Atorvastatin promotes bone formation in aged apoE–/– mice through the Sirt1–Runx2 axis

Abstract

Background: Statins 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. Methods: Twenty-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. Results: The 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. Conclusions: Accordingly, 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.

Preparation, Characterization and in vitro/in vivo Evaluation of Lovastatin-Loaded PLGA Microspheres by Local Administration for Femoral Head Necrosis

“…Relevant in vitro experiments have shown that statins can inhibit the effect of hormones, upregulate the expression of Cbfa1 (Growth rate compared to group 1: Group3 12%; Group4 19%; Group 26%) and Runx2 (Growth rate compared to group 1: Group3 16%; Group4 21%; Group 29%), and inhibit the expression of PPAR-γ, so as to prevent the fatty marrow cavity, reduce the intramedullary pressure, improve the local blood flow, reduce the cytotoxicity and increase the osteogenesis. 25 , 26 The current research results show that statins can prevent the necrosis of the femoral head and early treatment in animal models or in the human body with a large amount of hormone. However, due to necrosis of the femoral head, 85% of statins are metabolized in the liver, and only 5% of the remaining 15% exist in the blood in a free state, so that few drugs reach the local area.…”

Novel Aptamer-Based Small-Molecule Drug Screening Assay to Identify Potential Sclerostin Inhibitors against Osteoporosis

“…Both in vitro and in vivo studies support that statins, or HMG-CoA reductase inhibitors, promote osteogenesis and bone formation [ 42 ]. Atorvaststin was proven to enhance bone formation in apolipoprotein E-deficient (apoE –/– ) mice by increasing the gene and protein expression of Sirt1 and Runx2 [ 43 ]. Although its association with bone formation was unclear, treatment of adipocytes with avasimibe resulted in significant reduction of lipid accumulation, which is the reciprocal effect of osteogenic differentiation in mesenchymal stem cells [ 44 , 45 ].…”

Association between Osteoporosis and Previous Statin Use: A Nested Case-Control Study

“…In addition, statins inhibit osteoclast activation and differentiation [26]. A few preclinical studies have reported the anabolic effects of statins on bone [26,27]. For instance, in an apolipoprotein E-deficient (apoE −/− ) mouse study, atorvastatin administration for as long as 12 weeks increased bone mass and improved bone microarchitecture in trabecular bone and increased the mRNA expression of the serum bone formation marker osteocalcin [27].…”