title: Prevention of Simvastatin-Induced Inhibition of Tendon Cell Proliferation and Cell Cycle Progression by Geranylgeranyl Pyrophosphate.
abstract: Statins have been reported to induce tendinopathy and even tendon rupture. The present study was designed to investigate the potential molecular mechanism underlying the adverse effect of simvastatin on tendon cells. An in vitro tendon healing model was performed using tendon cells isolated from rat Achilles tendons. The viability of tendon cells and cell cycle progression were examined by the MTT assay and flow cytometric analysis, respectively. Immunofluorescent staining for Ki-67 was used to assess the proliferation activity of tendon cells. Western blot analysis and coimmunoprecipitation was used to determine the protein expression of cell cycle-related proteins. To investigate the potential mechanism underlying the effect of statins on tendon cells, mevalonate, farnesyl pyrophosphate (FPP), or geranylgeranyl pyrophosphate (GGPP) was added to simvastatin-treated tendon cells. Simvastatin inhibited the in vitro tendon healing model and tendon cell proliferation in a dose-dependent manner. Immunofluorescent staining demonstrated reduced ki-67 expression in simvastatin-treated tendon cells. Furthermore, simvastatin induced cell cycle arrest at the G1 phase. The expression levels of cdk1, cdk2, cyclin A, and cyclin E were downregulated by simvastatin in a dose-dependent manner. The inhibitory effect of simvastatin was proved to mediate the reduction of mevalonate, and the addition of exogenous GGPP completely prevented the inhibitory effect of simvastatin on tendon cells. The present study demonstrated, for the first time, the molecular mechanism underlying simvastatin-induced tendinopathy or tendon rupture. GGPP was shown to prevent the adverse effect of simvastatin in tendon cells without interfering with its cholesterol-reducing efficacy.
authors.affiliation: *Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Taoyuan City, Taiwan; College of Medicine, Chang Gung University, Taoyuan City, Taiwan;
authors.forename: Wen-Chung
authors.initials: WC
authors.lastname: Tsai
authors.affiliation: *Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Taoyuan City, Taiwan;
authors.forename: Tung-Yang
authors.initials: TY
authors.lastname: Yu
authors.affiliation: *Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Taoyuan City, Taiwan;
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Lin
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan City, Taiwan;
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Cheng
authors.affiliation: *Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Taoyuan City, Taiwan;
authors.forename: Cheng-Lun
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan City, Taiwan jonghwei@mail.cgu.edu.tw.
authors.forename: Jong-Hwei S
authors.initials: JH
authors.lastname: Pang
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*; D013710:Tendons / Q000166:cytology / Q000187:drug effects*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D019821:Simvastatin; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid
keywords: geranylgeranyl pyrophosphate; proliferation; simvastatin; tendon cell