Tendinopathy is one of the most common orthopaedic pathological conditions characterized by tendon degenerative changes. Excessive mechanical loading is considered as a major causative factor in the development of tendinopathy, but the mechanisms of pathogenesis remain unclear. High mobility group box-1 (HMGB1), a potent inflammatory mediator when released into the matrix, has been identified in the early stage tendinopathy patients. Since the release and contribution of HMGB1 in tendinopathy development due to mechanical overloading is unknown, we investigated the role of HMGB1 in tendinopathy using a mouse intensive treadmill running (ITR) model and injection of glycyrrhizin (GL), a specific inhibitor of HMGB1.

A total of 48 mice were divided into four groups, Cage Control group: The animals were allowed to move freely in their cage, GL group: The animals were received daily IP injection of GL (50 mg/kg body weight) for 24 weeks, ITR group: The animals ran on treadmill at 15 meters/min for three h/ day, five days a week for 12 or 24 weeks, GL+ITR group: The animals ran the same protocol as that of ITR group plus daily IP injection of GL for 12 or 24 weeks. Six mice/group were sacrificed at 12 or 24 weeks and the Achilles and patellar tendon tissues were harvested and used for histochemical staining and immunostaining.

Mechanical overloading induced HMGB1 released from the cell nuclei to the matrix (Fig. 1a, b) caused tendon inflammation (Fig. 1c, d) and led to tendon degenerative changes (Fig. 1e-j). After 12 weeks of ITR, the tendon tissue near the bone insertion site showed typical tendinopathic changes in cell shape, accumulation of glycosaminoglycans (GAG) (Fig. 1e, f), and increase in SOX-9 staining (Fig. 1g-j). After 24 weeks ITR, the distal site of Achilles tendon showed considerable changes in cell shape (Fig. 2A, g, arrows), which is round compared to more elongated in the control and GL groups (Fig. 2A, e, f). However, daily treatment with GL prior to ITR blocked the cell shape change (Fig. 2A, h) and, ITR induced extensive GAG accumulation in ITR group (Fig. 2B, bottom panel). Furthermore, GL inhibited ITR-induced expression of chondrogenic markers (SOX-9 and collagen II) in the tendons (Fig. 3).

Our results showed that mechanical overloading-induced HMGB1 plays a critical role in the development of tendinopathy by initiating tendon inflammation and eventual degeneration characterized by the presence of chondrocyte-like cells, accumulation of proteoglycans, high levels of collagen type II production, and chondrogenic marker SOX-9 expression. These results provide the first evidence for the role of HMGB1 as a therapeutic target to prevent tendinopathy before its onset and block further development at its early inflammation stages. The inhibition of tendinopathy development by GL administration in this study also suggests the putative therapeutic potential of this natural triterpene that is already in clinical use to treat other inflammation-related diseases.

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The Ilizarov technique of distraction osteogenesis is becoming a more common way of treating complicated fractures. It has been shown that shear IFMs will delay bone healing whilst axial IFMs are beneficial to the bone healing. Therefore to measure IFMs in conditions of mobility will provide critical information for research and clinic diagnosis. Such data are not provided by static measurements. Traditionally the IFMs were measured by implanting transducers to the bone or using radiological methods. However, these methods are not suitable for either clinic utilization or measurement of IFMS when patients are doing movements which simulate their daily activities. We have designed a dynamic IFMs measuring device.

It includes a displacement transducer array, which is connected to the Ilizarov wires. This transducer array consists of 6 parallel linear displacement transducers, each of which is attached to the fixing wires of the fix-ator. This arrangement of transducers can fit into the configuration of Stewart Platform. The Reverse Stewart Platform algorithm was employed to calculate IFMs. Without measuring the bone fracture segments directly, the two segments were fitted into two planes virtually. By studying the relative movements of the two virtual planes, the algorithm transfers the relative movement to relative axial & shear translation, and relative bending & torsion rotation, between the two fracture segments. Wireless interface was used to transfer the displacement readings from the transducer array to the computer. This setup allows patient perform activities which represent their routine activities.

In laboratory studies, we found the error of this system to be related to the IFMs. For small movements around 100 micron, the absolute error was 50 micron, whereas for larger movements around 1 mm, the error was within 0.22mm.

This real time monitoring method will allow kinematical and kinetic studies on fracture patients treated with Ilizarov frame. Measurements obtained using this novel device will reflect the natural pattern of IFMs during the patients’ daily life. Since use of the device requires no additional pin, wire or operative procedure, it will be clinically applicable. The accurate real-time IFMs measurements will help elucidate the complex interplay between movement and bone formation.