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      Lovastatin‐Mediated Changes in Human Tendon Cells

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          Abstract

          Statins are among the most widely prescribed drugs worldwide. Numerous studies have shown their beneficial effects in prevention of cardiovascular disease through cholesterol‐lowering and anti‐atherosclerotic properties. Although some statin patients may experience muscle‐related symptoms, severe side effects of statin therapy are rare, primarily due to extensive first‐pass metabolism in the liver. Skeletal muscles appear to be the main site of side effects; however, recently some statin‐related adverse effects have been described in tendon. The mechanism behind these side effects remains unknown. This is the first study that explores tendon‐specific effects of statins in human primary tenocytes. The cells were cultured with different concentrations of lovastatin for up to 1 week. No changes in cell viability or morphology were observed in tenocytes incubated with therapeutic doses. Short‐term exposure to lovastatin concentrations outside the therapeutic range had no effect on tenocyte viability; however, cell migration was reduced. Simvastatin and atorvastatin, two other drug family members, also reduced the migratory properties of the cells. Prolonged exposure to high concentrations of lovastatin induced changes in cytoskeleton leading to cell rounding and decreased levels of mRNA for matrix proteins, but increased BMP‐2 expression. Gap junctional communication was impaired but due to cell shape change and separation rather than direct gap junction inhibition. These effects were accompanied by inhibition of prenylation of Rap1a small GTPase. Collectively, we showed that statins in a dose‐dependent manner decrease migration of human tendon cells, alter their expression profile and impair the functional network, but do not inhibit gap junction function. J. Cell. Physiol. 230: 2543–2551, 2015. © 2015 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

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          Most cited references31

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          Biology of tendon injury: healing, modeling and remodeling.

          Tendon disorders are frequent, and are responsible for much morbidity both in sport and the workplace. Although the presence of degenerative changes does not always lead to symptoms, pre-existing degeneration has been implicated as a risk factor for acute tendon rupture. The term tendinopathy is a generic descriptor of the clinical conditions in and around tendons arising from overuse. The terms "tendinosis" and "tendinitis/tendonitis" should only be used after histopathological examination. Disordered healing is seen in tendinopathy, and inflammation is not typically seen. In acute injuries, the process of tendon healing is an indivisible process that can be categorized into three overlapping phases for descriptive purposes. Tendon healing can occur intrinsically, via proliferation of epitenon and endotenon tenocytes, or extrinsically, by invasion of cells from the surrounding sheath and synovium. Despite remodeling, the biochemical and mechanical properties of healed tendon tissue never match those of intact tendon. Tendon injuries account for considerable morbidity, and often prove disabling for several months, despite what is considered appropriate management. Chronic problems caused by overuse of tendons probably account for 30% of all running-related injuries, and the prevalence of elbow tendinopathy in tennis players can be as high as 40%. The basic cell biology of tendons is still not fully understood, and the management of tendon injury poses a considerable challenge for clinicians. This article describes the structure of tendons, and reviews the pathophysiology of tendon injury and healing.
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            The pathogenesis of tendinopathy. A molecular perspective.

            Lisa Riley (2004)
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              Structure-function relationships in tendons: a review.

              The purpose of the current review is to highlight the structure-function relationship of tendons and related structures to provide an overview for readers whose interest in tendons needs to be underpinned by anatomy. Because of the availability of several recent reviews on tendon development and entheses, the focus of the current work is primarily directed towards what can best be described as the 'tendon proper' or the 'mid-substance' of tendons. The review covers all levels of tendon structure from the molecular to the gross and deals both with the extracellular matrix and with tendon cells. The latter are often called 'tenocytes' and are increasingly recognized as a defined cell population that is functionally and phenotypically distinct from other fibroblast-like cells. This is illustrated by their response to different types of mechanical stress. However, it is not only tendon cells, but tendons as a whole that exhibit distinct structure-function relationships geared to the changing mechanical stresses to which they are subject. This aspect of tendon biology is considered in some detail. Attention is briefly directed to the blood and nerve supply of tendons, for this is an important issue that relates to the intrinsic healing capacity of tendons. Structures closely related to tendons (joint capsules, tendon sheaths, pulleys, retinacula, fat pads and bursae) are also covered and the concept of a 'supertendon' is introduced to describe a collection of tendons in which the function of the whole complex exceeds that of its individual members. Finally, attention is drawn to the important relationship between tendons and fascia, highlighted by Wood Jones in his concept of an 'ectoskeleton' over half a century ago - work that is often forgotten today.
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                Author and article information

                Journal
                J Cell Physiol
                J. Cell. Physiol
                10.1002/(ISSN)1097-4652
                JCP
                Journal of Cellular Physiology
                John Wiley and Sons Inc. (Hoboken )
                0021-9541
                1097-4652
                23 June 2015
                October 2015
                : 230
                : 10 ( doiID: 10.1002/jcp.v230.10 )
                : 2543-2551
                Affiliations
                [ 1 ] Botnar Research Centre Institute of Musculoskeletal Sciences Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal SciencesUniversity of Oxford OxfordUnited Kingdom
                Author notes
                [*] [* ] Correspondence to: Maria Kuzma‐Kuzniarska, Botnar Research Centre, Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom. E‐mail: maria.kuzmakuzniarska@ 123456gmail.com

                Article
                JCP25010
                10.1002/jcp.25010
                4832302
                25846724
                5eb35854-fe7c-4e1f-be37-80ffab0299cf
                © 2015 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 September 2014
                : 31 March 2015
                Page count
                Pages: 9
                Funding
                Funded by: Furlong Charitable Research Foundation
                Award ID: 401
                Award ID: 478
                Funded by: ENDO Stiftung
                Award ID: S 02/07
                Funded by: Arthritis Research UK
                Award ID: ARUK19482
                Categories
                Original Research Article
                Original Research Articles
                Custom metadata
                2.0
                jcp25010
                October 2015
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.8.6 mode:remove_FC converted:22.04.2016

                Anatomy & Physiology
                Anatomy & Physiology

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