Atorvastatin promotes bone formation in aged apoE–/– mice through the Sirt1–Runx2 axis
Tóm tắt
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. 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. 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. 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.
Tài liệu tham khảo
Ye C, Xu M, Wang S, Jiang S, Che X, Zhou X, He R. Decreased bone mineral density independent predictor for the development of atherosclerosis: systematic review and meta-analysis. PLoS One. 2016;11:e0154740.
Lange V, Dörr M, Schminke U, Völzk H, Nauck M, Wallaschofski H, Hannemann A. The association between bone quality and atherosclerosis: results from two large population-based studies. Int J Endocrinol. 2017;3946569.
Ahmadi N, Mao SS, Hajsadeghi F, Arnold B, Kiramijyan S, Gao Y, Flores F, Azen S, Budoff M. The relation of low levels of bone mineral density with coronary artery calcium and mortality. Osteoporos Int. 2018;29:1609–16.
Tasić I, Popović MR, Stojanović S, Stamenković B, Kostić S, Popović D, Lazarević G, Bogdanović D, Stefanović V. Osteoporosis—a risk factor for cardiovascular diseases: a follow-up study. Srp Arh Celok Lek. 2015;143:28–34.
Simões Sato AY, Bub GL, Campos AH. BMP-2 and -4 produced by vascular smooth muscle cells from atherosclerotic lesions induce monocyte chemotaxis through direct BMPRII activation. Atherosclerosis. 2014;235:45–55.
Szekanec Z, Raterman HG, Pethő Z, Lems WF. Common mechanisms and holistic care in atherosclerosis and osteoporosis. Arthritis Res Ther. 2019;21:15–22.
Caffarelli C, Montagnani A, Nuti R, Gonnelli S. Bisphosphonates atherosclerosis and vascular calcification: update and systematic review of clinical studies. Clin Interv Aging. 2017;12:1819–28.
Bartoli-Leonard F, Wilkinson FL, Langford-Smith AW, Alexander MY, Weston R. The interplay of SIRT1 and Wnt signaling in vascular calcification. Front Cardiovasc Med. 2018;5:183.
An T, Hao J, Sun S, Li R, Yang M, Cheng G, Zou M. Efficacy of statins for osteoporosis: a systematic review and meta-analysis. Osteoporos Int. 2017;28:47–57.
Cetinkaya Demir B, Uyar Y, Ozbilgin K, Köse C. Effect of raloxifene and atorvastatin in atherosclerotic process in ovariectomized rats. J Obstet Gynaecol Res. 2013;39:229–36.
Mundy G, Garrett R, Harris S, Chan J, Chen D, Rossini G, Boyce B, Zhao M, Gutierrez G. Stimulation of bone formation in vitro and in rodents by statins. Science. 1999;286:1946–9.
Chen PY, Sun JS, Tsuang YH, Chen MH, Weng PW, Lin FH. Simvastatin promotes osteoblast viability and differentiation via Ras/Smad/Erk/BMP-2 signaling pathway. Nutr Res. 2010;30:191–9.
Ghosh-Choudhury N, Mandal CC, Choudhury GG. Statin-induced Ras activation integrates the phosphatidylinositol 3-kinase signal to Akt and MAPK for bone morphogenetic protein-2 expression in osteoblast differentiation. Biol Chem. 2007;282:4983–93.
Lee WS, Lee EG, Sung MS, Choi YJ, Yoo WH. Atorvastatin inhibits osteoclast differentiation by suppressing NF-Κb and MAPK signaling during IL-1 β-induced osteoclastogenesis. Korean J Intern Med. 2018;33:397–406.
Dolci GS, Ballarini A, Gameiro GH, Onofrede Souza D, de Melo F, Fossati ACM. Atorvastatin inhibits osteoclastogenesis and arrests tooth movement. Am J Orthod Dentofac Orthop. 2018;153:872–82.
El-Nabarawi N, El-Wakd M, Salem M. Atorvastatin, a double weapon in osteoporosis treatment: an experimental and clinical study. Drug Des Dev Ther. 2017;2:1383–91.
Von Stechow D, Fish S, Yahalom D, Bab I, Chorev M, Müller R, Alexander JM. Does simvastatin stimulate bone formation in vivo? BMC Musculoskelet Disord. 2003;28:8.
Van Staa TP, Wegman S, De Vries F, Leufkens B, Cooper C. Use of statins and risk of fractures. JAMA. 2001;285:1850–5.
Zhou H, Xie Y, Baloch Z, Shi Q, Huo Q, Ma T. The effect of atorvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (HMG-CoA), on the prevention of osteoporosis in ovariectomized rabbits. J Bone Miner Metab. 2017;35:245–54.
Ibrahim N, Khamis MF, Mod Yunoh MF, Abdullah S, Mohamed N, Shuid AN. Targeted delivery of lovastatin and tocotrienol to fracture site promotes fracture healing in osteoporosis model: micro-computed tomography and biomechanical evaluation. PLoS One. 2014;9:e115595.
Oryan A, Kamali A, Moshiri A. Potential mechanisms and applications of statins on osteogenesis: current modalities, conflicts and future directions. J Control Release. 2015;10:12–24.
Chen ZG, Cai HJ, Jin X, Lu JH, Wang J, Fang NY. Effects of atorvastatin on bone mineral density (BMD) and bone metabolism in elderly males with osteopenia and mild dyslipidemia: a 1-year randomized trial. Arch Gerontol Geriatr. 2014;59:515–21.
Bone HG, Kiel DP, Lindsay RS, Lewiecki EM, Bolognese MA, Leary ET, Lowe W, McClung MR. Effects of atorvastatin on bone in postmenopausal women with dyslipidemia: a double-blind, placebo-controlled, dose-ranging trial. J Clin Endocrinol Metab. 2007;92:4671–7.
Tissenbaum HA, Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature. 2001;410:227–30.
Qian L, Ma L, Wu G, Yu Q, Lin H, Ying Q, Wen D, Gao C. G004, a synthetic sulfonylurea compound, exerts anti-atherosclerosis effects by targeting SIRT1 in apoE-/- mice. Vasc Pharmacol. 2017;89:49–57.
Yang X, Wei J, He Y, Jing T, Li Y, Xiao Y, Wang B, Wang W, Zhang J, Lin R. SIRT1 inhibition promotes atherosclerosis through impaired autophagy. Oncotarget. 2017;8:51447–61.
Bäckesjö CM, Li Y, Lindgren U, Haldosén LA. Activation of Sirt1 decreases adipocyte formation during osteoblast differentiation of mesenchymal stem cells. Cells Tissues Organs. 2009;189:93–7.
Zainabadi K. Drugs targeting SIRT1, a new generation of therapeutics for osteoporosis and other bone related disorders? Pharmacol Res. 2019;143:97–105.
Hong W, Xu XY, Qiu ZH, Gao JJ, Wei ZY, Zhen L, Zhang X, Ye ZB. Sirt1 is involved in decreased bone formation in aged apolipoprotein E-deficient mice. Acta Pharmacol Sin. 2015;36:1487–96.
Zainabadi K, Liu CJ, Guarente L. SIRT1 is a positive regulator of the master osteoblast transcription factor, RUNX2. PLoS One. 2017;12:e0178520.
Kilic U, Gok O, Elibol-Can B, Uysal O, Bacaksiz A. Efficacy of statins on sirtuin 1 and endothelial nitric oxide synthase expression: the role of sirtuin 1 gene variants in human coronary atherosclerosis. Clin Exp Pharmacol Physiol. 2015;42:321–30.
Du G, Song Y, Zhang T, Ma L, Bian N, Chen X, Feng J, Chang Q, Li Z. Simvastatin attenuates TNF-α-induced apoptosis in endothelial progenitor cells via the upregulation of SIRT1. Int J Mol Med. 2014;34:177–82.
Issa JP, Ingraci de Lucia C, Dos Santos Kotake BG, Gonçalves Gonzaga M, Tocchini de Figueiredo FA, Mizusaki Iyomasa D, Macedo AP, Ervolino E. The effect of simvastatin treatment on bone repair of femoral fracture in animal model. Growth Factors. 2015;33:139–48.
Li X, Song QS, Wang JY, Leng HJ, Chen ZQ, Liu ZJ, Dang GT, Song CL. Simvastatin induces oestrogen receptor-alpha expression in bone, restores bone loss, and decreases ERalpha expression and uterine wet weight in ovariectomized rats. J Bone Miner Metab. 2011;29:396–403.
Qadir F, Alam SM, Zehra T, Mehmood A, Siddiqi AQ. Role of Pitavastatin in prevention of osteopenic changes in ovariectomized rats. J Coll Physicians Surg Pak. 2016;26:41–5.
Wang W, Nyman JS, Moss HE, Gutierrez G, Mundy GR, Yang X, Elefteriou F. Local low-dose lovastatin delivery improves the bone-healing defect caused by Nf1 loss of function in osteoblasts. J Bone Miner Res. 2010;25:1658–67.
Qiao LJ, Kang KL, Heo JS. Simvastatin promotes osteogenic differentiation of mouse embryonic stem cells via canonical Wnt/beta catenin signaling. Mol Cell. 2011;32:437–44.
Goes P, Lima AP, Melo IM, Rêgo RO, Lima V. Effect of atorvastatin in radiographic density on alveolar bone loss in Wistar rats. Braz Dent J. 2010;21:193–8.
Uyar Y, Baytur Y, Inceboz U, Demir BC, Gumuser G, Ozbilgin K. Comparative effects of risedronate, atorvastatin, estrogen and SERMs on bone mass and strength in ovariectomized rats. Maturitas. 2009;63:261–7.
Maritz FJ, Conradie MM, Hulley PA, Gopal R, Hough S. Effect of statins on bone mineral density and bone histomorphometry in rodents. Arterioscler Thromb Vasc Biol. 2001;21:1636–41.
Yao W, Farmer R, Cooper R, Chmielewski PA, Tian XY, Setterberg RB, Jee WS, Lundy MW. Simvastatin did not prevent nor restore ovariectomy-induced bone loss in adult rats. J Musculoskelet Neuronal Interact. 2006;6:277–83.
Oka S, Matsumoto T, Kubo S, Matsushita T, Sasaki H, Nishizawa Y, Matsuzaki T, Saito T, Nishida K, Tabata Y. Local administration of low dose simvastatin-conjugated gelatin hydrogel for tendon-bone healing in anterior cruciate ligament reconstruction. Tissue Eng. 2013;19:1233–43.
Faziom S, Linton MF. Mouse models of hyperlipidemia and atherosclerosis. Front Biosci. 2001;6:515–25.
Ge C, Yang Q, Zhao G, Yu H, Kirkwood KL, Franceschi RT. Interactions between extracellular signal-regulated kinase 1/2 and p38 MAP kinase pathways in the control of RUNX2 phosphorylation and transcriptional activity. J Bone Miner Res. 2012;27:538–51.
Kaji H, Naito J, Inoue Y, Sowa H, Sugimoto T, Chihara K. Statin suppresses apoptosis in osteoblastic cells: role of transforming growth factor–beta-Smad3 pathway. Horm Metab Res. 2008;40:746–51.
Guarente L. Sir2 links chromatin silencing, metabolism, and aging. Genes Dev. 2000;14:1021–6.
Kitada M, Ogura Y, Koya D. The protective role of Sirt1 in vascular tissue: its relationship to vascular aging and atherosclerosis. Aging (Albany NY). 2016;810:2290–307.
Almeida M, Porter RM. Sirtuins and FoxOs in osteoporosis and osteoarthritis. Bone. 2019;121:284–92.
Hu HJ, Zhou SH, Liu QM. The magic and mystery of statins in aging: the potent preventive and therapeutic agent. Int J Cardiol. 2015;187:58–9.
Ota H, Eto M, Kano MR, Kahyo T, Setou M, Ogawa S, Iijima K, Akishita M, Ouchi Y. Induction of endothelial nitric oxide synthase, SIRT1, and catalase by statins inhibits endothelial senescence through the Akt pathway. Arterioscler Thromb Vasc Biol. 2010;30:2205–11.
Gong X, Ma Y, Ruan Y, Fu G, Wu S. Long-term atorvastatin improves age-related endothelial dysfunction by ameliorating oxidative stress and normalizing eNOS/iNOS imbalance in rat aorta. Exp Gerontol. 2014;52:9–17.
Komori T. Roles of Runx2 in skeletal development. Adv Exp Med Biol. 2017;962:83–93.
Shakibaei M, Shayan P, Busch F, Aldinger C, Buhrmann C, Lueders C, Mobasheri A. Resveratrol mediated modulation of Sirt-1/Runx2 promotes osteogenic differentiation of mesenchymal stem cells: potential role of Runx2 deacetylation. PLoS One. 2012;7:e35712.
Tseng PC, Hou SM, Chen RJ, Peng HW, Hsieh CF, Kuo ML, Yen ML. Resveratrol promotes osteogenesis of human mesenchymal stem cells by upregulating RUNX2 gene expression via the SIRT1/FOXO3A axis. J Bone Miner Res. 2011;26:2552–63.