to load and the pathogenesis of tendon pathology. The aim of this thesis was to investigate the pathogenesis and features of tendon pathology as characterised by UTC. As load is critical to the development of tendon pathology, the nature and temporal sequence of changes in the normal tendon in response to loading were investigated in both the short- (Chapters three and four) and medium-term (Chapter five). The appearance of normal and pathological tendons determined by UTC were investigated to ascertain whether the pathological tendon lacked sufficient amounts of aligned fibrillar structure and whether tendon dimensions were related to the amount of disorganisation (Chapter six). Finally, tendon structure, as quantified by UTC, was examined in the symptomatic and contralateral asymptomatic tendon in patients suffering from unilateral Achilles tendinopathy compared to normal tendons (Chapter seven). This thesis found evidence that the normal tendon is responsive to load, both in the short- (approximately 48hrs) and medium-term (five months). While definitive statements cannot be made as to whether these observed changes affect the health of the tendon (ie presence of pain and dysfunction), it suggests that the tendon is sensitive to load and that it may affect the structural integrity of the tendon. Furthermore, the pathological tendon exhibited a greater mean cross-sectional area of aligned fibrillar structure than a structurally normal tendon. With a significant relationship observed between tendon dimensions and the amount of disorganisation, tendon thickening may be an adaption to maintain sufficient levels of aligned fibrillar structure in the pathological tendon. The findings of this thesis contributes to our understanding of the responsiveness of the normal tendon to load and provides insight into how the normal tendon transitions towards pathology. Despite the presence of disorganisation, the pathological tendon appears to maintain sufficient structure to tolerate load by increasing tendon dimensions. An improved understanding of the pathogenesis and the tendons response to load will lead to improvements in treatments and outcomes for those with tendinopathy.
Pathogenesis
Tendinosis
Tenosynovitis
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Tendon injuries are common yet often fail to heal naturally, especially in cases in which the native tendon-to-bone insertion site is disrupted. Surgical tendon repairs are often limited by the inability of the ruptured tendon to functionally attach back to the underlying bone. For patients with tendon injuries, poor tendon-to-bone integration prolongs recovery time and increases the risk of re-rupture. Improvements in tendon repair will require a more complete understanding of both the biological and mechanical phenomena that occur during natural tendon-to-bone healing. Mechanical studies of tendon repair often utilize larger animal models such as rabbits or canines, but these animals lack many of the genetic and biological tools that are available in the mouse. Thus, the objective of this study was to analyze the biomechanical outcomes of natural tendon-to-bone healing following surgical disruption of the enthesis in a murine model of patellar tendon injury. In particular, this study attempted to define the regional (insertion site versus midsubstance) strain patterns present in normal tendon and compare these patterns to those seen at various stages of healing following a central-third patellar tendon avulsion injury. We hypothesized that 1) murine patellar tendon avulsions would exhibit inferior structural properties compared to contralateral shams and normal controls and 2) insertional strains would greatly exceed midsubstance strains in the healing tendons, resulting in failure initiation at the tendon-bone junction.
Enthesis
Strain (injury)
Patellar ligament
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Tendinopathy is a common musculoskeletal condition affecting subjects regardless of their activity level. Multiple inflammatory molecules found in ex vivo samples of human tendons are related to the initiation or progression of tendinopathy. Their role in tendon healing is the subject of this review.An extensive review of current literature was conducted using PubMed, Embase and Cochrane Library using the term 'tendon', as well as some common terms of tendon conditions such as 'tendon injury OR (tendon damage) OR tendonitis OR tendinopathy OR (chronic tendonitis) OR tendinosis OR (chronic tendinopathy) OR enthesitis' AND 'healing' AND '(inflammation OR immune response)' as either key words or MeSH terms.An environment characterized by a low level of chronic inflammation, together with increased expression of inflammatory cytokines and growth factors, may influence the physiological tendon healing response after treatment.Most studies on this topic exhibited limited scientific translational value because of their heterogeneity. The evidence associated with preclinical studies is limited.The role of inflammation in tendon healing is still unclear, though it seems to affect the overall outcome. A thorough understanding of the biochemical mediators of healing and their pathway of pain could be used to target tendinopathy and possibly guide its management.We require further studies with improved designs to effectively evaluate the pathogenesis and progression of tendinopathy to identify cellular and molecular targets to improve outcomes.
Tendinosis
Tendonitis
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Introduction Tendinopathy is a common and costly diagnosis in workers with Activity-related Soft Tissue Disorder (ASTD), and in recreational and professional athletes. The associated pain results in reduced physical activity, reduced productivity, missed work days, and substantial costs to the government. Workers whose tendons are exposed to prolonged repetitive activity (eg, manual workers like fish processors) and/or high mechanical loads (eg, construction workers) are at high risk for the development of ASTD-associated tendinopathy. Pain is usually one of the first symptoms of tendinopathy; however imaging studies have demonstrated that significant degenerative tendon alterations can develop in response to mechanical loading, months before there are any overt symptoms. Goal: To identify circulation markers of early tendon degeneration. Research questions: (1) Will fatigue damage in tendons, caused by different loading regimes, correlate with changes in expression of genes involved in tendon degeneration? (2) Can we track the development of early phase tendon degeneration in vivo using ultrasound and measure indicators of tendon degradative activity in the circulation? It is hypothesised that different loading regimes will lead to characteristic, degradative differences in gene expression. Ultrasound will be able to visualise and follow early onset, degradative changes in the strained tendons. Methods Rabbit Achilles tendons will be subjected to varying loading regimens using the in-vivo Backman model. After set periods of exercise, microdialysis and blood samples will be taken and analysed for genes involved in degradation of tendons. At the same intervals, ultrasound images will be taken to track changes in the cross sectional area of the tendon. After the end of the full exercise period, the tendon tissue will be examined for characteristic degradative changes using microscopy. Results It is expected that the exercise regimen will lead to significant changes in gene expression in the tendon.1 Blood and microdialysis samples are expected to show significant changes in for example, collagen type I and III, matrix metalloproteinases (MMPs), tissue inhibitors for MMPs (TIMPs), and other genes involved.2 It is expected that the tissue will exhibit characteristic morphological changes seen in degradative tendon tissue, for example, rounded nuclei of tenocytes and a looser, kinked pattern of the collagen fibrils.3 Discussion Treatment for tendinopathies in workers can be a long and costly process which is not always successful, due to the degenerative nature of chronic tendinopathy. Detecting the early stages of tendinopathy could allow for the possibility of interventions to decrease or prevent tendon pain and/or rupture, and reduce healthcare and insurance costs.
Degeneration (medical)
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Tendon injury is painful and often debilitating, and is a one of the most prevalent soft tissue injuries encountered in the clinic. While common, the underlying molecular and genetic processes of tendon damage and repair remain poorly understood. This work describes three recent studies utilizing genome-wide expression analyses to investigate tendon injury and healing. The first study identified novel gene expression in tendon fibroblasts following their stimulation with nitric oxide (NO). The second study examined gene expression in an acute tendon injury model in the rat at the inflammation, proliferation, and remodelling phases of wound repair. Finally, gene expression in a supraspinatus tendinopathy model in the rat was investigated. The results of these studies contribute to a better understanding of the aetiology of several extremely common pathologies of this soft tissue, and may help to develop more targeted therapies for increasing the efficacy of tendon healing in future.
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Tendinosis
Tendonitis
Degeneration (medical)
Tendinitis
Etiology
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mechanobiology
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