Skip to main content
SpringerLink
Log in

Salvia plebeia R.Br. inhibits signal transduction of IL-6 and prevents ovariectomy-induced bone loss by suppressing osteoclastogenesis

  • Research Article
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

The interleukin-6 (IL-6) family of cytokines plays a key role in the pathogenesis of rheumatoid arthritis and osteoporosis through the regulation of bone formation and resorption. In this study, it was observed that ethanol extract of Salvia plebeia R.Br. (S.P-EE) inhibited IL-6-induced signaling cascade including phosphorylation of JAK2/STAT3 and ERK. Subsequently, it was examined whether S.P-EE treatment could recover bone loss in ovariectomized (OVX) mice. Indeed, S.P-EE exhibited both preventive and therapeutic effect on OVX-induced bone loss in trabecular microarchitecture along with significant increase in bone mineral density and content. To understand the mechanism of action of S.P-EE in bone metabolism, the effect of S.P-EE on osteoclast differentiation and activity was investigated. S.P-EE significantly inhibited RANKL-induced osteoclast differentiation by suppressing phosphorylation of MAPK and Akt, and expression of NFATc1 and osteoclast marker genes. S.P-EE also inhibited bone-resorbing activity of osteoclasts. Furthermore, isolation and identification of the active compounds which are responsible for the inhibitory effect of S.P-EE on osteoclast differentiation was carried out. Six major flavonoids and plebeiolide A–C were isolated and examined their effects on osteoclast differentiation. Luteolin and hispidulin, and plebeiolide A and C, not B exhibited potent inhibitory activity on RANKL-induced osteoclast formation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Banu J, Varela E, Fernandes G (2012) Alternative therapies for the prevention and treatment of osteoporosis. Nutr Rev 70:22–40

    Article  PubMed  Google Scholar 

  • Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337–342

    Article  CAS  PubMed  Google Scholar 

  • Chang JS, Lee SW, Kim MS, Yun BR, Park MH, Lee SG, Park SJ, Lee WS, Rho MC (2011) Manassantin A and B from Saururus chinensis inhibit interleukin-6-induced signal transducer and activator of transcription 3 activation in Hep3B cells. J Pharmacol Sci 115:84–88

    Article  CAS  PubMed  Google Scholar 

  • Choi JK, Oh HM, Lee S, Kwon TK, Shin TY, Rho MC, Kim SH (2014) Salvia plebeia suppresses atopic dermatitis-like skin lesions. Am J Chin Med 42:967–985

    Article  PubMed  Google Scholar 

  • Dai Y, Liu L, Xie G, Chen Y, Qin X, Wang Q, Li J, Qin M (2014) Four new eudesmane-type sesquiterpenes from the basal leaves of Salvia plebeia R.Br. Fitoterapia 94:142–147

    Article  CAS  PubMed  Google Scholar 

  • He L, Lee J, Jang JH, Lee SH, Nan MH, Oh BC, Lee SG, Kim HH, Soung NK, Ahn JS, Kim BY (2012) Ginsenoside Rh2 inhibits ostoclastogenesis through down-regulation of NF-κB, NFATc1 and c-Fos. Bone 50:1207–1213

    Article  CAS  PubMed  Google Scholar 

  • Heino TJ, Hentunen TA (2008) Differentiation of osteoblasts and osteocytes from mesenchymal stem cells. Curr Stem Cell Res Ther 3:131–145

    Article  CAS  PubMed  Google Scholar 

  • Hennigan S, Kavanaugh A (2008) Interleukin-6 inhibitors in the treatment of rheumatoid arthritis. Ther Clin Risk Manag 4:767–775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jin XF, Lu YH, Wei DZ, Wang ZT (2008) Chemical fingerprint and quantitative analysis of Salvia plebeia R.Br. by high-performance liquid chromatography. J Pharm Biomed Anal 48:100–104

    Article  CAS  PubMed  Google Scholar 

  • Kim MS, Day CJ, Morrison NA (2005) MCP-1 is induced by receptor activator of nuclear factor-κB ligand, promotes human osteoclast fusion, and rescues granulocyte macrophage colony-stimulating factor suppression of osteoclast formation. J Biol Chem 280:16163–16169

    Article  CAS  PubMed  Google Scholar 

  • Kim JH, Kim K, Youn BU, Jin HM, Kim JY, Moon JB, Ko A, Seo SB, Lee KY, Kim N (2011a) RANKL induces NFATc1 acetylation and stability via histone acetyltransferases during osteoclast differentiation. Biochem J 436:253–262

    Article  CAS  PubMed  Google Scholar 

  • Kim TH, Jung JW, Ha BG, Hong JM, Park EK, Kim HJ, Kim SY (2011b) The effects of luteolin on osteoclast differentiation, function in vitro and ovariectomy-induced bone loss. J Nutr Biochem 22:8–15

    Article  CAS  PubMed  Google Scholar 

  • Kim SD, Kim HN, Lee JH, Jin WJ, Hwang SJ, Kim HH, Ha H, Lee ZH (2013) Trapidil, a platelet-derived growth factor antagonist, inhibits osteoclastogenesis by down-regulating NFATc1 and suppresses bone loss in mice. Biochem Pharmacol 86:782–790

    Article  CAS  PubMed  Google Scholar 

  • Kim KW, Kim BM, Moon HW, Lee SH, Kim HR (2015) Role of C-reactive protein in osteoclastogenesis in rheumatoid arthritis. Arthritis Res Ther 17:41

    Article  PubMed  PubMed Central  Google Scholar 

  • Kudo O, Sabokbar A, Pocock A, Itonaga I, Fujikawa Y, Athanasou NA (2003) Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism. Bone 32:1–7

    Article  CAS  PubMed  Google Scholar 

  • Le Goff B, Blanchard F, Berthelot JM, Heymann D, Maugars Y (2010) Role for interleukin-6 in structural joint damage and systemic bone loss in rheumatoid arthritis. Joint Bone Spine 77:201–205

    Article  PubMed  Google Scholar 

  • Lee JW, Ahn JY, Hasegawa S, Cha BY, Yonezawa T, Nagai K, Seo HJ, Jeon WB, Woo JT (2009) Inhibitory effect of luteolin on osteoclast differentiation and function. Cytotechnology 61:125–134

    Article  CAS  PubMed  Google Scholar 

  • Leibbrandt A, Penninger JM (2008) RANK/RANKL: regulators of immune responses and bone physiology. Ann N Y Acad Sci 1143:123–150

    Article  CAS  PubMed  Google Scholar 

  • Léotoing L, Wauquier F, Guicheux J, Miot-Noirault E, Wittrant Y, Coxam V (2013) The polyphenol fisetin protects bone by repressing NF-κB and MKP-1-dependent signaling pathways in osteoclast. PLoS One 8:e68388

    Article  PubMed  PubMed Central  Google Scholar 

  • Li Y, Bäckesjö CM, Haldosén LA, Lindgren U (2008) IL-6 receptor expression and IL-6 effects change during osteoblast differentiation. Cytokine 43:165–173

    Article  CAS  PubMed  Google Scholar 

  • Li CH, Zhao JX, Sun L, Yao ZQ, Deng XL, Liu R, Liu XY (2013) AG490 inhibits NFATc1 expression and STAT3 activation during RANKL induced osteoclastogenesis. Biochem Biophys Res Commun 435:533–539

    Article  CAS  PubMed  Google Scholar 

  • Li S, Miller CH, Giannopoulou E, Hu X, Ivashkiv LB, Zhao B (2014) RBP-J imposes a requirement for ITAM-mediated costimulation of osteoclastogenesis. J Clin Invest 124:5057–5073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nepal M, Choi HJ, Choi BY, Yang MS, Chae JI, Li L, Soh Y (2013) Hispidulin attenuates bone resorption and osteoclastogenesis via the RANKL-induced NF-κB and NFATc1 pathways. Eur J Pharmacol 715:96–104

    Article  CAS  PubMed  Google Scholar 

  • O’Brien CA, Gubrij I, Lin SC, Saylors RL, Manolagas SC (1999) STAT3 activation in stromal/osteoblastic cells is required for induction of the receptor activator of NF-κB ligand and stimulation of osteoclastogenesis by gp130-utilizing cytokines or interleukin-1 but not 1,25-dihydroxyvitamin D3 or parathyroid hormone. J Biol Chem 274:19301–19308

    Article  PubMed  Google Scholar 

  • Oh HM, Lee SW, Yun BR, Hwang BS, Kim SN, Park CS, Jeoung SH, Kim HK, Lee WS, Rho MC (2014) Vigna angularis inhibits IL-6-induced cellular signalling and ameliorates collagen-induced arthritis. Rheumatology (Oxford) 53:56–64

    Article  CAS  Google Scholar 

  • Putnam SE, Scutt AM, Bicknell K, Priestley CM, Williamson EM (2007) Natural products as alternative treatments for metabolic bone disorders and for maintenance of bone health. Phytother Res 21:99–112

    Article  PubMed  Google Scholar 

  • Seibel MJ (2005) Biochemical markers of bone turnover: part I: biochemistry and variability. Clin Biochem Rev 26:97–122

    PubMed  PubMed Central  Google Scholar 

  • Shinohara M, Chang BY, Buggy JJ, Nagai Y, Kodama T, Asahara H, Takayanagi H (2014) The orally available Btk inhibitor ibrutinib (PCI-32765) protects against osteoclast-mediated bone loss. Bone 60:8–15

    Article  CAS  PubMed  Google Scholar 

  • Sims NA, Jenkins BJ, Quinn JM, Nakamura A, Glatt M, Gillespie MT, Ernst M, Martin TJ (2004) Glycoprotein 130 regulates bone turnover and bone size by distinct downstream signaling pathways. J Clin Invest 113:379–389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Saiura A, Isobe M, Yokochi T, Inoue J, Wagner EF, Mak TW, Kodama T, Taniguchi T (2002) Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 3:889–901

    Article  CAS  PubMed  Google Scholar 

  • Wada T, Nakashima T, Hiroshi N, Penninger JM (2006) RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med 12:17–25

    Article  CAS  PubMed  Google Scholar 

  • Wong PK, Campbell IK, Egan PJ, Ernst M, Wicks IP (2003) The role of the interleukin-6 family of cytokines in inflammatory arthritis and bone turnover. Arthritis Rheum 48:1177–1189

    Article  CAS  PubMed  Google Scholar 

  • Yoshitake F, Itoh S, Narita H, Ishihara K, Ebisu S (2008) Interleukin-6 directly inhibits osteoclast differentiation by suppressing receptor activator of NF-κB signaling pathways. J Biol Chem 283:11535–11540

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Ministry of Agriculture, Food and Rural Affairs (MAFRA) through Agri-Bio industry Technology Development Program and a KRIBB Research Initiative Program.

Author information

Authors and Affiliations

  1. Natural Product Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 1404 Sinjeong-dong, Jeongeup-si, Jeonbuk, 580-185, Republic of Korea

    Mi-Hwa Kim, Kyungsook Jung, Hyun-Jae Jang, Seung Woong Lee, Yesol Kim, Chan Sun Park, Mun-Chual Rho & Hyun-Mee Oh

  2. Interdisciplinary Graduate Program in Molecular Medicine, Chonnam National University, Gwangju, 501-746, Republic of Korea

    Mi-Hwa Kim & Tae-Hoon Lee

  3. Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang-eup, Cheongwon-gun, Chungbuk, 36-883, Republic of Korea

    Ki-Hoan Nam

  4. Department of Oral Biochemistry, Dental Science Research Institute, Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, 500-757, Republic of Korea

    Tae-Hoon Lee

  5. R&D Center, Korean Drug Co., Ltd., Seoul, 135-270, Republic of Korea

    Jee Hun Park & Jung Ho Choi

Authors
  1. Mi-Hwa Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kyungsook Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ki-Hoan Nam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hyun-Jae Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Seung Woong Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yesol Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chan Sun Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tae-Hoon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jee Hun Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jung Ho Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Mun-Chual Rho
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hyun-Mee Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Mun-Chual Rho or Hyun-Mee Oh.

Ethics declarations

Conflict of interest

The authors have declared no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, MH., Jung, K., Nam, KH. et al. Salvia plebeia R.Br. inhibits signal transduction of IL-6 and prevents ovariectomy-induced bone loss by suppressing osteoclastogenesis. Arch. Pharm. Res. 39, 1671–1681 (2016). https://doi.org/10.1007/s12272-016-0810-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-016-0810-0

Keywords

Search

Navigation