Effects of metformin on bone metabolism

Abstract

Abstract: Metformin [1-(diaminomethylidene)-3,3-dimethylguani-dine] is an antihyperglycemia drug commonly used for the management of type 2 diabetes, which has been widely used for more than fifty years and had safety, valid and full-scale effects on controlling plasma glucose in patients with diabetes mellitus. Recent years, more and more studies found that metformin induced osteoblastic growth and differentiation, increased the mineralization of the extracellular matrix, reversed the deleterious effects of high glucose on osteoblast function and also inhibited osteoclastogenesis; Furthermore, in vivo, treatment of mice with metformin has been found to increase bone mineral content, trabecular bone volume and induce bone formation. In addition, using a model of minimal bone defect metformin treatment stimulated bone reossification in both control and diabetic rats. Furthermore, in clinical research, metformin influenced bone mineral density in patients with diabetes mellitus. However, the effects of metformin on bone metabolism and the molecular mechanisms for the action of metformin are still unclear. This article reviews the effects of metformin on bone metabolism and discusses its possible mechanisms.

Key words: Metformin, Osteoblast, Osteoclast

CLC Number:

ZHEN Dong-Hu, LIU Li-Juan, TANG Xu-Lei, CHEN Jian-Guo. Effects of metformin on bone metabolism[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2012, 17(11): 1314-1320.

References

[1] Kirpichnikov D,McFarlane SI,Sowers JR. Metformin: an update[J].Arm Intern Med, 2002, 137(1): 25-33.
[2] 方丽娟, 刘乃丰. 甲双胍的心血管保护作用[J]. 中国临床药理学与治疗学, 2011, 16(2): 232-236.
[3] Wiernsperger NF.Metformin: intrinsic vasculorotective properties[J]. Diabetes Technol The, 2000, 2(2):259-272.
[4] 赵丹,修锐. 二甲双胍临床应用研究概述[J]. 药物流行病学杂志, 2010, 19(3):164-166.
[5] Cortizo AM, Sedlinsky C, McCarthy AD, et al. Osteogenic actions of the anti-diabetic drug metformin on osteoblasts in culture[J]. Eur J Pharmacol, 2006, 536(1-2):38-46.
[6] 吕娇, 刘洪臣, 鄂玲玲, 等. 盐酸二甲双胍对大鼠下颌骨成骨细胞增殖、分化及矿化功能的影响[J]. 中华老年口腔医学杂志, 2008, 6(1):48-50.
[7] 吕娇, 刘洪臣, 王东胜, 等. 二甲双胍对成骨细胞葡萄糖摄取及葡萄糖转运蛋白-1表达的影响[J]. 口腔颌面修复学杂志, 2008, 9(2):56-89.
[8] Donghu Z, Yirong C, Xulei T.Metformin reverses the deleterious effects of high glucose on osteoblast function[J]. J Diabetes Complicat, 2010, 24(5):334-344.
[9] Terada M, Inaba M, Yano Y, et al.Growth-inhibitory effect of a high glucose concentration on osteoblast-like cells[J]. Bone, 1998, 22(1):17-23.
[10] Gopalakrishnan V, Vignesh RC, Arunakaran J, et al.Effects of glucose and its modulation by insulin and estradiol on BMSC differentiation into osteoblastic lineages[J]. Biochem Cell Biol, 2006, 84(1):93-101.
[11] Maor G, Karnieli E.The insulin-sensitive glucose transporter (GLUT4)is involved in early bone growth in control and diabetic mice, but is regulated through the insulin-like growth factor I receptor[J]. Endocrinology, 1999, 140(4):1841-1851.
[12] Al-Khalili L, Forsgren M, Kannisto K, et al.Enhanced insulin-stimulated glycogen synthesis in response to insulin, metformin or rosiglitazone is associated with increased mRNA expression of GLUT4 and peroxisomal proliferator activator receptor gamma co-activator 1[J]. Diabetologia, 2005, 48(1):1173-1179.
[13] Tessier D, Maheux P, Khalil A, et al.Effects of gliclazide versus metformin on the clinical profile and lipid peroxidation markers in type 2 diabetes[J]. Metabolism, 1999, 48(7):897-903.
[14] Ruggiero-Lopez D, Lecomte M, Moinet G, et al.Reaction of metformin with dicarbonyl compounds. Possible implication in the inhibition of advanced glycation end products formation[J]. Biochem Pharmacol, 1999, 58(11):1765-1773.
[15] Yan SD, Schmidt AM, Anderson GM, et al.Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins[J]. J Biol Chem, 1994, 269(13):9889-9897.
[16] Schurman L, McCarthy AD, Sedlinsky C, et al. Metformin reverts deleterious effects of advanced glycation end-Products (AGEs) on osteoblastic Cells[J]. Exp Clin Endocrinol Diabetes, 2008, 116(6):333-340.
[17] Burdon T, Smith A, Savatier P, et al.Signaling, cell cycle and pluripotency in embryonic stem cells[J]. Trends Cell Biol, 2002, 12(9):432-438.
[18] Lai CF, Chaudhary A, Fausto L, et al.Erk is essential for growth differentiation integrin expression and cell function in human osteoblastic cells[J]. J Biol Chem, 2001, 276(17):14443-14450.
[19] Shah M, Kola B, Bataveljic A, et al.AMP-activated protein kinase (AMPK) activation regulates in vitro bone formation and bone mass[J]. Bone, 2010, 47(2):309-319.
[20] Adams J, Chen ZP, Van Denderen.Intrasteric control of AMPK via the gamma1 subunit AMP allosteric regulatory site[J]. Protein Sci, 2004, 13(1):155-165.
[21] Kanazawa I, Yamaguchi T, Yano S, et al.Adiponectin and AMP kinase activator stimulate proliferation, differentiation, and mineralization of osteoblastic MC3T3-E1 cells[J]. BMC Cell Biol, 2007, 8:51-62.
[22] Kanazawa I, Yamaguchi T, Yano S, et al.Activation of AMP kinase and inhibition of Rho kinase induce the mineralization of osteoblastic MC3T3-E1 cells through endothelial NOS and BMP2 expression[J]. Am J Physiol Endocrinol Metab, 2009, 296(1):E139-146.
[23] Ippei K, Toru Y, Shozo Y, et al.Metformin enhances the differentiation and mineralization of osteoblastic MC3T3-E1 cells via AMP kinase activation as well as eNOS and BMP-2 expression[J]. Biochem Bioph Res Co, 2008, 375(3):414-419.
[24] Won GJ, Eun JK, Kkot-Nim L, et al.AMP-activated protein kinase (AMPK) positively regulates osteoblast differentiation via induction of Dlx5-dependent Runx2 expression in MC3T3E1 cells[J]. Biochem Bioph Res Co, 2011, 404(4):1004-1009.
[25] Seol W, Choi HS, Moore DD.An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors[J]. Science, 1996, 272(5266):1336-1339.
[26] Lee YS, Chanda D, Sim J, et al.Structure and function of the atypical orphan nuclear receptor small heterodimer partner[J]. Int Rev Cytol, 2007, 261:117-158.
[27] Kim YD, Park KG, Lee YS, et al.Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP[J]. Diabetes, 2008, 57(2):306-314.
[28] Chanda D, Li T, Song KH, et al.Hepatocyte growth factor family negatively regulates hepatic gluconeogenesis via induction of orphan nuclear receptor small heterodimer partner in primary hepatocytes[J]. J Biol Chem, 2009, 284(42):28510-28521.
[29] Jeong BC, Lee YS, Bae IH, et al.The orphan nuclear receptor SHP is a positive regulator of osteoblastic bone formation[J]. J Bone Miner Res, 2010, 25(2):262-274.
[30] Won GJ, Eun JK, In-Ho B, et al.Metformin induces osteoblast differentiation via orphan nuclear receptor SHP-mediated transactivation of Runx2[J]. Bone, 2011, 48(4):885-893.
[31] Takayuki K, KenJiro B, Hiraku S, et al. Osteoblast differentiation Is functionally associated with decreased AMP kinase activity[J]. J Cell Physiol, 2009, 221(3):740-749.
[32] Macsai CE, Foster BK, Xian CJ.Roles of Wnt signalling in bone growth, remodelling, skeletal disorders and fracture repair[J]. J Cell Physiol, 2008, 215(3):578-587.
[33] Strutt D.Frizzled signalling and cell polarisation in Drosophila and vertbrates[J]. Development, 2003, 130(19),4501-4513.
[34] Hartmann C.A Wnt canon orchestrating osteoblastogenesis[J]. Trends Cell Biol, 2006, 16(3):151-158.
[35] Tomozumi T, Masanori M, Rieko T, et al.AMP-activated protein kinase attenuates Wnt/β-catenin signaling in human osteoblastic Saos-2 cells[J]. Mol Cell Endocrinol, 2011, 339(1/2):114-119.
[36] Boyce BF, Xing L.Functions of RANKL/RANK/OPG in bone modeling and remodeling[J]. Arch biochem Biophys, 2008, 473(2):139-146.
[37] Sato K, Suematsu A, Nakashima T, et al.Regulation of osteoclast differentiation and function by the CaMK-CREB pathway. Nat Med, 2006, 12(12):1410-1416.
[38] Young-Sun L, Yang-Soon K, Sun-Young L, et al.AMP kinase acts as a negative regulator of RANKL in the differentiation of osteoclasts[J]. Bone, 2010, 47(5):926-937.
[39] Baka E, Kima M, Parka H, et al.Effect of metformin on osteoclastogenesis stimulated by bone resorption inducing factors[J]. Bone, 2009, 44(2):S253-S338.
[40] Lecka-Czernik B, Moerman EJ, Grant DF, et al.Divergent effects of selective peroxisome proliferators activated receptor-γ2 ligands on adipocyte versus osteoblast differentiation[J]. Endocrinology, 2002, 143(6):2376-2384.
[41] Kahn SE, Haffner SM, Heise MA, et al.Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy[J]. New Engl J Med, 2006, 355(23):2427-2443.
[42] Komori T.Runx2, a multifunctional transcription factor in skeletal development[J]. J Cell Biochem, 2002, 87(1):1-8.
[43] Duque G, Macorittoc M, Kremer R.1,25 (OH)2D3 inhibit bone marrow adipogenesis in senescence accelerated mice(SAM-P/ 6) by decreasing the expression of peroxisome proliferatorsact ivated receptor gamma2 (PPARγ2)[J]. Exp Gerontol, 2004, 39(3):333-338.
[44] Ying G, Jing X, Xiaoyu L, et al.Metformin regulates osteoblast and adipocyte differentiation of rat mesenchymal stem cells[J]. J pharm pharmacol, 2008, 60(12):1695-1700.
[45] Molinuevo MS, Schurman L, McCarthy AD, et al. Effect of metformin on bone marrow progenitor cell differentiation: in vitro and in vivo studies[J]. J Bone Miner Res, 2010, 25(2):211-221.
[46] Claudia S, María SM, Ana MC, et al.Metformin prevents anti-osteogenic in vivo and ex vivo effects of rosiglitazone in rats[J]. Eur J Pharmacol, 2011, 668(3):477-485.
[47] Ying G, Yunfeng L, Jing X, et al.Effect of the anti-diabetic drug metformin on bone mass in ovariectomized rats[J]. Eur J Pharmacol, 2010, 635(1-3):231-236.
[48] Vestergaard P, Rejnmark L, Mosekilde L.Relative fracture risk in patients with diabetes mellitus, and the impact of insulin and oral antidiabetic medication on relative fracture risk[J]. Diabetologia, 2005, 48(7):1292-1299
[49] 张瑞美. 不同剂量二甲双胍对2型糖尿病性骨质疏松症并发骨折恢复的影响[J].青岛医药卫生, 2011, 43(3):197-198.
[50] Vestergaard P.Discrepancies in bone mineral density and fracture risk in patients with type1 and type2 diabetes-a meta-analysis[J]. Osteoporos Int, 2007, 18(4):427-444.