BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Ginsenoside Rg2 inhibits osteoclastogenesis by downregulating the NFATc1, c-Fos, and MAPK pathways

  • Sung-Hoon Lee (Department of Life Science and Genetic Engineering, Graduate School of PaiChai University) ;
  • Shin-Young Park (Division of Software Engineering, PaiChai University) ;
  • Jung Ha Kim (Department of Pharmacology, Chonnam National University Medical School) ;
  • Nacksung Kim (Department of Pharmacology, Chonnam National University Medical School) ;
  • Junwon Lee (Department of Life Science and Genetic Engineering, Graduate School of PaiChai University)
  • Received : 2023.06.28
  • Accepted : 2023.08.14
  • Published : 2023.10.31
Download PDF
⟨ Previous Next ⟩

Abstract

Ginsenosides, among the most active components of ginseng, exhibit several therapeutic effects against cancer, diabetes, and other metabolic diseases. However, the molecular mechanism underlying the anti-osteoporotic activity of ginsenoside Rg2, a major ginsenoside, has not been clearly elucidated. This study aimed to determine the effects of ginsenoside Rg2 on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation. Results indicate that ginsenoside Rg2 inhibits RANKL-induced osteoclast differentiation of bone marrow macrophages (BMMs) without cytotoxicity. Pretreatment with ginsenoside Rg2 significantly reduced the RANKL-induced gene expression of c-fos and nuclear factor of activated T-cells (Nfatc1), as well as osteoclast-specific markers tartrate-resistant acid phosphatase (TRAP, Acp5) and osteoclast-associated receptor (Oscar). Moreover, RANKL-induced phosphorylation of mitogen-activated protein kinases (MAPKs) was decreased by ginsenoside Rg2 in BMM. Therefore, we suggest that ginsenoside Rg2 suppresses RANKL-induced osteoclast differentiation through the regulation of MAPK signaling-mediated osteoclast markers and could be developed as a therapeutic drug for the prevention and treatment of osteoporosis.

Keywords

Acknowledgement

This work was supported by the Ministry of Science and ICT (MSIT), Korea, under the Innovative Human Resource Development for Local Intellectualization Support Program (IITP-2023-RS-2022-00156334) supervised by the Institute for Information & Communications Technology Planning & Evaluation (IITP), and by an NRF grant funded by the Korean Government (MSIT) (2021R1A2C1008317).

References

  1. Novack DV and Teitelbaum SL (2008) The osteoclast: friend or foe? Annu Rev Pathol 3, 457-484  https://doi.org/10.1146/annurev.pathmechdis.3.121806.151431
  2. Nakashima T, Hayashi M, Fukunaga T et al (2011) Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 17, 1231-1234  https://doi.org/10.1038/nm.2452
  3. Rodan GA and Martin TJ (2000) Therapeutic approaches to bone diseases. Science 289, 1508-1514  https://doi.org/10.1126/science.289.5484.1508
  4. Rivollier A, Mazzorana M, Tebib J et al (2004) Immature dendritic cell transdifferentiation into osteoclasts: a novel pathway sustained by the rheumatoid arthritis microenvironment. Blood 104, 4029-4037  https://doi.org/10.1182/blood-2004-01-0041
  5. Roodman GD (1999) Cell biology of the osteoclast. Exp Hematol 27, 1229-1241  https://doi.org/10.1016/S0301-472X(99)00061-2
  6. Takeshita S, Namba N, Zhao JJ et al (2002) SHIP-deficient mice are severely osteoporotic due to increased numbers of hyper-resorptive osteoclasts. Nat Med 8, 943-949  https://doi.org/10.1038/nm752
  7. Genant HK, Baylink DJ and Gallagher JC (1989) Estrogens in the prevention of osteoporosis in postmenopausal women. Am J Obstet Gynecol 161, 1842-1846  https://doi.org/10.1016/S0002-9378(89)80004-3
  8. Reid IR (2002) Pharmacotherapy of osteoporosis in postmenopausal women: focus on safety. Expert Opin Drug Saf 1, 93-107  https://doi.org/10.1517/14740338.1.1.93
  9. Kong YY, Yoshida H, Sarosi I et al (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315-323  https://doi.org/10.1038/16852
  10. Lee ZH and Kim HH (2003) Signal transduction by receptor activator of nuclear factor kappa B in osteoclasts. Biochem Biophys Res Commun 305, 211-214  https://doi.org/10.1016/S0006-291X(03)00695-8
  11. Lee SE, Woo KM, Kim SY et al (2002) The phosphatidylinositol 3-kinase, p38, and extracellular signal-regulated kinase pathways are involved in osteoclast differentiation. Bone 30, 71-77  https://doi.org/10.1016/S8756-3282(01)00657-3
  12. Li J, Sarosi I, Yan XQ et al (2000) RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci U S A 97, 1566-1571  https://doi.org/10.1073/pnas.97.4.1566
  13. Walsh MC, Kim N, Kadono Y et al (2006) Osteoimmunology: interplay between the immune system and bone metabolism. Annu Rev Immunol 24, 33-63  https://doi.org/10.1146/annurev.immunol.24.021605.090646
  14. Chang Y, Huang WJ, Tien LT and Wang SJ (2008) Ginsenosides Rg1 and Rb1 enhance glutamate release through activation of protein kinase A in rat cerebrocortical nerve terminals (synaptosomes). Eur J Pharmacol 578, 28-36  https://doi.org/10.1016/j.ejphar.2007.09.023
  15. Chen WF, Lau WS, Cheung PY, Guo DA and Wong MS (2006) Activation of insulin-like growth factor I receptor-mediated pathway by ginsenoside Rg1. Br J Pharmacol 147, 542-551  https://doi.org/10.1038/sj.bjp.0706640
  16. Lau WS, Chan RY, Guo DA and Wong MS (2008) Ginsenoside Rg1 exerts estrogen-like activities via ligand-independent activation of ERalpha pathway. J Steroid Biochem Mol Biol 108, 64-71  https://doi.org/10.1016/j.jsbmb.2007.06.005
  17. Pan XY, Guo H, Han J et al (2012) Ginsenoside Rg3 attenuates cell migration via inhibition of aquaporin 1 expression in PC-3M prostate cancer cells. Eur J Pharmacol 683, 27-34  https://doi.org/10.1016/j.ejphar.2012.02.040
  18. Kim HR, Cui Y, Hong SJ et al (2008) Effect of ginseng mixture on osteoporosis in ovariectomized rats. Immunopharmacol Immunotoxicol 30, 333-345  https://doi.org/10.1080/08923970801949125
  19. Liu J, Shiono J, Shimizu K et al (2009) 20(R)-ginsenoside Rh2, not 20(S), is a selective osteoclastgenesis inhibitor without any cytotoxicity. Bioorg Med Chem Lett 19, 3320-3323  https://doi.org/10.1016/j.bmcl.2009.04.054
  20. Yuan HD, Kim DY, Quan HY, Kim SJ, Jung MS and Chung SH (2012) Ginsenoside Rg2 induces orphan nuclear receptor SHP gene expression and inactivates GSK3beta via AMP-activated protein kinase to inhibit hepatic glucose production in HepG2 cells. Chem Biol Interact 195, 35-42  https://doi.org/10.1016/j.cbi.2011.10.006
  21. Zhang G, Liu A, Zhou Y, San X, Jin T and Jin Y (2008) Panax ginseng ginsenoside-Rg2 protects memory impairment via anti-apoptosis in a rat model with vascular dementia. J Ethnopharmacol 115, 441-448  https://doi.org/10.1016/j.jep.2007.10.026
  22. Xue Q, Yu T, Wang Z et al (2023) Protective effect and mechanism of ginsenoside Rg2 on atherosclerosis. J Ginseng Res 47, 237-245  https://doi.org/10.1016/j.jgr.2022.08.001
  23. Zhou L, Wang F, Sun R et al (2016) SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense. EMBO Rep 17, 811-822  https://doi.org/10.15252/embr.201541643
  24. Yao F, Xue Q, Li K, Cao X, Sun L and Liu Y (2019) Phenolic compounds and ginsenosides in ginseng shoots and their antioxidant and anti-inflammatory capacities in LPS-induced RAW264.7 mouse macrophages. Int J Mol Sci 20, 2951 
  25. Wang ZQ, Ovitt C, Grigoriadis AE, Mohle-Steinlein U, Ruther U and Wagner EF (1992) Bone and haematopoietic defects in mice lacking c-fos. Nature 360, 741-745  https://doi.org/10.1038/360741a0
  26. Takayanagi H, Kim S, Koga T et al (2002) Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 3, 889-901  https://doi.org/10.1016/S1534-5807(02)00369-6
  27. Lee JH, Jin H, Shim HE, Kim HN, Ha H and Lee ZH (2010) Epigallocatechin-3-gallate inhibits osteoclastogenesis by down-regulating c-Fos expression and suppressing the nuclear factor-kappaB signal. Mol Pharmacol 77, 17-25  https://doi.org/10.1124/mol.109.057877
  28. Nedeva IR, Vitale M, Elson A, Hoyland JA and Bella J (2021) Role of OSCAR signaling in osteoclastogenesis and bone disease. Front Cell Dev Biol 9, 641162 
  29. Kim HN, Baek JK, Park SB et al (2019) Anti-inflammatory effect of Vaccinium oldhamii stems through inhibition of NF-kappaB and MAPK/ATF2 signaling activation in LPS-stimulated RAW264.7 cells. BMC Complement Altern Med 19, 291 
  30. Teitelbaum SL and Ross FP (2003) Genetic regulation of osteoclast development and function. Nat Rev Genet 4, 638-649  https://doi.org/10.1038/nrg1122
  31. Teitelbaum SL (2004) RANKing c-Jun in osteoclast development. J Clin Invest 114, 463-465  https://doi.org/10.1172/JCI200422644
  32. Kiefer D and Pantuso T (2003) Panax ginseng. Am Fam Physician 68, 1539-1542 
  33. Grigoriadis AE, Wang ZQ, Cecchini MG et al (1994) c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science 266, 443-448  https://doi.org/10.1126/science.7939685
  34. Yamashita T, Yao Z, Li F et al (2007) NF-kappaB p50 and p52 regulate receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1. J Biol Chem 282, 18245-18253  https://doi.org/10.1074/jbc.M610701200
  35. Wagner EF and Eferl R (2005) Fos/AP-1 proteins in bone and the immune system. Immunol Rev 208, 126-140  https://doi.org/10.1111/j.0105-2896.2005.00332.x
  36. Gohda J, Akiyama T, Koga T, Takayanagi H, Tanaka S and Inoue J (2005) RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis. EMBO J 24, 790-799  https://doi.org/10.1038/sj.emboj.7600564
  37. Takayanagi H (2007) Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol 7, 292-304  https://doi.org/10.1038/nri2062
  38. Boyle WJ, Simonet WS and Lacey DL (2003) Osteoclast differentiation and activation. Nature 423, 337-342  https://doi.org/10.1038/nature01658
  39. Ang E, Liu Q, Qi M et al (2011) Mangiferin attenuates osteoclastogenesis, bone resorption, and RANKL-induced activation of NF-kappaB and ERK. J Cell Biochem 112, 89-97  https://doi.org/10.1002/jcb.22800
  40. Kim HJ, Lee Y, Chang EJ et al (2007) Suppression of osteoclastogenesis by N,N-dimethyl-D-erythro-sphingosine: a sphingosine kinase inhibition-independent action. Mol Pharmacol 72, 418-428  https://doi.org/10.1124/mol.107.034173
  41. Monje P, Hernandez-Losa J, Lyons RJ, Castellone MD and Gutkind JS (2005) Regulation of the transcriptional activity of c-Fos by ERK. A novel role for the prolyl isomerase PIN1. J Biol Chem 280, 35081-35084  https://doi.org/10.1074/jbc.C500353200
  42. Ikeda F, Nishimura R, Matsubara T et al (2004) Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation. J Clin Invest 114, 475-484  https://doi.org/10.1172/JCI200419657
  43. Matsumoto M, Sudo T, Saito T, Osada H and Tsujimoto M (2000) Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-kappa B ligand (RANKL). J Biol Chem 275, 31155-31161 https://doi.org/10.1074/jbc.M001229200