Skip to main content
Top
Published in: BMC Complementary Medicine and Therapies 1/2018

Open Access 01-12-2018 | Research article

Inhibition of RANKL-stimulated osteoclast differentiation by Schisandra chinensis through down-regulation of NFATc1 and c-fos expression

Authors: Eun-Jung Kim, Haesu Lee, Mi Hye Kim, Woong Mo Yang

Published in: BMC Complementary Medicine and Therapies | Issue 1/2018

Login to get access

Abstract

Background

Schisandra chinenesis (SC) has been reported to have ameliorative effect on osteoporosis. However, the mechanisms underlying the anti-osteoporosis activity of SC have not been clearly elucidated. In the present study, we determined the effects of SC on The receptor activator of NF-kB ligand (RANKL)-induced osteoclastogenesis and its potential mechanism.

Methods

Raw 264.7 cells were treated with 0.6, 6 and 60 μg/mL SC in the presence of 100 ng/mL RANKL for 7 days. RANKL-induced osteoclast formation was analyzed by tartrate resistant acid phosphatase (TRAP) staining. The osteoclast differentiation-related factors were confirmed along with TNF-α.

Results

SC inhibits the RANKL-induced osteoclast differentiation in dose-dependent manner within non-toxic concentrations. The supernatant concentrations of TNF-α were significantly decreased by SC treatment. In addition, osteoclastogenesis-related factors, TRAP6 and NF-κB, were markedly decreased by SC in RANKL-induced osteoclasts. Mechanistically, SC reduced the RANKL-triggered NFATc1 and c-fos expressions.

Conclusions

Taken together, our data suggest that SC can modulate bone metabolism by suppressing RANKL-induced osteoclast differentiation.
Appendix
Available only for authorised users
Literature
1.
go back to reference Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423(6937):337–42.CrossRef Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423(6937):337–42.CrossRef
2.
go back to reference Gruber H, Ivey J, Thompson E, Chesnut C 3rd, Baylink D. Osteoblast and osteoclast cell number and cell activity in postmenopausal osteoporosis. Miner Electrol Metab. 1985;12(4):246–54. Gruber H, Ivey J, Thompson E, Chesnut C 3rd, Baylink D. Osteoblast and osteoclast cell number and cell activity in postmenopausal osteoporosis. Miner Electrol Metab. 1985;12(4):246–54.
3.
go back to reference Roato I, Grano M, Brunetti G, Colucci S, Mussa A, Bertetto O, Ferracini R. Mechanisms of spontaneous osteoclastogenesis in cancer with bone involvement. FASEB J. 2005;19(2):228–30.CrossRef Roato I, Grano M, Brunetti G, Colucci S, Mussa A, Bertetto O, Ferracini R. Mechanisms of spontaneous osteoclastogenesis in cancer with bone involvement. FASEB J. 2005;19(2):228–30.CrossRef
4.
go back to reference Sakellari D, Menti S, Konstantinidis A. Free soluble receptor activator of nuclear factor-κb ligand in gingival crevicular fluid correlates with distinct pathogens in periodontitis patients. J Clin Periodontol. 2008;35(11):938–43.CrossRef Sakellari D, Menti S, Konstantinidis A. Free soluble receptor activator of nuclear factor-κb ligand in gingival crevicular fluid correlates with distinct pathogens in periodontitis patients. J Clin Periodontol. 2008;35(11):938–43.CrossRef
5.
go back to reference Neale S, Smith R, Wass J, Athanasou N. Osteoclast differentiation from circulating mononuclear precursors in Paget’s disease is hypersensitive to 1, 25-dihydroxyvitamin D 3 and RANKL. Bone. 2000;27(3):409–16.CrossRef Neale S, Smith R, Wass J, Athanasou N. Osteoclast differentiation from circulating mononuclear precursors in Paget’s disease is hypersensitive to 1, 25-dihydroxyvitamin D 3 and RANKL. Bone. 2000;27(3):409–16.CrossRef
6.
go back to reference Hirayama T, Danks L, Sabokbar A, Athanasou N. Osteoclast formation and activity in the pathogenesis of osteoporosis in rheumatoid arthritis. Rheumatology. 2002;41(11):1232–9.CrossRef Hirayama T, Danks L, Sabokbar A, Athanasou N. Osteoclast formation and activity in the pathogenesis of osteoporosis in rheumatoid arthritis. Rheumatology. 2002;41(11):1232–9.CrossRef
7.
go back to reference Arai F, Miyamoto T, Ohneda O, Inada T, Sudo T, Brasel K, Miyata T, Anderson DM, Suda T. Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor κB (RANK) receptors. J Exp Med. 1999;190(12):1741–54.CrossRef Arai F, Miyamoto T, Ohneda O, Inada T, Sudo T, Brasel K, Miyata T, Anderson DM, Suda T. Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor κB (RANK) receptors. J Exp Med. 1999;190(12):1741–54.CrossRef
8.
go back to reference Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell. 2002;2(4):389–406.CrossRef Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell. 2002;2(4):389–406.CrossRef
9.
go back to reference Wong BR, Josien R, Lee SY, Vologodskaia M, Steinman RM, Choi Y. The TRAF family of signal transducers mediates NF-κB activation by the TRANCE receptor. J Biol Chem. 1998;273(43):28355–9.CrossRef Wong BR, Josien R, Lee SY, Vologodskaia M, Steinman RM, Choi Y. The TRAF family of signal transducers mediates NF-κB activation by the TRANCE receptor. J Biol Chem. 1998;273(43):28355–9.CrossRef
10.
go back to reference Suda T, Nakamura I, Jimi E, Takahashi N. Regulation of osteoclast function. J Bone Miner Res. 1997;12(6):869–79.CrossRef Suda T, Nakamura I, Jimi E, Takahashi N. Regulation of osteoclast function. J Bone Miner Res. 1997;12(6):869–79.CrossRef
11.
go back to reference Lacey D, Timms E, Tan H-L, Kelley M, Dunstan C, Burgess T, Elliott R, Colombero A, Elliott G, Scully S. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998;93(2):165–76.CrossRef Lacey D, Timms E, Tan H-L, Kelley M, Dunstan C, Burgess T, Elliott R, Colombero A, Elliott G, Scully S. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998;93(2):165–76.CrossRef
12.
go back to reference Aoki K, Saito H, Itzstein C, Ishiguro M, Shibata T, Blanque R, Mian AH, Takahashi M, Suzuki Y, Yoshimatsu M. A TNF receptor loop peptide mimic blocks RANK ligand–induced signaling, bone resorption, and bone loss. J Clin Invest. 2006;116(6):1525–34.CrossRef Aoki K, Saito H, Itzstein C, Ishiguro M, Shibata T, Blanque R, Mian AH, Takahashi M, Suzuki Y, Yoshimatsu M. A TNF receptor loop peptide mimic blocks RANK ligand–induced signaling, bone resorption, and bone loss. J Clin Invest. 2006;116(6):1525–34.CrossRef
13.
go back to reference Chae H-S, Kang O-H, Oh Y-C, Choi J-G, Keum J-H, Kim S-B, Kim Y-S, Mun S-H, Shin D-W, Han S-H. Gomisin N has anti-allergic effect and inhibits inflammatory cytokine expression in mouse bone marrow-derived mast cells. Immunopharm Immunot. 2011;33(4):709–13.CrossRef Chae H-S, Kang O-H, Oh Y-C, Choi J-G, Keum J-H, Kim S-B, Kim Y-S, Mun S-H, Shin D-W, Han S-H. Gomisin N has anti-allergic effect and inhibits inflammatory cytokine expression in mouse bone marrow-derived mast cells. Immunopharm Immunot. 2011;33(4):709–13.CrossRef
14.
go back to reference Szopa A, Ekiert R, Ekiert H. Current knowledge of Schisandra chinensis (Turcz.) Baill. (Chinese magnolia vine) as a medicinal plant species: a review on the bioactive components, pharmacological properties, analytical and biotechnological studies. Phytochem Rev: Pr Phyt Soc. 2017;16(2):195–218.CrossRef Szopa A, Ekiert R, Ekiert H. Current knowledge of Schisandra chinensis (Turcz.) Baill. (Chinese magnolia vine) as a medicinal plant species: a review on the bioactive components, pharmacological properties, analytical and biotechnological studies. Phytochem Rev: Pr Phyt Soc. 2017;16(2):195–218.CrossRef
15.
go back to reference Nakajima K, Taguchi H, Ikeya Y, Endo T, Yosioka I. Constituents of Schizandra chinensis Baill. XIII. Quantitative analysis of lignans in the fruits of Schizandra chinensis Baill. By high performance liquid chromatography. Yakugaku Zasshi. 1983;103(7):743.CrossRef Nakajima K, Taguchi H, Ikeya Y, Endo T, Yosioka I. Constituents of Schizandra chinensis Baill. XIII. Quantitative analysis of lignans in the fruits of Schizandra chinensis Baill. By high performance liquid chromatography. Yakugaku Zasshi. 1983;103(7):743.CrossRef
16.
go back to reference Caichompoo W, Zhang QY, Hou TT, Gao HJ, Qin LP, Zhou XJ. Optimization of extraction and purification of active fractions from Schisandra chinensis (Turcz.) and its osteoblastic proliferation stimulating activity. Phytother Res. 2009;23(2):289–92.CrossRef Caichompoo W, Zhang QY, Hou TT, Gao HJ, Qin LP, Zhou XJ. Optimization of extraction and purification of active fractions from Schisandra chinensis (Turcz.) and its osteoblastic proliferation stimulating activity. Phytother Res. 2009;23(2):289–92.CrossRef
17.
go back to reference Kim MH, Choi YY, Han JM, H-S L, Hong SB, S-G L, Yang WM. Ameliorative effects of Schizandra chinensis on osteoporosis via activation of estrogen receptor (ER)-α/−β. Food Funct. 2014;5(7):1594–601.CrossRef Kim MH, Choi YY, Han JM, H-S L, Hong SB, S-G L, Yang WM. Ameliorative effects of Schizandra chinensis on osteoporosis via activation of estrogen receptor (ER)-α/−β. Food Funct. 2014;5(7):1594–601.CrossRef
18.
go back to reference Kang Y-S, Han M-H, Hong S-H, Park C, Hwang H-J, Kim BW, Kyoung KH, Young Whan Choi CMK, Choi YH. Anti-inflammatory effects of Schisandra chinensis (Turcz.) Baill fruit through the inactivation of nuclear factor-κB and mitogen-activated protein kinases signaling pathways in lipopolysaccharide-stimulated murine macrophages. J Cancer Prev. 2014;19(4):279–87.CrossRef Kang Y-S, Han M-H, Hong S-H, Park C, Hwang H-J, Kim BW, Kyoung KH, Young Whan Choi CMK, Choi YH. Anti-inflammatory effects of Schisandra chinensis (Turcz.) Baill fruit through the inactivation of nuclear factor-κB and mitogen-activated protein kinases signaling pathways in lipopolysaccharide-stimulated murine macrophages. J Cancer Prev. 2014;19(4):279–87.CrossRef
19.
go back to reference Guo LY, Hung TM, Bae KH, Shin EM, Zhou HY, Hong YN, Kang SS, Kim HP, Kim YS. Anti-inflammatory effects of schisandrin isolated from the fruit of Schisandra chinensis Baill. Eur J Pharmacol. 2008;591(1):293–9.CrossRef Guo LY, Hung TM, Bae KH, Shin EM, Zhou HY, Hong YN, Kang SS, Kim HP, Kim YS. Anti-inflammatory effects of schisandrin isolated from the fruit of Schisandra chinensis Baill. Eur J Pharmacol. 2008;591(1):293–9.CrossRef
20.
go back to reference Oh S-Y, Kim YH, Bae DS, Um BH, Pan C-H, Kim CY, Lee HJ, Lee JK. Anti-inflammatory effects of gomisin N, gomisin J, and schisandrin C isolated from the fruit of Schisandra chinensis. Biosci Biotechnol Biochem. 2010;74(2):285–91.CrossRef Oh S-Y, Kim YH, Bae DS, Um BH, Pan C-H, Kim CY, Lee HJ, Lee JK. Anti-inflammatory effects of gomisin N, gomisin J, and schisandrin C isolated from the fruit of Schisandra chinensis. Biosci Biotechnol Biochem. 2010;74(2):285–91.CrossRef
21.
go back to reference He Y, Zhang Q, Shen Y, Chen X, Zhou F, Peng D. Schisantherin a suppresses osteoclast formation and wear particle-induced osteolysis via modulating RANKL signaling pathways. Biochem Bioph Res Co. 2014;449(3):344–50.CrossRef He Y, Zhang Q, Shen Y, Chen X, Zhou F, Peng D. Schisantherin a suppresses osteoclast formation and wear particle-induced osteolysis via modulating RANKL signaling pathways. Biochem Bioph Res Co. 2014;449(3):344–50.CrossRef
22.
go back to reference Lu Y, Chen D-F. Analysis of Schisandra chinensis and Schisandra sphenanthera. J Chromatogr. 2009;1216(11):1980–90.CrossRef Lu Y, Chen D-F. Analysis of Schisandra chinensis and Schisandra sphenanthera. J Chromatogr. 2009;1216(11):1980–90.CrossRef
23.
go back to reference Teitelbaum SL. Bone resorption by osteoclasts. Science. 2000;289(5484):1504–8.CrossRef Teitelbaum SL. Bone resorption by osteoclasts. Science. 2000;289(5484):1504–8.CrossRef
24.
go back to reference Zou W, Hakim I, Tschoep K, Endres S, Bar-Shavit Z. Tumor necrosis factor-α mediates RANK ligand stimulation of osteoclast differentiation by an autocrine mechanism. J Cell Biochem. 2001;83(1):70–83.CrossRef Zou W, Hakim I, Tschoep K, Endres S, Bar-Shavit Z. Tumor necrosis factor-α mediates RANK ligand stimulation of osteoclast differentiation by an autocrine mechanism. J Cell Biochem. 2001;83(1):70–83.CrossRef
25.
go back to reference Yamashita T, Yao Z, Li F, Zhang Q, Badell IR, Schwarz EM, Takeshita S, Wagner EF, Noda M, Matsuo K. NF-κB p50 and p52 regulate receptor activator of NF-κB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1. J Biol Chem. 2007;282(25):18245–53.CrossRef Yamashita T, Yao Z, Li F, Zhang Q, Badell IR, Schwarz EM, Takeshita S, Wagner EF, Noda M, Matsuo K. NF-κB p50 and p52 regulate receptor activator of NF-κB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1. J Biol Chem. 2007;282(25):18245–53.CrossRef
26.
go back to reference Mizukami J, Takaesu G, Akatsuka H, Sakurai H, Ninomiya-Tsuji J, Matsumoto K, Sakurai N. Receptor activator of NF-κB ligand (RANKL) activates TAK1 mitogen-activated protein kinase kinase kinase through a signaling complex containing RANK, TAB2, and TRAF6. Mol Cell Biol. 2002;22(4):992–1000.CrossRef Mizukami J, Takaesu G, Akatsuka H, Sakurai H, Ninomiya-Tsuji J, Matsumoto K, Sakurai N. Receptor activator of NF-κB ligand (RANKL) activates TAK1 mitogen-activated protein kinase kinase kinase through a signaling complex containing RANK, TAB2, and TRAF6. Mol Cell Biol. 2002;22(4):992–1000.CrossRef
27.
go back to reference Leibbrandt A, Penninger JM. RANK/RANKL: regulators of immune responses and bone physiology. Ann N Y Acad Sci. 2008;1143(1):123–50.CrossRef Leibbrandt A, Penninger JM. RANK/RANKL: regulators of immune responses and bone physiology. Ann N Y Acad Sci. 2008;1143(1):123–50.CrossRef
28.
go back to reference Kaji K, Katogi R, Azuma Y, Naito A, Inoue JI, Kudo A. Tumor necrosis factor α-induced Osteoclastogenesis requires tumor necrosis factor receptor-associated factor 6. J Bone Miner Res. 2001;16(9):1593–9.CrossRef Kaji K, Katogi R, Azuma Y, Naito A, Inoue JI, Kudo A. Tumor necrosis factor α-induced Osteoclastogenesis requires tumor necrosis factor receptor-associated factor 6. J Bone Miner Res. 2001;16(9):1593–9.CrossRef
29.
go back to reference Franzoso G, Carlson L, Xing L, Poljak L, Shores EW, Brown KD, Leonardi A, Tran T, Boyce BF, Siebenlist U. Requirement for NF-κB in osteoclast and B-cell development. Genes Dev. 1997;11(24):3482–96.CrossRef Franzoso G, Carlson L, Xing L, Poljak L, Shores EW, Brown KD, Leonardi A, Tran T, Boyce BF, Siebenlist U. Requirement for NF-κB in osteoclast and B-cell development. Genes Dev. 1997;11(24):3482–96.CrossRef
30.
go back to reference Lee ZH, Kim H-H. Signal transduction by receptor activator of nuclear factor kappa B in osteoclasts. Biochem Bioph Res Co. 2003;305(2):211–4.CrossRef Lee ZH, Kim H-H. Signal transduction by receptor activator of nuclear factor kappa B in osteoclasts. Biochem Bioph Res Co. 2003;305(2):211–4.CrossRef
31.
go back to reference Bruzzaniti A, Baron R. Molecular regulation of osteoclast activity. Rev Endocr Metab Disord. 2006;7(1–2):123–39.PubMed Bruzzaniti A, Baron R. Molecular regulation of osteoclast activity. Rev Endocr Metab Disord. 2006;7(1–2):123–39.PubMed
32.
go back to reference Matsumoto M, Sudo T, Saito T, Osada H, Tsujimoto M. Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-κB ligand (RANKL). J Biol Chem. 2000;275(40):31155–61.CrossRef Matsumoto M, Sudo T, Saito T, Osada H, Tsujimoto M. Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-κB ligand (RANKL). J Biol Chem. 2000;275(40):31155–61.CrossRef
33.
go back to reference Lee J-H, Jin H, Shim H-E, Kim H-N, Ha H, Lee ZH. Epigallocatechin-3-gallate inhibits osteoclastogenesis by down-regulating c-Fos expression and suppressing the nuclear factor-κB signal. Mol Pharmacol. 2010;77(1):17–25.CrossRef Lee J-H, Jin H, Shim H-E, Kim H-N, Ha H, Lee ZH. Epigallocatechin-3-gallate inhibits osteoclastogenesis by down-regulating c-Fos expression and suppressing the nuclear factor-κB signal. Mol Pharmacol. 2010;77(1):17–25.CrossRef
34.
go back to reference David J-P, Sabapathy K, Hoffmann O, Idarraga MH, Wagner EF. JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation-dependent and-independent mechanisms. J Cell Sci. 2002;115(22):4317–25.CrossRef David J-P, Sabapathy K, Hoffmann O, Idarraga MH, Wagner EF. JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation-dependent and-independent mechanisms. J Cell Sci. 2002;115(22):4317–25.CrossRef
35.
go back to reference Grigoriadis AE, Wang Z-Q, Cecchini MG, Hofstetter W, Felix R, Fleisch HA, Wagner EF. C-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science. 1994;266(5184):443–9.CrossRef Grigoriadis AE, Wang Z-Q, Cecchini MG, Hofstetter W, Felix R, Fleisch HA, Wagner EF. C-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science. 1994;266(5184):443–9.CrossRef
36.
go back to reference Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Saiura A, Isobe M, Yokochi T, J-I I. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 2002;3(6):889–901.CrossRef Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Saiura A, Isobe M, Yokochi T, J-I I. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 2002;3(6):889–901.CrossRef
37.
go back to reference Kim JH, Kim N. Regulation of NFATc1 in osteoclast differentiation. J Bone Metab. 2014;21(4):233–41.CrossRef Kim JH, Kim N. Regulation of NFATc1 in osteoclast differentiation. J Bone Metab. 2014;21(4):233–41.CrossRef
38.
go back to reference Asagiri M, Sato K, Usami T, Ochi S, Nishina H, Yoshida H, Morita I, Wagner EF, Mak TW, Serfling E. Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med. 2005;202(9):1261–9.CrossRef Asagiri M, Sato K, Usami T, Ochi S, Nishina H, Yoshida H, Morita I, Wagner EF, Mak TW, Serfling E. Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med. 2005;202(9):1261–9.CrossRef
39.
go back to reference Takayanagi H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol. 2007;7(4):292–304.CrossRef Takayanagi H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol. 2007;7(4):292–304.CrossRef
40.
go back to reference Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet. 2003;4(8):638–49.CrossRef Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet. 2003;4(8):638–49.CrossRef
41.
go back to reference Sato K, Suematsu A, Nakashima T, Takemoto-Kimura S, Aoki K, Morishita Y, Asahara H, Ohya K, Yamaguchi A, Takai T. Regulation of osteoclast differentiation and function by the CaMK-CREB pathway. Nat Med. 2006;12(12):1410–6.CrossRef Sato K, Suematsu A, Nakashima T, Takemoto-Kimura S, Aoki K, Morishita Y, Asahara H, Ohya K, Yamaguchi A, Takai T. Regulation of osteoclast differentiation and function by the CaMK-CREB pathway. Nat Med. 2006;12(12):1410–6.CrossRef
Metadata
Title
Inhibition of RANKL-stimulated osteoclast differentiation by Schisandra chinensis through down-regulation of NFATc1 and c-fos expression
Authors
Eun-Jung Kim
Haesu Lee
Mi Hye Kim
Woong Mo Yang
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2018
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-018-2331-5

Other articles of this Issue 1/2018

BMC Complementary Medicine and Therapies 1/2018 Go to the issue