Rotator cuff tendinopathy accounts for the majority of cases of shoulder pain, however, the aetiology and pathophysiology of the condition is poorly understood and treatment interventions for the condition have been introduced on an empirical basis, guided only by unproven theories of biological and structural changes in and around the affected tissue. This thesis explores changes in the provision of surgical interventions for rotator cuff tendinopathy, showing a rapid, sustained increase over the last decade. Investigation into the use of ultrasound as a clinical and research tool led to the development of an independent learning method for surgeons using the modality for shoulder imaging and highlighted the technological limitations of contrast enhanced ultrasound in assessing the microvascularity of the supraspinatus tendon. Development of a novel biopsy method for sampling the supraspinatus tendon permitted collection of tissue samples from several cohorts of individuals with rotator cuff tendinopathy. These studies, for the first time, described tissue changes across the whole spectrum of pathology suggesting the possibility of an early inflammatory phase of the condition followed by tissue senescence and reduced viability as pathology progressed. Paired samples taken before and after treatment identified reduced tissue activity in response to glucocorticoid therapy and a potential healing response from the supraspinatus tendon following surgical repair. Significant deterioration in tissue activity and viability was shown as age increased in a large cohort of individuals, highlighting the major impact of ageing as a factor in the onset and progression of rotator cuff tendinopathy. The techniques introduced provide standardised, reproducible methods for further evaluation of rotator cuff tendinopathy and the development of novel therapeutic interventions.

Les tendinopathies sont la première cause de maladie professionnelle en France. Elles sont devenues une préoccupation majeure de santé publique. Cependant, leurs mécanismes physiopathologiques restent encore mal définis. Au cours de cette thèse, nous nous sommes intéressés aux phases précoces de la tendinopathie engendrées par une sur-utilisation du tendon supra-épineux (tSE) de la coiffe de rotateurs de l’épaule chez le rat. Nous avons tenté de comprendre les mécanismes à l’origine de cette pathologie afin de pouvoir agir et la traiter en amont de l’apparition des symptômes.Nous montrons que le profil d’évolution moléculaire des collagènes, des protéoglycanes et des glycosaminoglycanes (GAGs) associé aux phases précoces de la sur-utilisation, témoigne d’un profond remaniement matriciel et d’une différenciation chondroïde des fibroblastes tendineux. Nous avons identifié les métalloprotéinases (MMPs) majeures et leurs inhibiteurs (TIMPs) susceptibles d’être impliqués dans ce remaniement. Nos résultats suggèrent que le mécanisme lésionnel initial et les changements matriciels observés sont dus à un processus induit par des médiateurs locaux libérés par les ténocytes et non à une réaction inflammatoire. Enfin, nous avons cherché à établir une corrélation entre les changements moléculaires observés et le degré de sévérité d’une tendinopathie diagnostiquée chez l’Homme. Nous avons montré, sur des échantillons de tendon patellaire humain une relation entre la quantité des GAGs et le score (VISA score) reflétant le degré pathologique du tendon.Cette étude nous a donc permis d’améliorer nos connaissances des phases précoces du processus d’altération du tSE. Cependant, d’importants efforts restent néanmoins à accomplir dans la caractérisation de la pathogenèse précoce notamment pour préciser le contexte biomécanique qui la génère. / Tendinopathies are the first cause of professional diseases in France. They are a major public health concern. However, their physiopathological mechanisms remain poorly understood. This project aimed at investigating the early stages of supraspinatus tendinopathy caused by overuse. Using a rat animal model, we attempted to understand the mechanisms behind this disease in order to act and treat the symptoms upstream of their onset.We have shown that the molecular changes of collagens, proteoglycans and glycosaminoglycans (GAGs) associated with the early events of overuse attest a major matrix remodeling and chondrogenic differentiation of tendon cells. We identified the main metalloproteinases (MMPs) and their inhibitors (TIMPs) that may be involved in this remodeling. Our results further suggest that the initial mechanisms linked to the observed matrix changes are due to local mediators release by tenocytes rather than an inflammatory process. Finally, we attempted to correlate molecular changes observed during overuse with the severity of the tendinopathy diagnosed in humans. We have shown a relationship between the amount of GAGs and the pathological score (VISA score) on human patellar tendons.This study improved our knowledge of the early pathological events of the supraspinatus tendon. However, more remains to be done for characterizing the early stages of tendinopathy especially to clarify the biomechanical context up-stream.