Lovastatin‐Mediated Changes in Human Tendon Cells

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.

Simvastatin and atorvastatin reduce the mechanical properties of tendon constructs in vitro and introduce catabolic changes in the gene expression pattern

“…Besides the increased MMP expression in this study, we also found a decreased expression of both collagen type 1 and 3. This has previously been shown after lovastatin treatment on human tendon fibroblasts in 2D culture, an effect that was assumed to be mediated via prenylation of GTPases [17]. Atorvastatin has also been shown to have a negative effect on collagen type 1 gene expression in rat Achilles tendons [10].…”

Improvement of oral bioavailability of lovastatin by using nanostructured lipid carriers

“…Lovastatin (LVT), a highly lipophilic drug (log P =4.3) isolated from a fungus of Aspergillus terreus , belongs to the class of cholesterol-lowering drugs and is the first clinically used statin. 1 It is a prodrug which lowers the cholesterol level through reversible competitive inhibition of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, an enzyme involved in biosynthesis of cholesterol. However, LVT exhibits poor oral bioavailability (<5%) because of its poor water solubility (0.4×10 −3 mg/mL) and short half-life (1–2 hours).…”

Achilles tendon structure is negatively correlated with body mass index, but not influenced by statin use: A cross-sectional study using ultrasound tissue characterization

“…In keeping with this possibility, a number of laboratory studies have demonstrated a direct impairment of collagen metabolism in response to statin exposure, including reduced type I collagen levels and increased expression and activity of several matrix metalloproteinases. [ 7 , 8 , 9 ] However, the best evidence available to date comprises a propensity-score matched study of over 500,000 statin-users in the UK: in that study, statin use was not associated with an increased risk of Achilles tendon rupture. [ 10 ] In their discussion, the authors noted that their study could not exclude the possibility that statins might lead to milder tendon injury such as tendinopathy.…”