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

Abstract

Treatment with lipid-lowering drugs, statins, is common all over the world. Lately, the occurrence of spontaneous tendon ruptures or tendinosis have suggested a negative influence of statins upon tendon tissue. But how statins might influence tendons is not clear. In the present study, we investigated the effect of statin treatment on mechanical strength, cell proliferation, collagen content and gene expression pattern in a tendon-like tissue made from human tenocytes in vitro. Human tendon fibroblasts were grown in a 3D tissue culture model (tendon constructs), and treated with either simvastatin or atorvastatin, low or high dose, respectively, for up to seven days. After seven days of treatment, mechanical testing of the constructs was performed. Collagen content and cell proliferation were also determined. mRNA levels of several target genes were measured after one or seven days. The maximum force and stiffness were reduced by both statins after 7 days (p<0.05), while the cross sectional area was unaffected. Further, the collagen content was reduced by atorvastatin (p = 0.01) and the cell proliferation rate was decreased by both types of statins (p<0.05). Statin treatment also introduced increased mRNA levels of MMP-1, MMP-3, MMP-13, TIMP-1 and decreased levels of collagen type 1 and 3. In conclusion, statin treatment appears to have a negative effect on tendon matrix quality as seen by a reduced strength of the tendon constructs. Further, activated catabolic changes in the gene expression pattern and a reduced collagen content indicated a disturbed balance in matrix production of tendon due to statin administration.

Simvastatin does not adversely affect Achilles tendon properties in a diet induced hypercholesterolemia rat model

“…These features were noted in all groups, including controls, and were not more prevalent in any specific group. In vitro studies have demonstrated changes in matrix production due to statin treatment 27 , but our findings did not support a notable change in proteoglycan content with any treatment condition. In this study, we found consistent and significant differences in weights of the animals in the CTL group versus those in the HC and HC+S groups.…”

Exploring the In Vivo Anti-Inflammatory Actions of Simvastatin-Loaded Porous Microspheres on Inflamed Tenocytes in a Collagenase-Induced Animal Model of Achilles Tendinitis

“…Despite their positive effects, statins also have adverse effects on muscle, including myalgias, myositis, rhabdomyolysis, and myopathies [ 14 , 15 , 16 ]. Eliasson et al recently reported that simvastatin and atorvastatin have negative effects on tendons due to the decreased mechanical properties of tendon constructs and catabolic changes in the gene expression pattern [ 17 ]. These adverse effects mainly occur in the setting of high statin doses.…”

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.…”