Mohammed I, Hollenberg MD, Ding H, Triggle CR. A critical review of the evidence that metformin is a putative anti-aging drug that enhances healthspan and extends lifespan. Front Endocrinol (Lausanne). 2021;5(12):718942. https://doi.org/10.3389/fendo.2021.718942.
Song Y, Wu Z, Zhao P. The function of metformin in aging-related musculoskeletal disorders. Front Pharmacol. 2022;8(13):865524. https://doi.org/10.3389/fphar.2022.865524.
•• Shaik AR, Singh P, Shaik C, Kohli S, Vohora D, Ferrari SL. Metformin: is it the well wisher of bone beyond glycemic control in diabetes mellitus? Calcif Tissue Int. 2021;108(6):693-707. https://doi.org/10.1007/s00223-021-00805-8Excellent review and meta-analysis on the positive effects of metformin on bone, both in vitro and in vivo.
Ala M, Ala M. Metformin for cardiovascular protection, inflammatory bowel disease, osteoporosis, periodontitis, polycystic ovarian syndrom, neurodegeneration, cancer, inflammation and senescence: What is next? ACS Pharmacol Transl Sci. 2021;4(6):1727–70. https://doi.org/10.1021/acsptsci.1c00167
Lim YZ, Wang Y, Estee M, Abidi J, Udaya Kumar M, Hussain SM, Wluka AE, Little CB, Cicuttini FM. Metformin as a potential disease-modifying drug in osteoarthritis: a systematic review of pre-clinical and human studies. Osteoarthritis Cartilage. 2022;30(11):1434–42. https://doi.org/10.1016/j.joca.2022.05.005.
Article CAS PubMed Google Scholar
Takane H, Shikata E, Otsubo K, Higuchi S, Ieiri I. Polymorphism in human organic cation transporters and metformin action. Pharmacogenomics. 2008;9(4):415–22.
Article CAS PubMed Google Scholar
Chen L, Pawlikowski B, Schlessinger A, More SS, Stryke D, Johns SJ, Portman MA, Chen E, Ferrin TE, Sali A, Giacomini KM. Role of organic cation transporter 3 (SLC22A3) and its missense variants in the pharmacologic action of metformin. Pharmacogenet Genomics. 2010;20(11):687–99. https://doi.org/10.1097/FPC.0b013e32833fe789.
Article CAS PubMed PubMed Central Google Scholar
Roth M, Obaidat A, Hagenbuch B. OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br J Pharmacol. 2012;165(5):1260–87. https://doi.org/10.1111/j.1476-5381.2011.01724.x.
Article CAS PubMed PubMed Central Google Scholar
LaMoia TE, Shulman GI. Cellular and molecular mechanisms of metformin action. Endocr Rev. 2021;42(1):77–96. https://doi.org/10.1210/endrev/bnaa023.
Klein-Nulend J, Bakker AD, Bacabac RG, Vatsa A, Weinbaum S. Mechanosensation and transduction in osteocytes. Bone. 2013;54(2):182–90. https://doi.org/10.1016/j.bone.2012.10.013.
Article CAS PubMed Google Scholar
Kato Y, Windle JJ, Koop BA, Mundy GR, Bonewald LF. Establishment of an osteocyte-like cell line, MLO-Y4. J Bone Miner Res. 1997;12(12):2014–23. https://doi.org/10.1359/jbmr.1997.12.12.2014.
Article CAS PubMed Google Scholar
Zhang C, van Essen HW, Sie D, Micha D, Pals G, Klein-Nulend J, Bravenboer N. Mapping the response of human osteocytes in native matrix to mechanical loading using RNA sequencing. JBMR Plus. 2023;7(4):e10721. https://doi.org/10.1002/jbm4.10721 eCollection 2023 Apr.
Kositsawat J, Vogrin S, French C, Gebauer M, Candow DG, Duque G, Kirk B. Relationship between plasma homocysteine and bone density, lean mass, muscle strength and physical function in 1480 middle-aged and older adults: data from NHANES. Calcif Tissue Int. 2023;112(1):45–54. https://doi.org/10.1007/s00223-022-01037-0.
Article CAS PubMed Google Scholar
Takeno A, Kanazawa I, Tanaka K, Notsu M, Yokomoto M, Yamaguchi T, Sugimoto T. Activation of AMP-activated protein kinase protects against homocysteine-induced apoptosis of osteocytic MLO-Y4 cells by regulating the expressions of NADPH oxidase 1 (Nox1) and Nox2. Bone. 2015;77:135–41. https://doi.org/10.1016/j.bone.2015.04.025.
Article CAS PubMed Google Scholar
Felice JI, Schurman L, McCarthy AD, Sedlinsky C, Aguirre JI, Cortizo AM. Effects of fructose-induced metabolic syndrome on rat skeletal cells and tissue, and their responses to metformin treatment. Diabetes Res Clin Pract. 2017;126:202–13. https://doi.org/10.1016/j.diabres.2017.02.011.
Article CAS PubMed Google Scholar
Pigeaud KE, Rietveld ML, Witvliet AF, Hogervorst JMA, Zhang C, Forouzanfar T, Bravenboer N, Schoenmaker T, de Vries TJ. The effect of sclerostin and monoclonal sclerostin antibody romosozumab on osteogenesis and osteoclastogenesis mediated by periodontal ligament fibroblasts. Int J Mol Sci. 2023;24(8):7574. https://doi.org/10.3390/ijms24087574.
Article CAS PubMed PubMed Central Google Scholar
•• Yan Z, Zhu S, Tian X, Ye Z, Zhai D, Zhu Z, Wei D, Zhu Q, Lu Z, Cao X. Metformin protects bone mass in ultra-high-molecular-weight polyethylene particle-induced osteolysis by regulating osteocyte secretion. J Bone Miner Metab. 2019;37(3):399-410. https://doi.org/10.1007/s00774-018-0939-7Both in vitro and in vivo findings of metformin, effects on the various bone cells as well as inflammatory cytokines.
•• Park SH, Kang MA, Moon YJ, Jang KY, Kim JR. Metformin coordinates osteoblast/osteoclast differentiation associated with ischemic osteonecrosis. Aging (Albany NY). 2020;12(6):4727–4741. https://doi.org/10.18632/aging.102796 Epub 2020 Feb 11. PMID: 32045366 (In a drug screening system, metformin was discovered as an anabolic agent as well as inhibiting osteoclast formation. Furthermore, in an ischemia model, metformin protected against necrosis. Protein effects were studied extensively with immunohistochemistry.)
Song F, Lee WD, Marmo T, Ji X, Song C, Liao X, Seeley R, Yao L, Liu H, Long F. Osteoblast-intrinsic defect in glucose metabolism impairs bone formation in type II diabetic male mice. Elife. 2023;5(12):e85714. https://doi.org/10.7554/eLife.85714.
Yang K, Pei L, Zhou S, Tao L, Zhu Y. Metformin attenuates H2O2-induced osteoblast apoptosis by regulating SIRT3 via the PI3K/AKT pathway. Exp Ther Med. 2021;22(5):1316. https://doi.org/10.3892/etm.2021.10751.
Article CAS PubMed PubMed Central Google Scholar
Huang X, Li S, Lu W, Xiong L. Metformin activates Wnt/β-catenin for the treatment of diabetic osteoporosis. BMC Endocr Disord. 2022;22(1):189. https://doi.org/10.1186/s12902-022-01103-6.
Article CAS PubMed PubMed Central Google Scholar
Ma J, Zhang ZL, Hu XT, Wang XT, Chen AM. Metformin promotes differentiation of human bone marrow derived mesenchymal stem cells into osteoblast via GSK3β inhibition. Eur Rev Med Pharmacol Sci. 2018;22(22):7962–8. https://doi.org/10.26355/eurrev_201811_16424.
Article CAS PubMed Google Scholar
Shen M, Yu H, Jin Y, Mo J, Sui J, Qian X, Chen T. Metformin facilitates osteoblastic differentiation and M2 macrophage polarization by PI3K/AKT/mTOR pathway in human umbilical cord mesenchymal stem cells. Stem Cells Int. 2022;18(2022):9498876. https://doi.org/10.1155/2022/9498876.
Mai QG, Zhang ZM, Xu S, Lu M, Zhou RP, Zhao L, Jia CH, Wen ZH, Jin DD, Bai XC. Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. J Cell Biochem. 2011;112(10):2902–9. https://doi.org/10.1002/jcb.23206.
Article CAS PubMed Google Scholar
Shahrezaee M, Salehi M, Keshtkari S, Oryan A, Kamali A, Shekarchi B. In vitro and in vivo investigation of PLA/PCL scaffold coated with metformin-loaded gelatin nanocarriers in regeneration of critical-sized bone defects. Nanomedicine. 2018;14(7):2061–73. https://doi.org/10.1016/j.nano.2018.06.007.
Article CAS PubMed Google Scholar
Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, Bonewald LF, Kodama T, Wutz A, Wagner EF, Penninger JM, Takayanagi H. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med. 2011;17(10):1231–4. https://doi.org/10.1038/nm.2452.
Article CAS PubMed Google Scholar
de Vries TJ, Schoenmaker T, Hooibrink B, Leenen PJ, Everts V. Myeloid blasts are the mouse bone marrow cells prone to differentiate into osteoclasts. J Leukoc Biol. 2009;85(6):919–27. https://doi.org/10.1189/jlb.0708402.
Article CAS PubMed Google Scholar
••Tao LY, Łagosz-Ćwik KB, Hogervorst JMA, Schoenmaker T, Grabiec AM, Forouzanfar T, van der Weijden FA, de Vries TJ. Diabetes medication metformin inhibits osteoclast formation and activity in in vitro models for periodontitis. Front Cell Dev Biol. 2022;9:777450. https://doi.org/10.3389/fcell.2021.777450An extensive study using various human osteoclastogenesis models (co-culture, PBMCs without cytokines, monocytes cultured with M-CSF and RANKL) and the effects of metformin. Effects on osteogenesis is also studied.
Chen Z, Zige L, Sai Kiang Y, Desheng C. Experimental study on the inhibition of RANKL-induced osteoclast differentiation in vitro by metformin hydrochloride. Int J Endocrinol. 2022;2022:6778332. https://doi.org/10.1155/2022/6778332.
Article CAS PubMed PubMed Central Google Scholar
Guo H, Ding D, Wang L, Yan J, Ma L, Jin Q. Metformin attenuates osteoclast-mediated abnormal subchondral bone remodeling and alleviates osteoarthritis via AMPK/NF-κB/ERK signaling pathway. PLoS ONE. 2021;16(12):e0261127. https://doi.org/10.1371/journal.pone.0261127.
Article CAS PubMed PubMed Central Google Scholar
McCarthy AD, Cortizo AM, Sedlinsky C. Metformin revisited: does this regulator of AMP-activated protein kinase secondarily affect bone metabolism and prevent diabetic osteopathy. World J Diabetes. 2016;7(6):122–33. https://doi.org/10.4239/wjd.v7.i6.122.
Article PubMed PubMed Central Google Scholar
Xie X, Hu L, Mi B, Xue H, Hu Y, Panayi AC, Endo Y, Chen L, Yan C, Lin Z, Li H, Zhou W, Liu G. Metformin alleviates bone loss in ovariectomized mice through inhibition of autophagy of osteoclast precursors mediated by E2F1. Cell Commun Signal. 2022;20(1):165. https://doi.org/10.1186/s12964-022-00966-5.
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