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Yangonin treats inflammatory osteoporosis by inhibiting the secretion of inflammatory factors and RANKL expression

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Inflammopharmacology Aims and scope Submit manuscript

Abstract

Objectives

As the main cause of osteoporosis, abnormal activity of osteoclasts could disrupt the balance between bone resorption and formation. Moreover, up-regulation of nuclear factor-kappa ligand (RANKL) expression by chronic inflammation-mediated inflammatory factors might contribute to the differentiation of osteoclast precursor cells. Therefore, an anti-inflammatory agent named yangonin was presented for inhibiting osteoclast and relieving inflammatory osteoporosis through down-regulating inflammatory factors.

Methods

We established a model of macrophage inflammation and then verified the anti-inflammatory effect of yangonin. The inhibitory effect of yangonin on osteoclasts was detected by tartrate-resistant acid phosphatase (TRAP) staining, Western blotting and quantitative real-time PCR (qRT-PCR). Finally, micro-CT, TRAP and hematoxylin–eosin (HE) staining were used to show the effect of yangonin on inflammatory osteoporosis in vivo.

Results

Our results suggested that yangonin was able to reduce the secretion of inflammatory factors, down-regulate osteoclast-related genes such as TRAP, RANKL, cathepsin K (CTSK) and nuclear factor-activated T-cell 1 (NFATc1). Furthermore, it was demonstrated that yangonin could suppress the function of inflammatory cytokines in osteoclast differentiation and reporting, wherein NF-κB, AKT and downstream c-Fos/NFATc1 signaling pathways were involved. In an in vivo study, we implied that yangonin has a relieving effect on inflammatory osteoporosis.

Conclusion

Our research shows that yangonin down-regulates inflammatory factors and inhibits the bone-breaking effect of inflammation through NF-κB, AKT and downstream c-Fos/NFATc1 signaling pathways to achieve the purpose of treating inflammatory osteoporosis.

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Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.

Abbreviations

RANKL:

Receptor activator of nuclear factor-kappa ligand

LPS:

Lipopolysaccharide

CM:

Conditional medium

HE:

Hematoxylin–eosin

TRAP:

Tartrate-resistant acid phosphatase

CTSK:

Cathepsin K

NFATc1:

Nuclear factor-activated T-cell 1

M-CSF:

Macrophage colony stimulation factor

TRAF6:

Tumor necrosis factor receptor-associated factor 6

TNF-α:

Tumor necrosis factor-α

BMDM:

Bone marrow-derived macrophages/monocytes

RIPA:

Radio-immunoprecipitation assay buffer

PMSF:

Phenylmethanesulfonyl fluoride

References

  • Alizada A, Khyzha N, Wang L, Antounians L, Chen X, Khor M et al (2021) Conserved regulatory logic at accessible and inaccessible chromatin during the acute inflammatory response in mammals. Nat Commun 12(1):567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Asagiri M, Takayanagi H (2007) The molecular understanding of osteoclast differentiation. Bone 40(2):251–264

    Article  CAS  PubMed  Google Scholar 

  • Black DM, Rosen CJ (2016) Clinical practice. Postmenop Osteop. N Engl J Med 374(3):254–262

    Article  CAS  PubMed  Google Scholar 

  • Botto S, Streblow DN, De Filippis V, White L, Kreklywich CN, Smith PP et al (2011) IL-6 in human cytomegalovirus secretome promotes angiogenesis and survival of endothelial cells through the stimulation of survivin. Blood 117(1):352–361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cao JJ, Gregoire BR, Shen C-L (2017) A high-fat diet decreases bone mass in growing mice with systemic chronic inflammation induced by low-dose. Slow-release lipopolysaccharide pellets. J Nutr 147(10):1909–1916

    Article  CAS  PubMed  Google Scholar 

  • Dinarello CA (2019) The IL-1 family of cytokines and receptors in rheumatic diseases. Nat Rev Rheumatol 15(10):612–632

    Article  CAS  PubMed  Google Scholar 

  • Dong R, Yang X, Wang C, Liu K, Liu Z, Ma X et al (2019) Yangonin protects against non-alcoholic fatty liver disease through farnesoid X receptor. Phytomedicine 53:134–142

    Article  CAS  PubMed  Google Scholar 

  • Folmer F, Blasius R, Morceau F, Tabudravu J, Dicato M, Jaspars M et al (2006) Inhibition of TNFalpha-induced activation of nuclear factor kappaB by kava (Piper methysticum) derivatives. Biochem Pharmacol 71(8):1206–1218

    Article  CAS  PubMed  Google Scholar 

  • Hirano T (2010) Interleukin 6 in autoimmune and inflammatory diseases: a personal memoir. Proc Jpn Acad Ser B Phys Biol Sci 86(7):717–730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Boyle WJ, Riggs BL (2000) The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res 15(1).

  • Ishida N, Hayashi K, Hoshijima M, Ogawa T, Koga S, Miyatake Y et al (2002) Large scale gene expression analysis of osteoclastogenesis in vitro and elucidation of NFAT2 as a key regulator. J Biol Chem 277(43):41147–41156

    Article  CAS  PubMed  Google Scholar 

  • Kim S-H, Kim K-J, Kang HJ, Son Y-J, Choi S-W, Lee M-J (2018) The dual role of oat bran water extract in bone homeostasis through the regulation of osteoclastogenesis and osteoblast differentiation. Molecules 23(12).

  • Kim J-M, Lin C, Stavre Z, Greenblatt MB, Shim J-H (2020) Osteoblast-Osteoclast Communication and Bone Homeostasis. Cells 9(9).

  • Kong Y, Gao X, Wang C, Ning C, Liu K, Liu Z et al (2018) Protective effects of yangonin from an edible botanical Kava against lithocholic acid-induced cholestasis and hepatotoxicity. Eur J Pharmacol 824:64–71

    Article  CAS  PubMed  Google Scholar 

  • Lee SE, Woo KM, Kim SY, Kim HM, Kwack K, Lee ZH et al (2002) The phosphatidylinositol 3-kinase, p38, and extracellular signal-regulated kinase pathways are involved in osteoclast differentiation. Bone 30(1):71–77

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Li Z, Hou H, Zhuang Y, Sun L (2018) Metal chelating, inhibitory DNA damage, and anti-inflammatory activities of phenolics from rambutan (Nephelium lappaceum) Peel and the Quantifications of Geraniin and Corilagin. Molecules 23(9):2263

    Article  PubMed Central  Google Scholar 

  • Li Z, Zhu X, Xu R, Wang Y, Hu R, Xu W (2019) Deacylcynaropicrin Inhibits RANKL-Induced Osteoclastogenesis by Inhibiting NF-κB and MAPK and Promoting M2 Polarization of Macrophages. Front Pharmacol 10:599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Y, Wang Z, Ma C, Wei Z, Chen K, Wang C et al (2020) Dracorhodin perchlorate inhibits osteoclastogenesis through repressing RANKL-stimulated NFATc1 activity. J Cell Mol Med 24(6):3303–3313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454(7203):428–435

    Article  CAS  PubMed  Google Scholar 

  • Michalski MN, McCauley LK (2017) Macrophages and skeletal health. Pharmacol Ther 174:43–54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Minoshima M, Kikuta J, Omori Y, Seno S, Suehara R, Maeda H et al (2019) Multicolor imaging with fluorescent probes revealed the dynamics and function of osteoclast proton pumps. ACS Cent Sci 5(6):1059–1066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Napimoga MH, Dantas Formiga WD, Abdalla HB, Trindade-da-Silva CA, Venturin CM, Martinez EF et al (2020) Secreted osteoclastogenic factor of activated T cells (SOFAT) is associated with rheumatoid arthritis and joint pain: initial evidences of a new pathway. Front Immunol 11:1442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nickoloff BJ, Ben-Neriah Y, Pikarsky E (2005) Inflammation and cancer: is the link as simple as we think? J Invest Dermatol. https://doi.org/10.1111/j.0022-202X.2005.23724.x

    Article  PubMed  PubMed Central  Google Scholar 

  • Park K-R, Kim E-C, Hong JT, Yun H-M (2018) Dysregulation of 5-hydroxytryptamine 6 receptor accelerates maturation of bone-resorbing osteoclasts and induces bone loss. Theranostics 8(11):3087–3098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qu X, Tang Y, Hua S (2018) Immunological approaches towards cancer and inflammation: a cross talk. Front Immunol 9:563

    Article  PubMed  PubMed Central  Google Scholar 

  • Rivers-Auty J, Daniels MJD, Colliver I, Robertson DL, Brough D (2018) Redefining the ancestral origins of the interleukin-1 superfamily. Nat Commun 9(1):1156

    Article  PubMed  PubMed Central  Google Scholar 

  • Saylor PJ, Lee RJ, Smith MR (2011) Emerging therapies to prevent skeletal morbidity in men with prostate cancer. J Clin Oncol 29(27):3705–3714

    Article  PubMed  PubMed Central  Google Scholar 

  • Sinder BP, Pettit AR, McCauley LK (2015) Macrophages: their emerging roles in bone. J Bone Miner Res 30(12):2140–2149

    Article  PubMed  Google Scholar 

  • Smith BJ, Lerner MR, Bu SY, Lucas EA, Hanas JS, Lightfoot SA et al (2006) Systemic bone loss and induction of coronary vessel disease in a rat model of chronic inflammation. Bone 38(3):378–386

    Article  CAS  PubMed  Google Scholar 

  • Sun X, Wang Y, Zhang M, Wang Q (2019) Intraarticular injection of dexamethasone promotes bone erosion in collagen-induced arthritis in mice through up-regulation of RANKL expression. Inflammopharmacology 27(3):503–509

    Article  CAS  PubMed  Google Scholar 

  • Talaat RM, Sidek A, Mosalem A, Kholief A (2015) Effect of bisphosphonates treatment on cytokine imbalance between TH17 and Treg in osteoporosis. Inflammopharmacology 23(2–3):119–125

    Article  CAS  PubMed  Google Scholar 

  • Tanaka T, Narazaki M, Kishimoto T (2014) IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 6(10):a016295

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang J, Wu X, Duan Y (2018) Magnesium lithospermate B protects against lipopolysaccharide-induced bone loss by inhibiting RANKL/RANK pathway. Front Pharmacol 9:64

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang X, Fu T, Wang J, Wang C, Liu K, Wu J et al (2019) Hepatoprotection of yangonin against hepatic fibrosis in mice via farnesoid X receptor activation. Int Immunopharmacol 75:105833

    Article  CAS  PubMed  Google Scholar 

  • Wei W, Wang X, Yang M, Smith LC, Dechow PC, Sonoda J et al (2010) PGC1beta mediates PPARgamma activation of osteoclastogenesis and rosiglitazone-induced bone loss. Cell Metab 11(6):503–516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Won H, Nandakumar V, Yates P, Sanchez S, Jones L, Huang XF et al (2014) Epigenetic control of dendritic cell development and fate determination of common myeloid progenitor by Mysm1. Blood 124(17):2647–2656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiong J, Cawley K, Piemontese M, Fujiwara Y, Zhao H, Goellner JJ et al (2018) Soluble RANKL contributes to osteoclast formation in adult mice but not ovariectomy-induced bone loss. Nat Commun 9(1):2909

    Article  PubMed  PubMed Central  Google Scholar 

  • Yan H, Shao D, Lao Y-H, Li M, Hu H, Leong KW (2019) Engineering cell membrane-based nanotherapeutics to target inflammation. Adv Sci (Weinh) 6(15):1900605

    Article  PubMed Central  Google Scholar 

  • Yao F, Xue Q, Li K, Cao X, Sun L, 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(12):2951

    Article  CAS  PubMed Central  Google Scholar 

  • Zeng Q, Lu W, Deng Z, Wu J, Guo R, Xu X (2020) Tablysin-15 inhibits osteoclastogenesis and LPS-induced bone loss via attenuating the integrin αβ pathway. Chem Biol Interact 327:109179

    Article  CAS  PubMed  Google Scholar 

  • Zhou P, Gross S, Liu J-H, Yu B-Y, Feng L-L, Nolta J et al (2010) Flavokawain B, the hepatotoxic constituent from kava root, induces GSH-sensitive oxidative stress through modulation of IKK/NF-kappaB and MAPK signaling pathways. FASEB J 24(12):4722–4732

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu N, Hou J (2021) Molecular mechanism of the anti-inflammatory effects of Sophorae Flavescentis Aiton identified by network pharmacology. Sci Rep 11(1):1005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by the Natural Science Foundation of Zhejiang Province (LY20H060006), Experimental Animal Science Project of Zhejiang Province (LGD19H310001). The authors thank Professor Li Wang of Research Center for Integrated Medicine Affiliated Traditional Medicine Hospital of Southwest Medical University for his guidance.

Author information

Authors and Affiliations

  1. Zhejiang University School of Medicine, Hangzhou, 310009, China

    Feng Lu, Huiqun Hu, Xiangang Jin & Haixiao Chen

  2. Department of Orthopedic, Taizhou Hospital of Zhejiang Province, Zhejiang University, No. 150 Ximen Street, Gucheng Street, Linhai City, Taizhou City, 317000, Zhejiang Province, China

    Feng Lu, Xiangang Jin & Haixiao Chen

  3. Wenzhou Medical University, Wenzhou, 325035, China

    Xinhui Wu, Jiapeng Zhang, Xiaoting Song & Jiacheng Sun

  4. Department of Orthopedic, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, 317000, China

    Xinhui Wu, Jiapeng Zhang, Xiaoting Song & Jiacheng Sun

  5. Department of Infectious Diseases, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China

    Huiqun Hu

  6. Enze Medical Research Center, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, 317000, China

    Lihua Chen & Haixiao Chen

Authors
  1. Feng Lu
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  2. Xinhui Wu
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  3. Huiqun Hu
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  4. Jiapeng Zhang
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  5. Xiaoting Song
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  6. Xiangang Jin
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  7. Lihua Chen
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  8. Jiacheng Sun
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  9. Haixiao Chen
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Contributions

HC and FL conceived the study. FL and HH contributed to the acquisition and interpretation of data. FL and XW did the data cleaning, statistical analysis and model building with assistance from ZJ, XS, XJ, LC and JS. FL and HH drafted the manuscript. All authors contributed to the critical revision of the manuscript for important intellectual content. All authors critically reviewed the manuscript for important intellectual content and gave final approval for the version to be published.

Corresponding author

Correspondence to Haixiao Chen.

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Lu, F., Wu, X., Hu, H. et al. Yangonin treats inflammatory osteoporosis by inhibiting the secretion of inflammatory factors and RANKL expression. Inflammopharmacol 30, 1445–1458 (2022). https://doi.org/10.1007/s10787-022-00985-1

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  • DOI: https://doi.org/10.1007/s10787-022-00985-1

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