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.
Highlights
Statins are among the most widely prescribed drugs worldwide
Effect of different concentrations of lovastatin on human tenocyte viability In order to investigate the effects of lovastatin on the viability of human tenocytes, the cells were incubated with different
Tenocytes were exposed to increasing concentrations of lovastatin and analysed using alamarBlue
Summary
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. Cholesterol reduction is thought to be the primary mechanism underlying the benefits of statin therapy, statins have been shown to act through a lipid-independent mechanism They prevent the first step of isoprenoid biosynthetic pathway, reducing coenzyme Q and selenoprotein production, and affecting isoprenylation of proteins such as small GTPases. Tenocytes are responsible for the formation and turnover of the extracellular matrix, including the major structural component of tendon, collagen I (Benjamin et al, 2008) They develop organised actin stress fibres aligned along the line of principal strain (Ralphs et al, 2002) as they form a network of longitudinal and lateral cell processes linked by gap junctions (McNeilly et al, 1996).
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