Tendinopathy in diabetes mellitus patients-Epidemiology, pathogenesis, and management.

Chronic tendinopathy is a frequent and disabling musculo-skeletal problem affecting the athletic and general populations. The affected tendon is presented with local tenderness, swelling, and pain which restrict the activity of the individual. Tendon degeneration reduces the mechanical strength and predisposes it to rupture. The pathogenic mechanisms of chronic tendinopathy are not fully understood and several major non-mutually exclusive hypotheses including activation of the hypoxia-apoptosis-pro-inflammatory cytokines cascade, neurovascular ingrowth, increased production of neuromediators, and erroneous stem cell differentiation have been proposed. Many intrinsic and extrinsic risk/causative factors can predispose to the development of tendinopathy. Among them, diabetes mellitus is an important risk/causative factor. This review aims to appraise the current literature on the epidemiology and pathology of tendinopathy in diabetic patients. Systematic reviews were done to summarize the literature on (a) the association between diabetes mellitus and tendinopathy/tendon tears, (b) the pathological changes in tendon under diabetic or hyperglycemic conditions, and (c) the effects of diabetes mellitus or hyperglycemia on the outcomes of tendon healing. The potential mechanisms of diabetes mellitus in causing and exacerbating tendinopathy with reference to the major non-mutually exclusive hypotheses of the pathogenic mechanisms of chronic tendinopathy as reported in the literature are also discussed. Potential strategies for the management of tendinopathy in diabetic patients are presented.

Alendronate reduced peri-tunnel bone loss and enhanced tendon graft to bone tunnel healing in anterior cruciate ligament reconstruction.

Peri-tunnel bone loss after anterior cruciate ligament (ACL) reconstruction is commonly observed, both clinically and experimentally. We aimed to study the effect and mechanisms of different doses of alendronate in the reduction of peri-tunnel bone loss and promotion of graft-bone tunnel healing in ACL reconstruction. Eighty-four ACL-reconstructed rats were divided into 4 groups. Alendronate at different dosages, or saline, were injected subcutaneously weekly, for 2 or 6 weeks post-reconstruction, for vivaCT (computed tomography) imaging, biomechanical tests, histology and immunohistochemistry. Alendronate significantly increased bone mass and density of tissue inside bone tunnels except at the epiphyseal region of tibial tunnel. The femoral tunnel diameter decreased significantly in the mid-dose and high-dose alendronate groups compared to that in the saline group at week 6. Alendronate significantly increased the peri-tunnel bone mass and density along all tunnel regions at week 6. Better graft-bone tunnel integration and intra-tunnel graft integrity were observed in the alendronate groups. The ultimate load was significantly higher in the mid-dose and high-dose alendronate groups at week 2, but not at week 6. There was a reduction in matrix metalloprotein (MMP)1, MMP13 and CD68-positive cells at the peri-tunnel region and graft-bone interface in the alendronate-treated group compared to the saline group. Alendronate reduced peri-tunnel bone resorption, increased mineralised tissue inside bone tunnel as well as histologically and biomechanically promoted graft-bone tunnel healing, probably by reducing the expression of MMP1, MMP13 and CD68-positive cells. Alendronate might be used for reducing peri-tunnel bone loss and promoting graft-bone tunnel healing at early stage post-ACL reconstruction.

Tenogenic differentiation of stem cells for tendon repair-what is the current evidence?

Tendon/ligament injuries are very common in sports and other rigorous activities. Tendons regenerate and repair slowly and inefficiently in vivo after injury. The limited ability of tendon to self-repair and the general inefficiencies of current treatment regimes have hastened the motivation to develop tissue-engineering strategies for tissue repair. Of particular interest in recent years has been the use of adult mesenchymal stem cells (MSCs) to regenerate functional tendons and ligaments. Different sources of MSCs have been studied for their effects on tendon repair. However, ectopic bone and tumour formation has been reported in some special circumstances after transplantation of MSCs. The induction of MSCs to differentiate into tendon-forming cells in vitro prior to transplantation is a possible approach to avoid ectopic bone and tumour formation while promoting tendon repair. While there are reports about the factors that might promote tenogenic differentiation, the study of tenogenic differentiation is hampered by the lack of definitive biomarkers for tendons. This review aims to summarize the cell sources currently used for tendon repair as well as their advantages and limitations. Factors affecting tenogenic differentiation were summarized. Molecular markers currently used for assessing tenogenic differentiation or neotendon formation are summarized and their advantages and limitations are commented upon. Finally, further directions for promoting and assessing tenogenic differentiation of stem cells for tendon repair are discussed.

What are the validated animal models for tendinopathy?

Chronic tendinopathy refers to a broad spectrum of pathological conditions in tendons and their insertion, with symptoms including activity-related chronic pain. To study the pathogenesis and management strategies of chronic tendinopathy, studies in animal models are essential. The different animal models in the literature present advantages and limitations, and there is no consensus regarding the criteria of a universal tendinopathy animal model. Based on the review of literature and the discussion in the International Symposium on Ligaments and Tendons-X, we concluded that established clinical, histopathological and functional characteristics of human tendinopathy were all important and relevant criteria to be met, if possible, by animal models. As tendinopathy is a progressive, multifactorial tendon disorder affecting different anatomical structures, it may not be realistic to expect a single animal model to study all aspects of tendinopathy. Staging of tendinopathy over time and clearer definition of tendinopathies in relation to severity and type would enable realistic targets with any animal model. The existing animal models can be used for answering specific questions (horses for courses) but should not be used to conclude the general aspects of tendinopathy neither in animals nor in human.