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 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.

Novel Role of the SIRT1 in Endocrine and Metabolic Diseases

“…Runx2 haploinsufficiency leads to the skeletal disorder characterized by bone and dental abnormalities known as cleidocranial dysplasia [70]. Hong et al found that atorvastatin increases bone mass and promotes osteogenesis in ageing apolipoprotein E-deficient mice by activating SIRT1-Runx2 axis [71]. Additionally, Res increases the formation of SIRT1 and FOXO3a complex, regulates the activity of Runx2 promoter, and promotes ossification of human MSCs [72].…”