Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

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.

O trabalho realizado estudou experimentalmente os efeitos do ultra-som terapêutico na prevenção de aderências tendinosas e no reparo tendíneo. Foi selecionado para o estudo o tendão flexor profundo do 3º dedo na transição das zonas 3 e 4 da pata dianteira direita de coelho. Foram utilizados 30 coelhos fêmeas adultas jovens, com peso corporal médio de 2,7 Kg, divididos em 3 grupos (A, B e C) de 10 animais, sob anestesia para a produção da lesão no tendão, feita por escarificação com o uso do bisturi e o esmagamento num segmento de 5 mm de diâmetro, utilizando um dispositivo de carga de 15 Kg, durante 10 minutos. As patas foram imobilizadas com órtese de material termoplástico durante todo o período experimental (21 dias). O ultra som terapêutico foi iniciado no 3º PO, e continuado por 7 dias consecutivos, com 5 minutos de duração. Foi empregado um ultra-som terapêutico, regulado na freqüência de 3 MHz, no modo contínuo, sendo que a intensidade de 0,2 W/'CM POT.2' foi aplicada nos animais do grupo A, 0,4 W/'CM POT.2' no grupo B e ultra-som desligado como placebo no grupo C. No 21º PO os animais foram sacrificados, e o tendão submetido à análise histológica. Os resultados foram submetidos à análise estatística e demonstraram que houve uma menor formação de aderência no grupo A. A aceleração do reparo tendinoso foi observada em todos os grupos / The work accomplished studied experimentally the effects of therapeutics ultrasound in prevention of tendon adherences and in tendon repair. The deep flexor tendon of the 3rd finger between zones 3 and 4 of a rabbit's right fore-foot was selected for the study. Thirty young adult female rabbits, with a body weight average of 2.7 Kg, divided into 3 groups (A, B, and C) of 10 animals each, were used. The tendon injury was made, under the effect of anesthesia, by reaming with the use of a scalpel, and the 5mm diameter crushing was made by the use of a device of 15 Kg load for 10 minutes. The feet were immobilized with orthesis made of thermoplastic material during all the experiment period (21 days). A therapeutics ultrasound, set at the frequency of 3 MHz, was applied. The intensity of 0.2 W/'CM POT.2' was applied to the animals of group A; 0.4 W/'CM POT.2' to the group B; and the equipment was off when applied to group C as a placebo. The therapeutics ultrasound was started in the 3rd PO and kept on for 7 consecutive days, with a duration of 5 minutes. On the 21st day the animals were sacrificed; the tendon was analysed histologically. The results were analysed statistically and showed that there was a minor adherence formation in group A. The acceleration of the tendon repair was observed in all groups

Un des problèmes majeurs contribuant à la réduction de la mobilité chez la personne âgée est la hausse de l’occurrence des chutes. La capacité à maintenir l’équilibre ou la stabilité posturale a été précédemment associée à la structure et aux propriétés mécaniques des tendons du membre inférieur. Cette étude fut menée afin d’évaluer les effets de l’intensité d’entrainement et de l’âge sur les changements de l’architecture tendineuse et ses propriétés mécaniques ainsi que sur les adaptations musculaires du membre inférieur. Ce projet avait ainsi pour objectif de comparer les effets de deux conditions d’entrainement pour un volume équivalent (intensité modérée (55% d’une répétition maximale (1RM) vs élevée (80% de 1RM)) sur deux groupes musculaires différents (quadriceps vs triceps sural), sur les adaptations des tendons d’Achille et patellaire associés aux adaptations de ces groupes musculaires respectifs. Enfin, le dernier objectif de cette étude était de montrer si des changements de la balance posturale et de la capacité de mouvement pouvaient s’expliquer par les évolutions de l’architecturale et de propriétés mécaniques des structures musculaires et tendineuses avec l’âge. Dix hommes jeunes (Age : 24.8 ± 3.6) et 27 séniors (Age : 69.9 ± 4.5) sédentaires ont été recrutés et ont participé à un programme d’entrainement en résistance de 12 semaines (3 fois/semaine) sur les muscles du triceps sural et du quadriceps. Le groupe de jeunes (n=10) ainsi qu’un groupe de séniors (n=13) ont participé à un programme d’entrainement modéré correspondant à 55% de 1RM, tandis qu’un deuxième groupe de seniors s’est vu imposer une intensité d’entrainement de 80% de 1RM (n=14). Chaque groupe a reçu exactement le même volume d'entraînement sur les muscles quadriceps et triceps sural en utilisant des machines de musculation guidées : la presse à jambes, l'extension des jambes et la machine à mollets assis. Afin de pouvoir obtenir les paramètres nécessaires à cette étude, l’utilisation d’ergomètres, d’images échographiques et IRM et d’un système de capture de mouvement ont été nécessaires. En comparant deux populations de jeunes et de séniors, cette étude a ainsi permis de quantifier une diminution de la force, couplée ou non suivant le tendon considéré à une diminution des propriétés intrinsèques du matériau tendineux. L’obtention de l’architecture musculaire a permis de construire les courbes d’évolutions de la section de chacun des muscles du quadriceps et du triceps sural pour les populations jeunes et séniors. Les deux conditions d’entrainement nous ont permis de mettre en évidence une amélioration des propriétés mécaniques des tendons d’Achille et patellaire, et plus sensiblement le tendon d’Achille, sur les deux populations jeunes et séniors sans toutefois observer de gain supplémentaire pour une intensité élevée. Des gains similaires suite à la période d’entrainement ont pu être observés chez les séniors sur les volumes des muscles du triceps sural et du quadriceps sans distinction de l’intensité considérée. L’analyse du mouvement nous a permis de mettre en évidence l’amélioration de la stabilité posturale et une évolution de la stratégie de flexion du tronc lors d’un lever de chaise suite à l’entrainement chez les séniors sans bénéfice supplémentaire entre une intensité modérée et élevée. De plus, les effets de l’âge sur les propriétés mécaniques des tendons ont pu être corrélés avec les performances liées aux exercices de stabilité posturale, de saut et de lever de chaise. Ce travail a donc permis de quantifier les effets de l’âge sur les capacités musculaires, tendineuses et de mouvement. Cette étude nous a également permis de mettre en évidence un seuil d’intensité d’entrainement (55% de 1RM) à partir duquel les personnes âgées ne semblent pas montrer de gain additionnel pour les systèmes musculaires et tendineux. Ce travail permet donc de proposer une optimisation de l’activité physique prescrite à la personne âgée ou vieillissante. / The ability to maintain balance has previously been associated with the structure and mechanical properties of the tendons of the lower limb. In order to evaluate the effects of training intensity (moderate vs. high intensity) and age on changes in tendon architecture (Achilles and patellar) and its mechanical properties, 10 young men and 27 sedentary seniors participated in a 12-week resistance training program (3 times/week) on the muscles of the triceps surae (TS) an quadriceps (QF). The young group and a senior group participated in a moderate training program corresponding to 55% of IRM (maximum repetition), while a second group of seniors received a training intensity of 80% of IRM. Each group received the same volume of training on the TS and QF muscles using guided weight machines. The use of ergometers, ultrasound and MRI images and a motion capture system were required. A decrease in strength, coupled or not depending on the tendon under consideration, and a decrease in the properties of the tendon material have been quantified with age. Evolution curves of each of the QF and TS muscles for both populations were constructed. The two training conditions showed an improvement in the mechanical properties of the Achilles and patellar tendons, and more significantly the Achilles, on both populations without any additional gain for a high intensity. Similar gains after training between the two intensities could be observed in seniors on muscle volumes. The improvement of postural stability and an evolution of the strategy during a chair lift were observed in seniors without any additional benefit between the two training intensities. This made it possible to quantify the effects of age on muscle, tendon and movement abilities by highlighting a threshold of training intensity (55% of IRM) from which seniors do not seem to show any additional gain. This work therefore makes it possible to propose an optimization of the physical activity prescribed to the elderly person

Growth factor delivery may be useful to accelerate the rate of tendon healing. We studied Platelet Concentrate, which in effect can be regarded as a cocktail of growth factors relevant for tendon healing. In a rat Achilles tendon transection model, one postoperative injection of Platelet Concentrate resulted in increased strength even 3 weeks later. Mechanical stimulation improves the repair of ruptured tendons. We studied the effects of platelets upon Achilles tendon regenerates in rats 3, 5 and 14 days after transection, either unloaded or mechanically stimulated. At 14 days, physical activity and platelets increased repair independently. Unloading decreased the mechanical properties of the repair tissue to less than half of normal. Moreover, the platelets had no effect without loading. Thrombin, which we used for platelet activation, improved healing of the rat Achilles tendon by itself. Conversely, continuous inhibition of thrombin by low molecular weight heparin (LMWH) inhibited tendon repair. However, intermittent inhibition, similar to clinical thromboprophylaxis, had no effect on tendon healing. Cartilage Derived Morphogenetic Protein-2 (CDMP-2) can improve tendon healing in loaded defect models. We now studied unloaded repair in a rabbit patellar tendon model. Two hours postoperative, the rabbits received CDMP-2 injected into the haematoma. The healing tendon became 65 % stronger than controls. We then studied Achilles tendon healing with CDMP-2 injections in sheep, to get a bigger animal model. There was an unexpectedly high variation of repair in these animals, and the study turned out to be underpowered. Spontaneous ruptures in humans have a more variable geometry than in our sheep model, so humans can also be expected to vary a lot in mechanical characteristics of Achilles tendon repair. This accentuates the importance of individualized rehabilitation programs. In conclusion, both platelet concentrate and CDMP-2 injections might be of interest for clinical use as a complement to surgical or conservative treatment of tendon ruptures. Platelet treatment for tendon ruptures should probably be combined with early physiotherapy.

Background: Achilles tendinopathy is a common clinical syndrome of chronic Achilles tendon pain combined with thickening of the tendon and impaired tendon function. Tendinopathy is often, but not always, induced by mechanical overload, and is frequently accompanied by abnormalities at the tissue level, such as hypercellularity and angiogenesis, in which case the condition is called tendinosis. In tendinosis, there are no signs of intratendinous inflammation, but occasionally increased apoptosis is observed. Tendinosis is often hard to treat and its pathogenesis is still not clear. Recently, a new hypothesis has gained support, suggesting a biochemical model based on the presence of a non-neuronal production of classically neuronal signal substances by the primary tendon cells (tenocytes) in tendinosis. The possible functional importance of these signal substances in tendons is unknown and needs to be studied. In particular, the neuropeptide substance P (SP) and catecholamines are of interest in this regard, since these substances have been found to be up-regulated in tendinosis. As both SP and catecholamines are known to exert effects in other tissues resulting in changes similar to those characteristic of tendinosis, it is possible that they have a role in tendinosis development. It is furthermore unknown what elicits the increased intratendinous neuropeptide production in tendinosis, but given that tendon overload is a prominent riskfactor, it is possible that mechanical stimuli are involved. The hypothesis of this thesis work was that intratendinous production of SP is up-regulated in response to load of Achilles tendons/tenocytes, and thatstimulation of the preferred SP receptor, the neurokinin-1 receptor (NK-1 R), aswell as stimulation of the catecholamine α2 adrenoreceptors, contribute to the hypercellularity seen in tendinosis, via increased proliferation and/or decreased apoptosis, and that SP stimulates tendon angiogenesis. The purpose of the studies was to test this hypothesis. To achieve this, two model systems were used: One in vivo (rabbit Achilles tendon overload model of tendinosis) and one in vitro (human primary Achilles tendon cell culture model). Results: In the rabbit Achilles tendon tissue, SP and NK-1 R expression was extensive in the blood vessel walls, but also to some extent seen in the tenocytes. Quantification of endogenously produced SP in vivo confirmed intratendinous production of the peptide. The production of SP by human tendon cells in vitro was furthermore demonstrated. The catecholamine synthesizing enzyme tyrosine hydroxylase (TH), as well as the α2A adrenoreceptor (α2A AR), were detected in the tenocytes, both in vivo in the rabbit tissue and in vitro in the human tendon cells. As a response to mechanical loading in the in vivo model, the intratendinous levels of SP increased, and this elevation was found to precede distinct tendinosis changes. The in vitro model demonstrated the same response to load, i.e. an increased SP expression, but in this case also a decrease in the NK-1 R expression. In the in vivo model, exogenously administered SP, as well as clonidine (an α2 AR agonist), accelerated tenocyte hypercellularity, an effect that was not seen when administrating a specific α2A AR antagonist. Exogenous administration of SP also resulted in intratendinous angiogenesis and paratendinous inflammation. In the in vitro model, both SP and clonidine had proliferative effects on the human tenocytes, specifically mediated via NK-1R and α2A AR, respectively; both of which in turn involved activation/phosphorylation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2). Exogenously administered SP, in Anti-Fas induced apoptosis of the tenocytes in vitro, confirmed SP to have an anti-apoptotic effect on these cells. This effect was specifically mediated via NK-1 R and the known anti-apoptotic Akt pathway. Conclusions: In summary, this thesis concludes that stimulation of NK-1 R and α2A AR on tenocytes, both in vitro and in vivo, mediates significant cell signalling effects leading to processes known to occur in tendinosis, including hypercellularity. The pathological role of the hypercellularity in tendinosis is still unclear, but it is likely to affect collagen metabolism/turnover and arrangement, and thereby indirectly tendon biomechanical function. Additional evidence is here provided showing that SP not only causes tenocyte proliferation, but also contributes to anti-apoptotic events. Furthermore, it was concluded that SP may be involved in the development of tendinosis, since its production is increased in response to load, preceding tendinosis, and since SP accelerates tendinosis changes, through some mechanistic pathways here delineated. These findings suggest that inhibition of SP, and possibly also catecholamines, could be beneficial in the reconstitution/normalization of tendon structure in tendinosis.

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Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

This study examined the effects of plyometrics on running economy, performance, and Achilles tendon properties in female distance runners. Seventeen University athletes matched by running economy were randomly assigned to an experimental group that received supplementary plyometrics training (n=9) or a control group that performed run-training only (n=8). Subject attrition led to a final sample of twelve runners (6 experimental, 6 controls). Measurements were made pre-post an 8-week training period. Running economy was measured as oxygen consumption at three submaximal speeds, performance as time to run 3000 meters, and Achilles tendon properties were estimated via ultrasound during ramp, quasi-isometric plantar flexion to maximum on an isokinetic dynamometer. No significant differences were found between the two groups after eight weeks because of poor subject compliance and excessive variability in ultrasound measurements. The results are inconclusive as to the effect of supplementary plyometric training on running economy, performance and Achilles tendon properties.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2008. / Härtill 4 uppsatser.