Abstract
BackgroundStatins are the most widely used drugs in elderly patients; the most common clinical application of statins is in aged hyperlipemia patients. There are few studies on the effects and mechanisms of statins on bone in elderly mice with hyperlipemia. The study is to examine the effects of atorvastatin on bone phenotypes and metabolism in aged apolipoprotein E-deficient (apoE–/–) mice, and the possible mechanisms involved in these changes.MethodsTwenty-four 60-week-old apoE–/– mice were randomly allocated to two groups. Twelve mice were orally gavaged with atorvastatin (10 mg/kg body weight/day) for 12 weeks; the others served as the control group. Bone mass and skeletal microarchitecture were determined using micro-CT. Bone metabolism was assessed by serum analyses, qRT-PCR, and Western blot. Bone marrow-derived mesenchymal stem cells (BMSCs) from apoE–/– mice were differentiated into osteoblasts and treated with atorvastatin and silent information regulator 1 (Sirt1) inhibitor EX-527.ResultsThe results showed that long-term administration of atorvastatin increases bone mass and improves bone microarchitecture in trabecular bone but not in cortical bone. Furthermore, the serum bone formation marker osteocalcin (OCN) was ameliorated by atorvastatin, whereas the bone resorption marker tartrate-resistant acid phosphatase 5b (Trap5b) did not appear obviously changes after the treatment of atorvastatin. The mRNA expression of Sirt1, runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), and OCN in bone tissue were increased after atorvastatin administration. Western blot showed same trend in Sirt1 and Runx2. The in vitro study showed that when BMSCs from apoE–/– mice were pretreated with EX527, the higher expression of Runx2, ALP, and OCN activated by atorvastatin decreased significantly or showed no difference compared with the control. The protein expression of Runx2 showed same trend.ConclusionsAccordingly, the current study validates the hypothesis that atorvastatin can increase bone mass and promote osteogenesis in aged apoE−/− mice by regulating the Sirt1–Runx2 axis.
Highlights
Statins are the most widely used drugs in elderly patients; the most common clinical application of statins is in aged hyperlipemia patients
Atorvastatin improved the balance of bone turnover in aged apoE−/− mice To further understand the changes in bone turnover in aged apoE−/− mice after treatment with atorvastatin, the levels of serum tartrate-resistant acid phosphatase 5b (TRAP5b) and OCN were measured between the two groups
Compared to the control group, the level of serum OCN significantly increased (+66.2%, **p < 0.01, Fig. 2d) in aged apoE−/− mice treated with atorvastatin, accompanied by a decrease in serum total cholesterol (TC, −51.6%, **p < 0.01, Fig. 2b) and oxidized low-density lipoprotein
Summary
Statins are the most widely used drugs in elderly patients; the most common clinical application of statins is in aged hyperlipemia patients. Clinical studies have demonstrated that cardiovascular diseases are associated with reduced bone mineral density (BMD) and increased bone fractures [1,2,3,4] These two age-related diseases may be sustained by similar risk factors, for example, oxidative stress, inflammation, free radicals, lipid metabolism, and estrogen deficiency, as well as common pathological mechanisms and molecular mediators, such as the Wnt pathway, receptor activator of nuclear factor kappa B ligand (RANKL), osteoprotegerin (OPG), bone morphogenic protein (BMP), and Sirt1 [5,6,7,8]. Bisphosphonates, raloxifene, and statins may be effective in treating both AS and OP, which suggests a common pathophysiological basis [7, 9, 10] Among these drugs, statins are the most widely used drugs in elderly patients with atherosclerosis. There are few studies on the effects and mechanisms of statins on bone in elderly mice with hyperlipidemia
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