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Ginsenoside Rg3 Attenuates Aluminum-Induced Osteoporosis Through Regulation of Oxidative Stress and Bone Metabolism in Rats

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Abstract

Aluminum (Al)-induced bone metabolism disorder is a primary cause of osteoporosis. Ginsenoside Rg3 (Rg3) has demonstrated therapeutic properties in the treatment of osteoporosis. The present study aimed to identify potential bone protection mechanisms of Rg3 against Al-induced osteoporosis in rats. In this study, forty healthy male Sprague-Dawley rats were randomly allocated into groups in which they were treated with AlCl3 (64 mg/kg/day) and/or Rg3 (20 mg/kg/day). AlCl3 was given orally to rats for 120 days, and from the 91st day, treated orally with Rg3 for 30 days. Rg3 attenuated AlCl3-induced accumulation of Al by decreasing the bone mineral density in the lumbar spines, femoral metaphysis, and tibia, and inhibited AlCl3-induced oxidative stress in rat bone by decreasing the levels of reactive oxygen species and malondialdehyde, while increasing glutathione peroxidase and superoxide dismutase activity. Rg3 facilitated bone formation by increasing the concentration of calcium, phosphorus, amino-terminal propeptide of type I procollagen, and carboxyl-terminal propeptide of type I procollagen, bone alkaline phosphatase activity in serum, and type I collagen, osteocalcin, and osteopontin protein expressions. Rg3 inhibited bone resorption by decreasing the content of N-terminal cross-linking telopeptide of type I collagen, C-terminal cross-linking telopeptide of type I collagen, and tartrate-resistant acid phosphatase 5b activity in serum. Rg3 promoted the mRNA expression of growth regulation factors by increasing transforming growth factor-β1, bone morphogenetic protein-2, insulin-like growth factor I, and core-binding factor α1. The results demonstrate that Rg3 can significantly attenuate Al accumulation, facilitate bone formation, inhibit bone resorption, resist oxidative stress, and promote the expression of factors that regulate growth. The results indicate that Rg3 is effective in alleviating AlCl3-induced osteoporosis.

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References

  1. Oliveira V.M., Assis C.R.D., Costa H.M.S., Silva R.P.F., Santos J.F., Jr L.B.C., Bezerra R.S (2017) Aluminium sulfate exposure: a set of effects on hydrolases from brain, muscle and digestive tract of juvenile Nile tilapia ( Oreochromis niloticus ). Comp Biochem Physiol 191: 101–108

  2. Wang F, Kang P, Li Z, Niu Q (2019) Role of MLL in the modification of H3K4me3 in aluminium-induced cognitive dysfunction. Chemosphere 232:121–129

    CAS  PubMed  Google Scholar 

  3. Weidenhamer JD, Fitzpatrick MP, Biro AM, Kobunski PA, Hudson MR, Corbin RW, Gottesfeld P (2017) Metal exposures from aluminum cookware: an unrecognized public health risk in developing countries. Sci Total Environ 579:805–813

    CAS  PubMed  Google Scholar 

  4. Nidheesh P.V., Khatri J., Anantha Singh T.S., Gandhimathi R., Ramesh S.T (2018) Review of zero-valent aluminium based water and wastewater treatment methods. Chemosphere 200: 621–631

  5. Dam JWV, Trenfield MA, Harries SJ, Streten C, Harford AJ, Parry D, Dam RAV (2016) A novel bioassay using the barnacle Amphibalanus amphitrite to evaluate chronic effects of aluminium, gallium and molybdenum in tropical marine receiving environments. Mar Pollut Bull 112:427–435

    PubMed  Google Scholar 

  6. Pagani S, Fini M, Giavaresi G, Salamanna F, Borsari V (2015) The active role of osteoporosis in the interaction between osteoblasts and bone metastases. Bone 79:176–182

    CAS  PubMed  Google Scholar 

  7. Yuan FL, Xu RS, Jiang DL, He XL, Su Q, Jin C, Li X (2015) Leonurine hydrochloride inhibits osteoclastogenesis and prevents osteoporosis associated with estrogen deficiency by inhibiting the NF-κB and PI3K/Akt signaling pathways. Bone 75:128–137

    CAS  PubMed  Google Scholar 

  8. Doğanlar ZB, Uzun M, Ovali MA, Dogan A, Ongoren G, Doğanlar O (2019) Melatonin attenuates caspase-dependent apoptosis in the thoracic aorta by regulating element balance and oxidative stress in pinealectomised rats. Appl Physiol Nutr Me 44:153–163

    Google Scholar 

  9. Yu Y, Zhou W, Zhou K, Liu W, Liang X, Chen Y, Sun D, Lin X (2018) Polyamines modulate aluminum-induced oxidative stress differently by inducing or reducing H2O2 production in wheat. Chemosphere 212:645–653

    CAS  PubMed  Google Scholar 

  10. Li P, Luo W, Zhang H, Zheng X, Liu C, Ouyang H (2016) Effects of aluminum exposure on the bone stimulatory growth factors in rats. Bio Trace Elem Res 172:166–171

    CAS  Google Scholar 

  11. Kanazawa I, Canaff L, Abi RJ, Angrula A, Li J, Riddle RC, Boraschidiaz I, Komarova SV, Clemens TL, Murshed M (2015) Osteoblast menin regulates bone mass in vivo. J Biochem 290:3910–3924

    CAS  Google Scholar 

  12. Hu YC, Cheng HL, Hsieh BS, Huang LW, Huang TC, Chang KL (2012) Arsenic trioxide affects bone remodeling by effects on osteoblast differentiation and function. Bone 50:1406–1415

    CAS  PubMed  Google Scholar 

  13. Song M, Huo H, Cao Z, Han Y, Gao L (2017) Aluminum trichloride inhibits the rat osteoblasts mineralization in vitro. Bio Trace Elem Res 175:186–193

    CAS  Google Scholar 

  14. Li X, Hu C, Zhu Y, Sun H, Li Y, Zhang Z (2011) Effects of aluminum exposure on bone mineral density, mineral, and trace elements in rats. Bio Trace Elem Res 143:378–385

    CAS  Google Scholar 

  15. Dénarié D, Constant E, Thomas T, Marotte H (2014) Could biomarkers of bone, cartilage or synovium turnover be used for relapse prediction in rheumatoid arthritis patients? Mediat Inflamm 2014:1–7

    Google Scholar 

  16. Duan X, Jin L, Zheng X, Zhe W, Zhang Y, Ying H, Yang T, Deng H (2016) Deficiency of ATP6V1H causes bone loss by inhibiting bone resorption and bone formation through the TGF-β1 pathway. Theranostics 6:2183–2195

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Yan J, Herzog JW, Tsang K, Brennan CA, Bower MA, Garrett WS, Sartor BR, Aliprantis AO, Charles JF (2016) Gut microbiota induce IGF-1 and promote bone formation and growth. Proc Natl Acad Sci 113:E7554–E7563

    CAS  PubMed  Google Scholar 

  18. Lee J.H., Lee H.J., Yang M., Moon C., Kim J.C., Bae C.S., Jo S.K., Jang J.S., Kim S.H (2013) Effect of Korean red ginseng on radiation-induced bone loss in C3H/HeN mice. J Ginseng Res 37: 435–441

  19. Kim J, Lee H, Kang KS, Chun KH, Hwang GS (2015) Protective effect of Korean red ginseng against glucocorticoid-induced osteoporosis in vitro and in vivo. J Ginseng Res 39:46–53

    CAS  PubMed  Google Scholar 

  20. Yu-Mi S, Hyun-Joo J, Woo-Yong C, Chang-Jin L (2013) Antioxidative, anti-inflammatory, and matrix metalloproteinase inhibitory activities of 20(S)-ginsenoside Rg3 in cultured mammalian cell lines. Mol Biol Rep 40:269–279

    Google Scholar 

  21. Hanif S.M., Zubair S.M., Sungeun A., Kang S., Yeon-Ju K., Natarajan S., Yang D.U., Yang D.C (2013) Ginseng saponins and the treatment of osteoporosis: mini literature review. J Ginseng Res 37: 261–268

  22. Siddiqi M.H., Siddiqi M.Z., Kang S., Noh H.Y., Ahn S., Simu S.Y., Aziz M.A., Sathishkumar N., Jiménez Pérez Z.E., Yang D.C (2015) Inhibition of osteoclast differentiation by ginsenoside Rg3 in RAW264.7 cells via RANKL, JNK and p38 MAPK pathways through a modulation of cathepsin K: an in Silico and in vitro study. Phytother Res 29: 1286–1294

  23. Tian J, Fu F, Geng M, Jiang Y, Yang J, Jiang W, Wang C, Liu K (2005) Neuroprotective effect of 20( S )-ginsenoside Rg 3 on cerebral ischemia in rats. Neurosci Lett 374:92–97

    CAS  PubMed  Google Scholar 

  24. Zhang X, Chen K, Wei B, Liu X, Lei Z, Bai X (2016) Ginsenosides Rg3 attenuates glucocorticoid-induced osteoporosis through regulating BMP-2/BMPR1A/Runx2 signaling pathway. Chem Biol Interact 256:188–197

    CAS  PubMed  Google Scholar 

  25. Sun X, Liu J, Zhuang C, Yang X, Han Y, Shao B, Song M, Li Y, Zhu Y (2016) Aluminum trichloride induces bone impairment through TGF-β1/Smad signaling pathway. Toxicol 371:49–57

    CAS  Google Scholar 

  26. Yang X, Yu K, Wang H (2018) Bone impairment caused by AlCl3 is associated with activation of the JNK apoptotic pathway mediated by oxidative stress. Food ChemToxicol 116:307–314

    CAS  Google Scholar 

  27. Yang X, Zhang X, Zhang J, Ji Q, Huang W, Zhang X, Li Y (2019) Spermatogenesis disorder caused by T-2 toxin is associated with germ cell apoptosis mediated by oxidative stress. Environ Pollut 251:372–379

    CAS  PubMed  Google Scholar 

  28. Fewtrell MS, Edmonds CJ, Isaacs E, Bishop NJ, Lucas A (2011) Aluminium exposure from parenteral nutrition in preterm infants and later health outcomes during childhood and adolescence. P Nutr Soc 70:299–304

    CAS  Google Scholar 

  29. EFSA Panel on Food additives f., processing aids, food m.i.c.w (2008) Safety of aluminium from dietary intake - scientific opinion of the panel on food additives, flavourings, processing aids and food contact materials (AFC). EFSA J 6: 1–34

  30. Li P, Luo W, Zhang H, Zheng X, Liu C, Ouyang H (2015) Effects of aluminum exposure on the bone stimulatory growth factors in rats. Bio Trace Elem Res 172:166–171

    Google Scholar 

  31. Ammann P, Brennan TC, Mekraldi S, Aubert ML, Rizzoli R (2010) Administration of growth hormone in selectively protein-deprived rats decreases BMD and bone strength. Bone 46:1574–1581

    CAS  PubMed  Google Scholar 

  32. Shibata Y, Ohsawa I, Watanabe T, Miura T, Sato Y (2003) Effects of physical training on bone mineral density and bone metabolism. J Physiol Anthropol Applied Hum Sci 22:203–208

    Google Scholar 

  33. Xu F, Wang P, Yao Q, Shao B, Yu H, Yu K, Li Y (2019) Lycopene alleviates AFB1-induced immunosuppression by inhibiting oxidative stress and apoptosis in the spleen of mice. Food Funct 10:3868–3879

    CAS  PubMed  Google Scholar 

  34. Zhang C., Li X.-N., Xiang L.-R., Qin L., Lin J., Li J.L (2017) Atrazine triggers hepatic oxidative stress and apoptosis in quails (Coturnix C. coturnix) via blocking Nrf2-mediated defense response. Ecotox Environ Safe 137: 49–56

  35. Zhang B, Guo H, Yang W, Li M, Zou Y, Loor JJ, Xia C, Xu C (2019) Effects of ORAI calcium release-activated calcium modulator 1 (ORAI1) on neutrophil activity in dairy cows with subclinical hypocalcemia1. J Anim Sci 97:3326–3336

    PubMed  PubMed Central  Google Scholar 

  36. Kwiecień S, Brzozowski T, Pch K, Konturek SJ (2020) The role of reactive oxygen species in action of nitric oxide-donors on stress-induced gastric mucosal lesions. J Physiol Pha 53:761–773

    Google Scholar 

  37. Roomruangwong C, Barbosa DS, de Farias CC, Matsumoto AK, Thl B, Morelli NR, Kanchanatawan B, Duleu S, Geffard M, Maes M (2018) Natural regulatory IgM-mediated autoimmune responses directed against malondialdehyde regulate oxidative and nitrosative pathways and coupled with IgM responses to nitroso-adducts attenuate depressive and physiosomatic symptoms at the end of term pregnancy. Psychiatry Clin Neurosci 72:116–130

    CAS  PubMed  Google Scholar 

  38. Zhen T, Cheng J, Qian L, Lin Z, Kenny J, Tao W, Lin X, Yuan J, Quinn JMW, Tickner J (2017) Neohesperidin suppresses osteoclast differentiation, bone resorption and ovariectomised-induced osteoporosis in mice. Mol Cell Endocrinol 439:369–378

    Google Scholar 

  39. Cheng L, Yan S, Jiang Z, Cai P, Wang T, Zheng S (2017) Exercise enhance the ectopic bone formation of calcium phosphate biomaterials in muscles of mice. Mat Sci Eng C 77:136–141

    CAS  Google Scholar 

  40. Komaba H, Kaludjerovic J, Hu DZ, Nagano K, Amano K, Ide N, Sato T, Densmore MJ, Hanai JI, Olauson H (2017) Klotho expression in osteocytes regulates bone metabolism and controls bone formation. Kidney Int 92:599–611

    CAS  PubMed  Google Scholar 

  41. Leeming DJ, Larsen DV, Zhang C, Hi Y, Veidal SS, Nielsen RH, Henriksen K, Zheng Q, Barkholt V, Riis BJ (2010) Enzyme-linked immunosorbent serum assays (ELISAs) for rat and human N-terminal pro-peptide of collagen type I (PINP)--assessment of corresponding epitopes. Clin Biochem 43:1249–1256

    CAS  PubMed  Google Scholar 

  42. Linder CH, Ek-Rylander B, Krumpel M, Norgård M, Narisawa S, Millán JL, Andersson G, Magnusson P (2017) Bone alkaline phosphatase and tartrate-resistant acid phosphatase: potential co-regulators of bone mineralization. Calcified Tissue Int 101:92–101

    Google Scholar 

  43. Lian F, Zhao C, Qu J, Lian Y, Cui Y, Shan L, Yan J (2018) Icariin attenuates titanium particle-induced inhibition of osteogenic differentiation and matrix mineralization via miR-21-5p. Cell Bio Int 42:931–939

    CAS  Google Scholar 

  44. De FC, Messina A, Monda V, Viggiano E, Moscatelli F, Valenzano A, Esposito T, Sergio C, Cibelli G, Monda M (2017) Osteopontin: relation between adipose tissue and bone homeostasis. Stem Cells Int 2017:1–6

    Google Scholar 

  45. Moghaddam A, Müller U, Roth HJ, Wentzensen A, Grützner PA, Zimmermann G (2011) TRACP 5b and CTX as osteological markers of delayed fracture healing. Injury 42:758–764

    CAS  PubMed  Google Scholar 

  46. Sun X, Jia H, Xu Q, Zhao C, Xu C (2019) Lycopene alleviates H2O2-induced oxidative stress, inflammation and apoptosis in bovine mammary epithelial cells via the NFE2L2 signaling pathway. Food Funct 10:6276–6285

    CAS  PubMed  Google Scholar 

  47. Ripamonti U, Parak R, Klar RM, Dickens C, Dix-Peek T, Duarte R (2016) The synergistic induction of bone formation by the osteogenic proteins of the TGF-β supergene family. Biomaterials 104:279–296

    CAS  PubMed  Google Scholar 

  48. Alvarez J, Horton J, Sohn P, Serra R (2001) The perichondrium plays an important role in mediating the effects of TGF-β1 on endochondral bone formation. Dev Dynam 221:311–321

    CAS  Google Scholar 

  49. Mbalaviele G, Sheikh S, Stains JP, Salazar VS, Cheng SL, Chen D, Civitelli R (2005) Beta-catenin and BMP-2 synergize to promote osteoblast differentiation and new bone formation. J Cell Biochem 94:403–418

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Sakata T, Halloran BP, Elalieh HZ, Munson SJ, Rudner L, Venton L, Ginzinger D, Rosen CJ, Bikle DD (2003) Skeletal unloading induces resistance to insulin-like growth factor I on bone formation. Bone 32:669–680

    CAS  PubMed  Google Scholar 

  51. Dai Z, Guo F, Wu F, Xu H, Yang C, Li J, Liang P, Zhang H, Qu L, Tan Y (2014) Integrin αvβ3 mediates the synergetic regulation of core-binding factor α1 transcriptional activity by gravity and insulin-like growth factor-1 through phosphoinositide 3-kinase signaling. Bone 69:126–132

    CAS  PubMed  Google Scholar 

  52. Duan X, Xu H, Wang Y, Wang H, Li G, Jing L (2014) Expression of core-binding factor α1 and osteocalcin in fluoride-treated fibroblasts and osteoblasts. Theranostics 6:2183–2195

    Google Scholar 

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Funding

The study was supported by a grant from the National Science Foundation Project (31872530).

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Authors and Affiliations

  1. College of Veterinary Medicine, Northeast Agricultural University, No. 600 Changjiang Road, Harbin, 150030, China

    Miao Song, Zheng Cao, Haiyang Zhang, Menglin Liu & Li Gao

  2. Liaoning Agricultural College, Yingkou, 115009, China

    Fubo Jia

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  1. Miao Song
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Correspondence to Li Gao.

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The design and experimental procedures of the animal studies were approved by the Animal Ethics Committee of the Northeast Agricultural University (Harbin, China).

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Song, M., Jia, F., Cao, Z. et al. Ginsenoside Rg3 Attenuates Aluminum-Induced Osteoporosis Through Regulation of Oxidative Stress and Bone Metabolism in Rats. Biol Trace Elem Res 198, 557–566 (2020). https://doi.org/10.1007/s12011-020-02089-9

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