Rotator Cuff Tendinopathy: Pathways of Apoptosis.

Rotator cuff repair is usually successful, but retear is not uncommon. It has been previously identified that there is a higher incidence of apoptosis in the edges of the torn supraspinatus tendon. A prospective cohort study was conducted with 28 patients-14 rotator cuff tear patients, 5 instability patients, and 9 Anterior cruciate ligament reconstruction patients to determine whether there was any increase in several genes implicated in apoptosis, including Fas receptor (FasR), Fas ligand, Aifm-1, Bcl-2, Fadd, Bax, and caspase-3. There was a significant expression of Bax (P=0.2) and FasR (P=0.005) in the edges of torn supraspinatus tendons, and in intact subscapularis tendons, there was a significant expression of caspase-3 (P=0.02) compared with samples from the torn supraspinatus tendon (P=0.04). The cytochrome c pathway, with its subsequent activation of caspase-3, as well as the TRAIL-receptor signaling pathway involving FasR have both been implicated. The elevated expression of Bax supported the model that the Bax to Bcl-2 expression ratio represents a cell death switch. The elevated expression of Bax in the intact subscapularis tissue from rotator cuff tear patients also may confirm that tendinopathy is an ongoing molecular process.

Management of de Quervain Tenosynovitis: A Systematic Review and Network Meta-Analysis.

Importance: There is a plethora of treatment options for patients with de Quervain tenosynovitis (DQT), but there are limited data on their effectiveness and no definitive management guidelines. Objective: To assess and compare the effectiveness associated with available treatment options for DQT to guide musculoskeletal practitioners and inform guidelines. Data Sources: Medline, Embase, PubMed, Cochrane Central, Scopus, OpenGrey.eu, and WorldCat.org were searched for published studies, and the World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov, The European Union Clinical Trials Register, and the ISRCTN registry were searched for unpublished and ongoing studies from inception to August 2022. Study Selection: All randomized clinical trials assessing the effectiveness of any intervention for the management of DQT. Data Extraction and Synthesis: This study was prospectively registered on PROSPERO and conducted and reported per Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions (PRISMA-NMA) and PRISMA in Exercise, Rehabilitation, Sport Medicine and Sports Science (PERSIST) guidance. The Cochrane Risk of Bias tool and the Grading of Recommendations, Assessment, Development, and Evaluations tool were used for risk of bias and certainty of evidence assessment for each outcome. Main Outcomes and Measures: Pairwise and network meta-analyses were performed for patient-reported pain using a visual analogue scale (VAS) and for function using the quick disabilities of the arm, shoulder, and hand (Q-DASH) scale. Mean differences (MD) with their 95% CIs were calculated for the pairwise meta-analyses. Results: A total of 30 studies with 1663 patients (mean [SD] age, 46 [7] years; 80% female) were included, of which 19 studies were included in quantitative analyses. From the pairwise meta-analyses, based on evidence of moderate certainty, adding thumb spica immobilization for 3 to 4 weeks to a corticosteroid injection (CSI) was associated with statistically but not clinically significant functional benefits in the short-term (MD, 10.5 [95% CI, 6.8-14.1] points) and mid-term (MD, 9.4 [95% CI, 7.0-11.9] points). In the network meta-analysis, interventions that included ultrasonography-guided CSI ranked at the top for pain. CSI with thumb spica immobilization had the highest probability of being the most effective intervention for short- and mid-term function. Conclusions and Relevance: This network meta-analysis found that adding a short period of thumb spica immobilization to CSI was associated with statistically but not clinically significant short- and mid-term benefits. These findings suggest that administration of CSI followed by 3 to 4 weeks immobilization should be considered as a first-line treatment for patients with DQT.

Effectiveness of Exercise Treatments with or without Adjuncts for Common Lower Limb Tendinopathies: A Living Systematic Review and Network Meta-analysis.

INTRODUCTION: Exercise therapy is usually prescribed as first-line treatment for lower limb tendinopathies. The multitude of exercise- and non-exercise-based management options can be overwhelming for the treating sports professional and patient alike. We chose to investigate the comparative effectiveness of exercise therapy with or without adjuncts for managing the commonest lower limb tendinopathies. METHODS: Through an extensive systematic literature search using multiple databases, we aimed to identify eligible randomised controlled trials (RCTs) on Achilles tendinopathy, patellar tendinopathy or greater trochanteric pain syndrome (GTPS) that included at least one exercise intervention in their treatment arms. Our primary outcomes were patient-reported pain and function (Victorian Institute of Sport Assessment; VISA). Follow-up was defined as short-term (≤ 12 weeks), mid-term (> 12 weeks to < 12 months) and long-term (≥ 12 months). The risk of bias and strength of evidence were assessed with the Cochrane Collaboration and GRADE-NMA tools, respectively. Analyses were performed separately for each one of the three tendinopathies. RESULTS: A total of 68 RCTs were included in the systematic review. All pairwise comparisons that demonstrated statistically and clinically significant differences between interventions were based on low or very low strength of evidence. Based on evidence of moderate strength, the addition of extracorporeal shockwave therapy to eccentric exercise in patellar tendinopathy was associated with no short-term benefit in pain or VISA-P. From the network meta-analyses, promising interventions such as slow resistance exercise and therapies administered alongside eccentric exercise, such as topical glyceryl trinitrate for patellar tendinopathy and high-volume injection with corticosteroid for Achilles tendinopathy were based on low/very low strength of evidence. CONCLUSION: In this network meta-analysis, we found no convincing evidence that any adjuncts administered on their own or alongside exercise are more effective than exercise alone. Therefore, we recommend that exercise monotherapy continues to be offered as first-line treatment for patients with Achilles and patellar tendinopathies and GTPS for at least 3 months before an adjunct is considered. We provide treatment recommendations for each tendinopathy. PROSPERO registration number CRD42021289534.

Determining minimal important differences for patient-reported outcome measures in shoulder, lateral elbow, patellar and Achilles tendinopathies using distribution-based methods.

BACKGROUND: Minimal important difference (MID) is a concept used inconsistently and arbitrarily in tendinopathy research. Our aim was to determine the MIDs for the most commonly used tendinopathy outcome measures using data-driven approaches. METHODS: Recently published systematic reviews of randomised controlled trials (RCTs) on tendinopathy management were identified and used for extraction of eligible studies through a literature search. Each eligible RCT was used to obtain information on MID where this was used and it also contributed data for the calculation of the baseline pooled standard deviation (SD) for each tendinopathy (shoulder, lateral elbow, patellar and Achilles). The rule of "half SD" was used for the computation of MIDs for patient-reported pain (visual analogue scale, VAS 0-10, single-item questionnaire) and function (multi-item questionnaires) and the rule of "one standard error of measurement (SEM)" was additionally used for the multi-item functional outcome measures. RESULTS: A total of 119 RCTs were included for the 4 tendinopathies. MID was defined and used by 58 studies (49%) and there were significant inconsistencies amongst studies where the same outcome measure was used as MID. From our data-driven methods the following suggested MIDs were obtained: a) Shoulder tendinopathy, pain VAS (combined) 1.3 points, Constant-Murley score 6.9 (half SD) and 7.0 (one SEM) points; b) lateral elbow tendinopathy, pain VAS (combined) 1.0 point, Disabilities of Arm, Shoulder and Hand questionnaire 8.9 (half SD) and 4.1 (one SEM) points; c) Patellar tendinopathy, pain VAS (combined) 1.2 points, Victorian Institute of Sport Assessment - Patella (VISA-P) 7.3 (half SD) and 6.6 points (one SEM); d) Achilles tendinopathy, pain VAS (combined) 1.1 points, VISA-Achilles (VISA-A) 8.2 (half SD) and 7.8 points (one SEM). The rules of half SD and one SEM produced very similar MIDs except for DASH due to its very high internal consistency. MIDs were also calculated for different pain settings for each tendinopathy. CONCLUSIONS: Our computed MIDs can be used in tendinopathy research to increase consistency. Clearly defined MIDs should be used with consistency in tendinopathy management studies in the future.

Characterization of Histone Modifications in Late-Stage Rotator Cuff Tendinopathy.

The development and progression of rotator cuff tendinopathy (RCT) is multifactorial and likely to manifest through a combination of extrinsic, intrinsic, and environmental factors, including genetics and epigenetics. However, the role of epigenetics in RCT, including the role of histone modification, is not well established. Using chromatin immunoprecipitation sequencing, differences in the trimethylation status of H3K4 and H3K27 histones in late-stage RCT compared to control were investigated in this study. For H3K4, 24 genomic loci were found to be significantly more trimethylated in RCT compared to control (p < 0.05), implicating genes such as DKK2, JAG2, and SMOC2 in RCT. For H3K27, 31 loci were shown to be more trimethylated (p < 0.05) in RCT compared to control, inferring a role for EPHA3, ROCK1, and DEFß115. Furthermore, 14 loci were significantly less trimethylated (p < 0.05) in control compared to RCT, implicating EFNA5, GDF6, and GDF7. Finally, the TGFß signaling, axon guidance, and regulation of focal adhesion assembly pathways were found to be enriched in RCT. These findings suggest that the development and progression of RCT is, at least in part, under epigenetic control, highlighting the influence of histone modifications in this disorder and paving the way to further understand the role of epigenome in RCT.

Is neurogenic inflammation involved in tendinopathy? A systematic review.

Neurogenic pain and inflammation have been hypothesised to play an important role in tendinopathy. This systematic review aimed to present and assess the evidence on neurogenic inflammation in tendinopathy. A systematic search was conducted through multiple databases to identify human case-control studies assessing neurogenic inflammation through the upregulation of relevant cells, receptors, markers and mediators. A newly devised tool was used for the methodological quality assessment of studies. Results were pooled based on the cell/receptor/marker/mediator assessed. A total of 31 case-control studies were eligible for inclusion. The tendinopathic tissue was obtained from Achilles (n=11), patellar (n=8), extensor carpi radialis brevis (n=4), rotator cuff (n=4), distal biceps (n=3) and gluteal (n=1) tendons. Through pooling the results of included studies based on the marker of neurogenic inflammation assessed, we identified possible upregulation of protein gene product 9.5 (PGP 9.5), N-methyl-D-aspartate Receptors, glutamate, glutamate receptors (mGLUT), neuropeptide Y (NPY) and adrenoreceptors in tendinopathic tissue versus control. Calcitonin gene-related peptide (CGRP) was not found to be upregulated, and the evidence was conflicting for several other markers. These findings show the involvement of the glutaminergic and sympathetic nervous systems and the upregulation of nerve ingrowth markers supporting the concept that neurogenic inflammation plays a role in tendinopathy.

Pathways driving tendinopathy and enthesitis: siblings or distant cousins in musculoskeletal medicine?

Tendinopathy and enthesitis share clinical, anatomical, and molecular parallels. However, their relationship is complex, presenting challenges in diagnosis and treatment. The biomechanics underlying these pathologies, together with relative immune and stromal contributions to pathology, are characterised by crucial comparative elements. However, methodologies used to study enthesitis and tendinopathy have been divergent, which could account for discrepancies in how these conditions are perceived and treated. In this Review, we summarise key clinical parallels between these two common presentations in musculoskeletal medicine and address factors that currently preclude development of more effective therapeutics. Furthermore, we describe molecular similarities and disparities that govern pathological mechanisms in tendinopathy and enthesitis, thus informing translational studies and treatment strategies.

Frozen shoulder.

Frozen shoulder is a common debilitating disorder characterized by shoulder pain and progressive loss of shoulder movement. Frozen shoulder is frequently associated with other systemic conditions or occurs following periods of immobilization, and has a protracted clinical course, which can be frustrating for patients as well as health-care professionals. Frozen shoulder is characterized by fibroproliferative tissue fibrosis, whereby fibroblasts, producing predominantly type I and type III collagen, transform into myofibroblasts (a smooth muscle phenotype), which is accompanied by inflammation, neoangiogenesis and neoinnervation, resulting in shoulder capsular fibrotic contractures and the associated clinical stiffness. Diagnosis is heavily based on physical examination and can be difficult depending on the stage of disease or if concomitant shoulder pathology is present. Management consists of physiotherapy, therapeutic modalities such as steroid injections, anti-inflammatory medications, hydrodilation and surgical interventions; however, their effectiveness remains unclear. Facilitating translational science should aid in development of novel therapies to improve outcomes among individuals with this debilitating condition.

Biopsychosocial approach to tendinopathy.

Tendinopathy describes a spectrum of changes that occur in damaged tendons, leading to pain and reduced function that remains extremely challenging for all clinicians. There is an increasing awareness of the influence that psychological and psychosocial components, such as self-efficacy and fear-avoidance, have on rehabilitation outcomes in musculoskeletal medicine. Although it is widely accepted that psychological/psychosocial factors exist in tendinopathy, there is currently a distinct lack of trials measuring how these factors affect clinical outcomes. Biopsychosocial treatments acknowledge and address the biological, psychological and social contributions to pain and disability are currently seen as the most efficacious approach to chronic pain. Addressing and modulating these factors are crucial in the pathway of personalised treatments in tendinopathy and offer a real opportunity to drive positive outcomes in patients. In this education review, we also provide the current evidence-based guidance on psychological and psychosocial developments in musculoskeletal medicine and how these may be translated to treating tendinopathy using a biopsychosocial model.

Post-surgical physiotherapy in frozen shoulder: A review.

Despite its prevalence, the optimal management of frozen shoulder is unclear. A range of conservative measures are often undertaken with varying degrees of success. In cases of severe and persistent symptoms, release procedures which could include any combination of manipulation under anaesthetic, arthroscopic capsular release or hydrodilatation are frequently offered, none of which has been shown to offer superior outcome over the others. When surgical release is performed a period of rehabilitation is normally recommended but no best practice guidelines exist resulting in considerable variations in practice which may or may not directly affect patient outcome. During this narrative review, we hypothesise that these differing responses to treatment (both conservative and surgical options) are potentially the result of different causal mechanisms for frozen shoulder and may also suggest that post-release rehabilitation may need to take this into account.

The effect of exercise on cytokines: implications for musculoskeletal health: a narrative review.

The physiological effects of physical exercise are ubiquitously reported as beneficial to the cardiovascular and musculoskeletal systems. Exercise is widely promoted by medical professionals to aid both physical and emotional wellbeing; however, mechanisms through which this is achieved are less well understood. Despite numerous beneficial attributes, certain types of exercise can inflict significant significant physiological stress. Several studies document a key relationship between exercise and immune activation. Activation of the innate immune system occurs in response to exercise and it is proposed this is largely mediated by cytokine signalling. Cytokines are typically classified according to their inflammatory properties and evidence has shown that cytokines expressed in response to exercise are diverse and may act to propagate, modulate or mitigate inflammation in musculoskeletal health. The review summarizes the existing literature on the relationship between exercise and the immune system with emphasis on how exercise-induced cytokine expression modulates inflammation and the immune response.

Management of patellar tendinopathy: a systematic review and network meta-analysis of randomised studies.

OBJECTIVES: We performed a systematic review and network meta-analysis (NMA) of randomised controlled trials (RCTs) to provide insights into the effectiveness of available treatment modalities in patellar tendinopathy(PT). METHODS: Several databases were searched in May 2021 for RCTs assessing the effectiveness of any intervention compared with any other intervention, placebo or no treatment for pain and/or function in PT. The risk of bias and strength of evidence were assessed with the Cochrane Collaboration and GRADE (Grading of Recommendations, Assessment, Development and Evaluations)/GRADE-NMA tools. RESULTS: A total of 37 RCTs were eligible that assessed 33 different interventions and their combinations, most represented by single studies. Based on pairwise meta-analyses of two RCTs, extracorporeal shockwave therapy (ESWT) does not appear to be superior to sham ESWT (eccentric exercise in both groups) for short-term pain (mean differences (MD) +0.1, 95% CI (-0.8 to 1), p=0.84) or function (MD -1.8, 95% CI (-8 to 4.4), p=0.57). Based on a pairwise meta-analysis of three RCTs, isometric exercise appears as effective as isotonic exercise for immediate postintervention pain relief (MD -1.03, 95% CI (-2.6 to 0.5), p=0.19). Our NMA showed that topical glyceryl trinitrate (GTN) and hyaluronic acid injection, both combined with eccentric exercise and moderate, slow resistance exercise had the highest probability of being the most effective interventions (low/very low strength of evidence). CONCLUSIONS: Promising interventions with inadequate evidence, such as topical GTN, hyaluronic acid injections and isometric and slow resistance exercise, should be further investigated through high-quality RCTs. Meanwhile, eccentric loading with or without adjuncts should remain the first-line treatment for all individuals with patellar tendinopathy.

Translational targeting of inflammation and fibrosis in frozen shoulder: Molecular dissection of the T cell/IL-17A axis.

Frozen shoulder is a common fibroproliferative disease characterized by the insidious onset of pain and restricted range of shoulder movement with a significant socioeconomic impact. The pathophysiological mechanisms responsible for chronic inflammation and matrix remodeling in this prevalent fibrotic disorder remain unclear; however, increasing evidence implicates dysregulated immunobiology. IL-17A is a key cytokine associated with inflammation and tissue remodeling in numerous musculoskeletal diseases, and thus, we sought to determine the role of IL-17A in the immunopathogenesis of frozen shoulder. We demonstrate an immune cell landscape that switches from a predominantly macrophage population in nondiseased tissue to a T cell-rich environment in disease. Furthermore, we observed a subpopulation of IL-17A-producing T cells capable of inducing profibrotic and inflammatory responses in diseased fibroblasts through enhanced expression of the signaling receptor IL-17RA, rendering diseased cells more sensitive to IL-17A. We further established that the effects of IL-17A on diseased fibroblasts was TRAF-6/NF-κB dependent and could be inhibited by treatment with an IKKß inhibitor or anti-IL-17A antibody. Accordingly, targeting of the IL-17A pathway may provide future therapeutic approaches to the management of this common, debilitating disease.

Targeting the CCR6/CCL20 Axis in Entheseal and Cutaneous Inflammation.

OBJECTIVE: To assess the involvement of the CCR6/CCL20 axis in psoriatic arthritis (PsA) and psoriasis (PsO) and to evaluate its potential as a therapeutic target. METHODS: First, we quantified CCL20 levels in peripheral blood and synovial fluid from PsA patients and examined the presence of CCR6+ cells in synovial and tendon tissue. Utilizing an interleukin-23 minicircle DNA (IL-23 MC) mouse model exhibiting key features of both PsO and PsA, we investigated CCR6 and CCL20 expression as well as the preventive and therapeutic effect of CCL20 blockade. Healthy tendon stromal cells were stimulated in vitro with IL-1ß to assess the production of CCL20 by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. The effect of conditioned media from stimulated tenocytes in inducing T cell migration was interrogated using a Transwell system. RESULTS: We observed an up-regulation of both CCR6 and CCL20 in the enthesis of IL-23 MC-treated mice, which was confirmed in human biopsy specimens. Specific targeting of the CCR6/CCL20 axis with a CCL20 locked dimer (CCL20LD) blocked entheseal inflammation, leading to profound reductions in clinical and proinflammatory markers in the joints and skin of IL-23 MC-treated mice. The stromal compartment in the tendon was the main source of CCL20 in this model and, accordingly, in vitro activated human tendon cells were able to produce this chemokine and to induce CCR6+ T cell migration, the latter of which could be blocked by CCL20LD. CONCLUSION: Our study highlights the pathogenic role of the CCR6/CCL20 axis in enthesitis and introduces the prospect of a novel therapeutic approach for treating patients with PsO and PsA.

Novel self-amplificatory loop between T cells and tenocytes as a driver of chronicity in tendon disease.

OBJECTIVES: Increasing evidence suggests that inflammatory mechanisms play a key role in chronic tendon disease. After observing T cell signatures in human tendinopathy, we explored the interaction between T cells and tendon stromal cells or tenocytes to define their functional contribution to tissue remodelling and inflammation amplification and hence disease perpetuation. METHODS: T cells were quantified and characterised in healthy and tendinopathic tissues by flow cytometry (FACS), imaging mass cytometry (IMC) and single cell RNA-seq. Tenocyte activation induced by conditioned media from primary damaged tendon or interleukin-1ß was evaluated by qPCR. The role of tenocytes in regulating T cell migration was interrogated in a standard transwell membrane system. T cell activation (cell surface markers by FACS and cytokine release by ELISA) and changes in gene expression in tenocytes (qPCR) were assessed in cocultures of T cells and explanted tenocytes. RESULTS: Significant quantitative differences were observed in healthy compared with tendinopathic tissues. IMC showed T cells in close proximity to tenocytes, suggesting tenocyte-T cell interactions. On activation, tenocytes upregulated inflammatory cytokines, chemokines and adhesion molecules implicated in T cell recruitment and activation. Conditioned media from activated tenocytes induced T cell migration and coculture of tenocytes with T cells resulted in reciprocal activation of T cells. In turn, these activated T cells upregulated production of inflammatory mediators in tenocytes, while increasing the pathogenic collagen 3/collagen 1 ratio. CONCLUSIONS: Interaction between T cells and tenocytes induces the expression of inflammatory cytokines/chemokines in tenocytes, alters collagen composition favouring collagen 3 and self-amplifies T cell activation via an auto-regulatory feedback loop. Selectively targeting this adaptive/stromal interface may provide novel translational strategies in the management of human tendon disorders.

Do we need to improve the reporting of evidence in tendinopathy management? A critical appraisal of systematic reviews with recommendations on strength of evidence assessment.

OBJECTIVE: To critically appraise the quality of published systematic reviews (SRs) of randomised controlled trials (RCTs) in tendinopathy with regard to handling and reporting of results with special emphasis on strength of evidence assessment. DATA SOURCES: Medline from inception to June 2020. STUDY ELIGIBILITY: All SRs of RCTs assessing the effectiveness of any intervention(s) on any location of tendinopathy. DATA EXTRACTION AND SYNTHESIS: Included SRs were appraised with the use of a 12-item tool devised by the authors arising from the Preferred Reporting Items in Systematic Reviews and Meta-Analyses statement and other relevant guidance. Subgroup analyses were performed based on impact factor (IF) of publishing journals and date of publication. RESULTS: A total of 57 SRs were included published in 38 journals between 2006 and 2020. The most commonly used risk-of-bias (RoB) assessment tool and strength of evidence assessment tool were the Cochrane Collaboration RoB tool and the Cochrane Collaboration Back Review Group tool, respectively. The mean score on the appraisal tool was 46.5% (range 0%-100%). SRs published in higher IF journals (>4.7) were associated with a higher mean score than those in lower IF journals (mean difference 26.4%±8.8%, p=0.004). The mean score of the 10 most recently published SRs was similar to that of the first 10 published SRs (mean difference 8.3%±13.7%, p=0.54). Only 23 SRs (40%) used the results of their RoB assessment in data synthesis and more than half (n=30; 50%) did not assess the strength of evidence of their results. Only 12 SRs (21%) assessed their strength of evidence appropriately. CONCLUSIONS: In light of the poor presentation of evidence identified by our review, we provide recommendations to increase transparency and reproducibility in future SRs.

Short-Term Western Diet Intake Promotes IL-23‒Mediated Skin and Joint Inflammation Accompanied by Changes to the Gut Microbiota in Mice.

We previously showed that exposure to a high-sugar and moderate-fat diet (i.e., Western diet [WD]) in mice induces appreciable skin inflammation and enhances the susceptibility to imiquimod-induced psoriasiform dermatitis, suggesting that dietary components may render the skin susceptible to psoriatic inflammation. In this study, utilizing an IL-23 minicircle-based model with features of both psoriasiform dermatitis and psoriatic arthritis, we showed that intake of WD for 10 weeks predisposed mice not only to skin but also to joint inflammation. Both WD-induced skin and joint injuries were associated with an expansion of IL-17A‒producing γδ T cells and increased expression of T helper type 17 cytokines. After IL-23 minicircle delivery, WD-fed mice had reduced microbial diversity and pronounced dysbiosis. Treatment with broad-spectrum antibiotics suppressed IL-23‒mediated skin and joint inflammation in the WD-fed mice. Strikingly, reduced skin and joint inflammation with a partial reversion of the gut microbiota were noted when mice switched from a WD to a standard diet after IL-23 minicircle delivery. These findings reveal that a short-term WD intake‒induced dysbiosis is accompanied by enhanced psoriasis-like skin and joint inflammation. Modifications toward a healthier dietary pattern should be considered in patients with psoriatic skin and/or joint disease.

Tendinopathy.

Tendinopathy describes a complex multifaceted pathology of the tendon, characterized by pain, decline in function and reduced exercise tolerance. The most common overuse tendinopathies involve the rotator cuff tendon, medial and lateral elbow epicondyles, patellar tendon, gluteal tendons and the Achilles tendon. The prominent histological and molecular features of tendinopathy include disorganization of collagen fibres, an increase in the microvasculature and sensory nerve innervation, dysregulated extracellular matrix homeostasis, increased immune cells and inflammatory mediators, and enhanced cellular apoptosis. Although diagnosis is mostly achieved based on clinical symptoms, in some cases, additional pain-provoking tests and imaging might be necessary. Management consists of different exercise and loading programmes, therapeutic modalities and surgical interventions; however, their effectiveness remains ambiguous. Future research should focus on elucidating the key functional pathways implicated in clinical disease and on improved rehabilitation protocols.