BMB Reports

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

DOI QR Code

Boeravinone B, a natural rotenoid, inhibits osteoclast differentiation through modulating NF-κB, MAPK and PI3K/Akt signaling pathways

  • Xianyu Piao (Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University) ;
  • Jung-Woo Kim (Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University) ;
  • Moonjung Hyun (Gyeongnam Biohealth Research Center, Gyeongnam Branch Institute, Korea Institute of Toxicology) ;
  • Zhao Wang (Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University) ;
  • Suk-Gyun Park (Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University) ;
  • In A Cho (Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University) ;
  • Je-Hwang Ryu (Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University) ;
  • Bin-Na Lee (Department of Conservative Dentistry, School of Dentistry, Chonnam National University) ;
  • Ju Han Song (Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University) ;
  • Jeong-Tae Koh (Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University)
  • Received : 2023.04.10
  • Accepted : 2023.08.12
  • Published : 2023.10.31
Download PDF
⟨ Previous Next ⟩

Abstract

Osteoporosis is a major public health concern, which requires novel therapeutic strategies to prevent or mitigate bone loss. Natural compounds have attracted attention as potential therapeutic agents due to their safety and efficacy. In this study, we investigated the regulatory activities of boeravinone B (BOB), a natural rotenoid isolated from the medicinal plant Boerhavia diffusa, on the differentiation of osteoclasts and mesenchymal stem cells (MSCs), the two main cell components responsible for bone remodeling. We found that BOB inhibited osteoclast differentiation and function, as determined by TRAP staining and pit formation assay, with no significant cytotoxicity. Furthermore, our results showing that BOB ameliorates ovariectomy-induced bone loss demonstrated that BOB is also effective in vivo. BOB exerted its inhibitory effects on osteoclastogenesis by downregulating the RANKL/RANK signaling pathways, including NF-κB, MAPK, and PI3K/Akt, resulting in the suppression of osteoclast-specific gene expression. Further experiments revealed that, at least phenomenologically, BOB promotes osteoblast differentiation of bone marrow-derived MSCs but inhibits their differentiation into adipocytes. In conclusion, our study demonstrates that BOB inhibits osteoclastogenesis and promotes osteoblastogenesis in vitro by regulating various signaling pathways. These findings suggest that BOB has potential value as a novel therapeutic agent for the prevention and treatment of osteoporosis.

Keywords

Acknowledgement

We thank Sin-Hye Oh and Seung Hee Kwon for their technical assistance. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2019R1A5A2027521); the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (No. NRF-2020R1I1A1A01061824); the Korean Fund for Regenerative Medicine (KFRM) grant (Ministry of Science and ICT, Ministry of Health & Welfare, 22A0104L1); and by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2021R1C1C2009626).

References

  1. Liang B, Burley G, Lin S and Shi YC (2022) Osteoporosis pathogenesis and treatment: existing and emerging avenues. Cell Mol Biol Lett 27, 72 
  2. Elson A, Anuj A, Barnea-Zohar M and Reuven N (2022) The origins and formation of bone-resorbing osteoclasts. Bone 164, 116538 
  3. Kim JH and Kim N (2014) Regulation of NFATc1 in osteoclast differentiation. J Bone Metab 21, 233-241  https://doi.org/10.11005/jbm.2014.21.4.233
  4. Park JH, Lee NK and Lee SY (2017) Current understanding of RANK signaling in osteoclast differentiation and maturation. Mol Cells 40, 706-713  https://doi.org/10.14348/molcells.2017.0225
  5. An J, Hao D, Zhang Q et al (2016) Natural products for treatment of bone erosive diseases: the effects and mechanisms on inhibiting osteoclastogenesis and bone resorption. Int Immunopharmacol 36, 118-131  https://doi.org/10.1016/j.intimp.2016.04.024
  6. Chen X, Zhi X, Pan P et al (2017) Matrine prevents bone loss in ovariectomized mice by inhibiting RANKL-induced osteoclastogenesis. FASEB J 31, 4855-4865  https://doi.org/10.1096/fj.201700316R
  7. Kang JH, Lim H, Jeong JE and Yim M (2016) Attenuation of RANKL-induced osteoclast formation via p38-mediated NFATc1 signaling pathways by extract of Euphorbia Lathyris L. J Bone Metab 23, 207-214  https://doi.org/10.11005/jbm.2016.23.4.207
  8. Raggatt LJ and Partridge NC (2010) Cellular and molecular mechanisms of bone remodeling. J Biol Chem 285, 25103-25108  https://doi.org/10.1074/jbc.R109.041087
  9. Akune T, Ohba S, Kamekura S et al (2004) PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest 113, 846-855  https://doi.org/10.1172/JCI200419900
  10. Han Y, Kim CY, Cheong H and Lee KY (2016) Osterix represses adipogenesis by negatively regulating PPARγ transcriptional activity. Sci Rep 6, 35655 
  11. Tosa I, Yamada D, Yasumatsu M et al (2019) Postnatal Runx2 deletion leads to low bone mass and adipocyte accumulation in mice bone tissues. Biochem Biophys Res Commun 516, 1229-1233  https://doi.org/10.1016/j.bbrc.2019.07.014
  12. Chandra A, Lagnado AB, Farr JN et al (2022) Bone marrow adiposity in models of radiation- and aging-related bone loss is dependent on cellular senescence. J Bone Miner Res 37, 997-1011  https://doi.org/10.1002/jbmr.4537
  13. Li J, Chen X, Lu L and Yu X (2020) The relationship between bone marrow adipose tissue and bone metabolism in postmenopausal osteoporosis. Cytokine Growth Factor Rev 52, 88-98  https://doi.org/10.1016/j.cytogfr.2020.02.003
  14. Bairwa K, Singh IN, Roy SK, Grover J, Srivastava A and Jachak SM (2013) Rotenoids from Boerhaavia diffusa as potential anti-inflammatory agents. J Nat Prod 76, 1393-1398  https://doi.org/10.1021/np300899w
  15. Mishra S, Aeri V, Gaur PK and Jachak SM (2014) Phytochemical, therapeutic, and ethnopharmacological overview for a traditionally important herb: Boerhavia diffusa Linn. Biomed Res Int 2014, 808302 
  16. Biradar SP, Tamboli AS, Khandare RV and Pawar PK (2019) Chebulinic acid and Boeravinone B act as anti-aging and anti-apoptosis phyto-molecules during oxidative stress. Mitochondrion 46, 236-246  https://doi.org/10.1016/j.mito.2018.07.003
  17. Huang Y, Sun Y, Wang WW and Zhang L (2018) Boeravinone B a natural rotenoid exerts anticancer activity via inducing internalization and degradation of inactivated EGFR and ErbB2 in human colon cancer cells. Am J Transl Res 10, 4183-4192 
  18. Singh S, Kalia NP, Joshi P et al (2017) Boeravinone B, a novel dual inhibitor of NorA bacterial efflux pump of Staphylococcus aureus and human P-glycoprotein, reduces the biofilm formation and intracellular invasion of bacteria. Front Microbiol 8, 1868 
  19. Yuan S and Zhang T (2021) Boeravinone B protects brain against cerebral ichemia reperfusion injury in rats: possible role of anti-inflammatory and antioxidant. J Oleo Sci 70, 927-936  https://doi.org/10.5650/jos.ess21037
  20. Armour KJ, Armour KE, van't Hof RJ et al (2001) Activation of the inducible nitric oxide synthase pathway contributes to inflammation-induced osteoporosis by suppressing bone formation and causing osteoblast apoptosis. Arthritis Rheum 44, 2790-2796  https://doi.org/10.1002/1529-0131(200112)44:12<2790::AID-ART466>3.0.CO;2-X
  21. Jayusman PA, Nasruddin NS, Baharin B, Ibrahim N', Ahmad Hairi H and Shuid AN (2023) Overview on postmenopausal osteoporosis and periodontitis: the therapeutic potential of phytoestrogens against alveolar bone loss. Front Pharmacol 14, 1120457 
  22. Xu Q, Cao Z, Xu J et al (2022) Effects and mechanisms of natural plant active compounds for the treatment of osteoclast-mediated bone destructive diseases. J Drug Target 30, 394-412  https://doi.org/10.1080/1061186X.2021.2013488
  23. Kwak HB, Lee BK, Oh J et al (2010) Inhibition of osteoclast differentiation and bone resorption by rotenone, through down-regulation of RANKL-induced c-Fos and NFATc1 expression. Bone 46, 724-731  https://doi.org/10.1016/j.bone.2009.10.042
  24. Kim BG, Kwak HB, Choi EY et al (2010) Amorphigenin inhibits osteoclast differentiation by suppressing c-Fos and nuclear factor of activated T cells. Anat Cell Biol 43, 310-316  https://doi.org/10.5115/acb.2010.43.4.310
  25. Zhang T, Zhao K, Han W et al (2019) Deguelin inhibits RANKL-induced osteoclastogenesis in vitro and prevents inflammation-mediated bone loss in vivo. J Cell Physiol 234, 2719-2729  https://doi.org/10.1002/jcp.27087
  26. Praveen Kumar PK, Priyadharshini A and Muthukumaran S (2021) A review on rotenoids: purification, characterization and its biological applications. Mini Rev Med Chem 21, 1734-1746  https://doi.org/10.2174/1389557521666210217092634
  27. Sugatani T and Hruska KA (2005) Akt1/Akt2 and mammalian target of rapamycin/Bim play critical roles in osteoclast differentiation and survival, respectively, whereas Akt is dispensable for cell survival in isolated osteoclast precursors. J Biol Chem 280, 3583-3589  https://doi.org/10.1074/jbc.M410480200
  28. Moon JB, Kim JH, Kim K et al (2012) Akt induces osteoclast differentiation through regulating the GSK3β/NFATc1 signaling cascade. J Immunol 188, 163-169  https://doi.org/10.4049/jimmunol.1101254
  29. Chen Q, Shou P, Zheng C et al (2016) Fate decision of mesenchymal stem cells: adipocytes or osteoblasts? Cell Death Differ 23, 1128-1139  https://doi.org/10.1038/cdd.2015.168
  30. Zang Y, Song JH, Oh SH et al (2020) Targeting NLRP3 inflammasome reduces age-related experimental alveolar bone loss. J Dent Res 99, 1287-1295 https://doi.org/10.1177/0022034520933533