BMB Reports

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

DOI QR Code

Dehydrocostus lactone inhibits NFATc1 via regulation of IKK, JNK, and Nrf2, thereby attenuating osteoclastogenesis

  • Lee, Hye In (Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University) ;
  • Lee, Gong-Rak (Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University) ;
  • Lee, Jiae (Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University) ;
  • Kim, Narae (Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University) ;
  • Kwon, Minjeong (Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University) ;
  • Kim, Hyun Jin (Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University) ;
  • Kim, Nam Young (Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University) ;
  • Park, Jin Ha (Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University) ;
  • Jeong, Woojin (Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University)
  • Received : 2019.08.28
  • Accepted : 2019.09.30
  • Published : 2020.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

Excessive and hyperactive osteoclast activity causes bone diseases such as osteoporosis and periodontitis. Thus, the regulation of osteoclast differentiation has clinical implications. We recently reported that dehydrocostus lactone (DL) inhibits osteoclast differentiation by regulating a nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), but the underlying mechanism remains to be elucidated. Here we demonstrated that DL inhibits NFATc1 by regulating nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and nuclear factor-erythroid 2-related factor 2 (Nrf2). DL attenuated IκBα phosphorylation and p65 nuclear translocation as well as decreased the expression of NF-κB target genes and c-Fos. It also inhibited c-Jun N-terminal kinase (JNK) but not p38 or extracellular signal-regulated kinase. The reporter assay revealed that DL inhibits NF-κB and AP-1 activation. In addition, DL reduced reactive oxygen species either by scavenging them or by activating Nrf2. The DL inhibition of NFATc1 expression and osteoclast differentiation was less effective in Nrf2-deficient cells. Collectively, these results suggest that DL regulates NFATc1 by inhibiting NF-κB and AP-1 via down-regulation of IκB kinase and JNK as well as by activating Nrf2, and thereby attenuates osteoclast differentiation.

Keywords

References

  1. Manolagas SC (2000) Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 21, 115-137 https://doi.org/10.1210/edrv.21.2.0395
  2. Rodan GA and Martin TJ (2000) Therapeutic approaches to bone diseases. Science 289, 1508-1514 https://doi.org/10.1126/science.289.5484.1508
  3. Ross FP and Teitelbaum SL (2005) alphavbeta3 and macrophage colony-stimulating factor: partners in osteoclast biology. Immunol Rev 208, 88-105 https://doi.org/10.1111/j.0105-2896.2005.00331.x
  4. Theill LE, Boyle WJ and Penninger JM (2002) RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu Rev Immunol 20, 795-823 https://doi.org/10.1146/annurev.immunol.20.100301.064753
  5. Asagiri M and Takayanagi H (2007) The molecular understanding of osteoclast differentiation. Bone 40, 251-264 https://doi.org/10.1016/j.bone.2006.09.023
  6. 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
  7. Lee NK, Choi YG, Baik JY et al (2005) A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation. Blood 106, 852-859
  8. Garrett IR, Boyce BF, Oreffo RO, Bonewald L, Poser J and Mundy GR (1990) Oxygen-derived free radicals stimulate osteoclastic bone resorption in rodent bone in vitro and in vivo. J Clin Invest 85, 632-639 https://doi.org/10.1172/JCI114485
  9. Bax BE, Alam AS, Banerji B et al (1992) Stimulation of osteoclastic bone resorption by hydrogen peroxide. Biochem Biophys Res Commun 183, 1153-1158 https://doi.org/10.1016/S0006-291X(05)80311-0
  10. Lean JM, Davies JT, Fuller K et al (2003) A crucial role for thiol antioxidants in estrogen-deficiency bone loss. J Clin Invest 112, 915-923 https://doi.org/10.1172/JCI200318859
  11. Chen JR, Lazarenko OP, Shankar K et al (2011) Inhibition of NADPH oxidases prevents chronic ethanol-induced bone loss in female rats. J Pharmacol Exp Ther 336, 734-742 https://doi.org/10.1124/jpet.110.175091
  12. Hong S, Huh JE, Lee SY, Shim JK, Rhee SG and Jeong W (2014) TRP14 inhibits osteoclast differentiation via its catalytic activity. Mol Cell Biol 34, 3515-3524 https://doi.org/10.1128/MCB.00293-14
  13. Hyeon S, Lee H, Yang Y and Jeong W (2013) Nrf2 deficiency induces oxidative stress and promotes RANKLinduced osteoclast differentiation. Free Radic Biol Med 65, 789-799 https://doi.org/10.1016/j.freeradbiomed.2013.08.005
  14. Jeong GS, Pae HO, Jeong SO et al (2007) The alphamethylene-gamma-butyrolactone moiety in dehydrocostus lactone is responsible for cytoprotective heme oxygenase-1 expression through activation of the nuclear factor E2-related factor 2 in HepG2 cells. Eur J Pharmacol 565, 37-44 https://doi.org/10.1016/j.ejphar.2007.02.053
  15. Choi EM, Kim GH and Lee YS (2009) Protective effects of dehydrocostus lactone against hydrogen peroxide-induced dysfunction and oxidative stress in osteoblastic MC3T3-E1 cells. Toxicol In Vitro 23, 862-867 https://doi.org/10.1016/j.tiv.2009.05.005
  16. Lee HI, Lee J, Hwang D et al (2019) Dehydrocostus lactone suppresses osteoclast differentiation by regulating NFATc1 and inhibits osteoclast activation through modulating migration and lysosome function. FASEB J 33, 9685-9694 https://doi.org/10.1096/fj.201900862r
  17. Wang J, Yu Z, Wang C et al (2017) Dehydrocostus lactone, a natural sesquiterpene lactone, suppresses the biological characteristics of glioma, through inhibition of the NF-kappaB/COX-2 signaling pathway by targeting IKKbeta. Am J Cancer Res 7, 1270-1284
  18. Hazzalin CA and Mahadevan LC (2002) MAPK-regulated transcription: a continuously variable gene switch? Nat Rev Mol Cell Biol 3, 30-40 https://doi.org/10.1038/nrm715
  19. Tu YC, Huang DY, Shiah SG, Wang JS and Lin WW (2013) Regulation of c-Fos gene expression by NF-kappaB: a p65 homodimer binding site in mouse embryonic fibroblasts but not human HEK293 cells. PLoS One 8, e84062 https://doi.org/10.1371/journal.pone.0084062
  20. Fujioka S, Niu J, Schmidt C et al (2004) NF-kappaB and AP-1 connection: mechanism of NF-kappaB-dependent regulation of AP-1 activity. Mol Cell Biol 24, 7806-7819 https://doi.org/10.1128/MCB.24.17.7806-7819.2004
  21. Whitmarsh AJ, Yang SH, Su MS, Sharrocks AD and Davis RJ (1997) Role of p38 and JNK mitogen-activated protein kinases in the activation of ternary complex factors. Mol Cell Biol 17, 2360-2371 https://doi.org/10.1128/MCB.17.5.2360
  22. Gloire G, Legrand-Poels S and Piette J (2006) NF-kappaB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol 72, 1493-1505 https://doi.org/10.1016/j.bcp.2006.04.011
  23. Jung Y, Kim H, Min SH, Rhee SG and Jeong W (2008) Dynein light chain LC8 negatively regulates NF-kappaB through the redox-dependent interaction with IkappaBalpha. J Biol Chem 283, 23863-23871 https://doi.org/10.1074/jbc.M803072200
  24. Kamata H, Honda S, Maeda S, Chang L, Hirata H and Karin M (2005) Reactive oxygen species promote TNFalphainduced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120, 649-661 https://doi.org/10.1016/j.cell.2004.12.041
  25. Hong SE, Lee J, Seo DH et al (2017) Euphorbia factor L1 inhibits osteoclastogenesis by regulating cellular redox status and induces Fas-mediated apoptosis in osteoclast. Free Radic Biol Med 112, 191-199 https://doi.org/10.1016/j.freeradbiomed.2017.07.030
  26. Chang TS, Jeong W, Woo HA, Lee SM, Park S and Rhee SG (2004) Characterization of mammalian sulfiredoxin and its reactivation of hyperoxidized peroxiredoxin through reduction of cysteine sulfinic acid in the active site to cysteine. J Biol Chem 279, 50994-51001 https://doi.org/10.1074/jbc.M409482200
  27. Kim H, Hyeon S, Kim H et al (2013) Dynein light chain LC8 inhibits osteoclast differentiation and prevents bone loss in mice. J Immunol 190, 1312-1318 https://doi.org/10.4049/jimmunol.1202525
  28. Jin SH, Kim H, Gu DR et al (2018) Actin-binding LIM protein 1 regulates receptor activator of NF-kappaB ligandmediated osteoclast differentiation and motility. BMB Rep 51, 356-361 https://doi.org/10.5483/BMBRep.2018.51.7.106
  29. Lee J, Son HS, Lee HI et al (2019) Skullcapflavone II inhibits osteoclastogenesis by regulating reactive oxygen species and attenuates the survival and resorption function of osteoclasts by modulating integrin signaling. FASEB J 33, 2026-2036 https://doi.org/10.1096/fj.201800866RR