Advertisement

Journal of Natural Medicines

, Volume 73, Issue 1, pp 59–66 | Cite as

The pivotal role of microRNA-21 in osteoclastogenesis inhibition by anthracycline glycoside aloin

  • Radha Madhyastha
  • Harishkumar Madhyastha
  • Yutthana Pengjam
  • Queen Intan Nurrahmah
  • Yuichi Nakajima
  • Masugi Maruyama
Original Paper
  • 136 Downloads

Abstract

Osteopenic disorders such as osteoporosis and rheumatoid arthritis are characterized by excessive bone resorption by osteoclasts relative to bone formation by osteoblasts. MicroRNAs are emerging as key players in bone remodeling, modulating the functions of both osteoblasts and osteoclasts. Among them, miR-21 is highly expressed in osteoclast precursors and is known to regulate genesis, differentiation, and apoptosis of osteoclasts. The pro-osteoclastogenic nature of miR-21 makes it a potential candidate as a therapeutic target to treat bone disorders. We had previously demonstrated that anthroglycoside aloin derived from Aloe vera was effective in promoting osteoblastogenesis and inhibiting osteoclastogenesis. The present study investigated the role of miR-21 in aloin’s inhibitory effect on osteoclast differentiation. Aloin effectively suppressed receptor activator of nuclear factor kappa-B (NFĸB) ligand (RankL)-induced miR-21 expression via repression of NFĸB activation. MiR-21 suppression resulted in upregulation of osteoclast suppressor programmed cell death protein 4 (PDCD4), and downregulation of osteoclast marker cathepsin K. Knockdown or gain-of-function studies revealed that miR-21 was pivotal to aloin’s inhibitory effect on osteoclastogenesis. This study also highlights the dynamic potential of aloin as a therapeutic agent to treat osteopenic disorders.

Keywords

MicroRNA-21 Osteoclastogenesis inhibition Aloin NFĸB 

Notes

Acknowledgements

This study was supported by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan to M.R.

Compliance with ethical standards

Conflict of interest

The authors declare no competing or financial interests.

References

  1. 1.
    W H Organization (2004) WHO scientific group on the assessment of osteoporosis at primary health care level. Summary Meeting Report, Brussels, Belgium, 5–7 May 2004, pp 13Google Scholar
  2. 2.
    Rodan GA, Martin TJ (2000) Therapeutic approaches to bone diseases. Science 289:1508–1514CrossRefGoogle Scholar
  3. 3.
    Asagiri M, Takayanagi H (2007) The molecular understanding of osteoclast differentiation. Bone 40:251–264CrossRefGoogle Scholar
  4. 4.
    Suda T, Udagawa N, Nakamura I, Miyaura C, Takahashi N (1995) Modulation of osteoclast differentiation by local factors. Bone 17:87S–91SCrossRefGoogle Scholar
  5. 5.
    Tanaka S, Nakamura K, Takahasi N, Suda T (2005) Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system. Immunol Rev 208:30–49CrossRefGoogle Scholar
  6. 6.
    Sugatani T, Hruska KA (2013) Down-regulation of miR-21 biogenesis by estrogen action contributes to osteoclastic apoptosis. J Cell Biochem 114:1217–1222CrossRefGoogle Scholar
  7. 7.
    Srivastava S, Toraldo G, Weitzmann MN, Cenci S, Ross FP, Pacifici R (2001) Estrogen decreases osteoclast formation by down-regulating receptor activator of NF-kappa B ligand (RANKL)-induced JNK activation. J Biol Chem 276:8836–8840CrossRefGoogle Scholar
  8. 8.
    Sugatani T, Hruska KA (2009) Impaired micro-RNA pathways diminish osteoclast differentiation and function. J Biol Chem 284:4667–4678CrossRefGoogle Scholar
  9. 9.
    Carthew RW, Sontheimer EJ (2009) Origins and mechanisms of miRNAs and siRNAs. Cell 136:642–655CrossRefGoogle Scholar
  10. 10.
    Bushati N, Cohen SM (2007) microRNA functions. Annu Rev Cell Dev Biol 23:175–205CrossRefGoogle Scholar
  11. 11.
    Rupaimoole R, Slack FJ (2017) MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov 16:203–222CrossRefGoogle Scholar
  12. 12.
    Gaur T, Hussain S, Mudhasani R, Parulkar I, Colby JL, Frederick D, Kream BE, van Wijnen AJ, Stein JL, Stein GS, Jones SN, Lian JB (2010) Dicer inactivation in osteoprogenitor cells compromises fetal survival and bone formation, while excision in differentiated osteoblasts increases bone mass in the adult mouse. Dev Biol 340:10–21CrossRefGoogle Scholar
  13. 13.
    Ji X, Chen X, Yu X (2016) MicroRNAs in osteoclastogenesis and function: potential therapeutic targets for osteoporosis. Int J Mol Sci 17(3):349.  https://doi.org/10.3390/ijms17030349 CrossRefGoogle Scholar
  14. 14.
    Taipaleenmäki H (2018) Regulation of bone metabolism by microRNAs. Curr Osteoporos Rep 16:1–12CrossRefGoogle Scholar
  15. 15.
    Braun T, Zwerina J (2011) Positive regulators of osteoclastogenesis and bone resorption in rheumatoid arthritis. Arthr Res Ther 13:235CrossRefGoogle Scholar
  16. 16.
    Pitari MR, Rossi M, Amodio N, Botta C, Morelli E, Federico C, Gullà A, Caracciolo D, Di Martino MT, Arbitrio M, Giordano A, Tagliaferri P, Tassone P (2015) Inhibition of miR-21 restores RANKL/OPG ratio in multiple myeloma-derived bone marrow stromal cells and impairs the resorbing activity of mature osteoclasts. Oncotarget 6:27343–27358CrossRefGoogle Scholar
  17. 17.
    Pengjam Y, Madhyastha H, Madhyastha R, Yamaguchi Y, Nakajima Y, Maruyama M (2016) Anthraquinone glycoside aloin induces osteogenic initiation of MC3T3-E1 cells: involvement of MAPK mediated Wnt and Bmp signaling. Biomol Ther (Seoul) 24:123–131CrossRefGoogle Scholar
  18. 18.
    Pengjam Y, Madhyastha H, Madhyastha R, Yamaguchi Y, Nakajima Y, Maruyama M (2016) NF-κB pathway inhibition by anthrocyclic glycoside aloin is key event in preventing osteoclastogenesis in RAW264.7 cells. Phytomedicine 23:417–428CrossRefGoogle Scholar
  19. 19.
    Madhyastha R, Madhyastha H, Pengjam Y, Nakajima Y, Maruyama M (2017) Aloin prevents osteoclastogenesis via downregulation of microRNA-21. FFC’s 22nd international conference, Boston, MA, USA, FFC and BIDMC, Harvard Medical School Teaching Hospital, pp 144–146Google Scholar
  20. 20.
    Madhyastha R, Madhyastha H, Pengjam Y, Nakajima Y, Omura S, Maruyama M (2014) NFkappaB activation is essential for miR-21 induction by TGFβ1 in high glucose conditions. Biochem Biophys Res Commun 451:615–621CrossRefGoogle Scholar
  21. 21.
    Zhou R, Hu G, Gong AY, Chen XM (2010) Binding of NF-kappaB p65 subunit to the promoter elements is involved in LPS-induced transactivation of miRNA genes in human biliary epithelial cells. Nucleic Acids Res 38:3222–3232CrossRefGoogle Scholar
  22. 22.
    Sugatani T, Vacher J, Hruska KA (2011) A microRNA expression signature of osteoclastogenesis. Blood 117:3648–3657CrossRefGoogle Scholar
  23. 23.
    An J, Yang H, Zhang Q, Liu C, Zhao J, Zhang L, Chen B (2016) Natural products for treatment of osteoporosis: the effects and mechanisms on promoting osteoblast-mediated bone formation. Life Sci 147:46–58CrossRefGoogle Scholar
  24. 24.
    An J, Hao D, Zhang Q, Chen B, Zhang R, Wang Y, Yang H (2016) Natural products for treatment of bone erosive diseases: the effects and mechanisms on inhibiting osteoclastogenesis and bone resorption. Int Immunopharmacol 36:118–131CrossRefGoogle Scholar
  25. 25.
    Yeh CC, Su YH, Lin YJ, Chen PJ, Shi CS, Chen CN, Chang HI (2015) Evaluation of the protective effects of curcuminoid (curcumin and bisdemethoxycurcumin)-loaded liposomes against bone turnover in a cell-based model of osteoarthritis. Drug Des Dev Ther 9:2285–2300Google Scholar
  26. 26.
    Shang W, Zhao LJ, Dong XL, Zhao ZM, Li J, Zhang BB, Cai H (2016) Curcumin inhibits osteoclastogenic potential in PBMCs from rheumatoid arthritis patients via the suppression of MAPK/RANK/c-Fos/NFATc1 signaling pathways. Mol Med Rep 14:3620–3626CrossRefGoogle Scholar
  27. 27.
    Wada T, Nakashima T, Hiroshi N, Penninger JM (2006) RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med 12:17–25CrossRefGoogle Scholar
  28. 28.
    Yang N, Wang G, Hu C, Shi Y, Liao L, Shi S, Cai Y, Cheng S, Wang X, Liu Y, Tang L, Ding Y, Jin Y (2013) Tumor necrosis factor α suppresses the mesenchymal stem cell osteogenesis promoter miR-21 in estrogen deficiency-induced osteoporosis. J Bone Miner Res 28:559–573CrossRefGoogle Scholar
  29. 29.
    Mei Y, Bian C, Li J, Du Z, Zhou H, Yang Z, Zhao RC (2013) miR-21 modulates the ERK-MAPK signaling pathway by regulating SPRY2 expression during human mesenchymal stem cell differentiation. J Cell Biochem 114:1374–1384CrossRefGoogle Scholar
  30. 30.
    Hu CH, Sui BD, Du FY, Shuai Y, Zheng CX, Zhao P, Yu XR, Jin Y (2017) miR-21 deficiency inhibits osteoclast function and prevents bone loss in mice. Sci Rep 7:43191CrossRefGoogle Scholar
  31. 31.
    Seeliger C, Karpinski K, Haug AT, Vester H, Schmitt A, Bauer JS, van Griensven M (2014) Five freely circulating miRNAs and bone tissue miRNAs are associated with osteoporotic fractures. J Bone Miner Res 29:1718–1728CrossRefGoogle Scholar
  32. 32.
    Panach L, Mifsut D, Tarín JJ, Cano A, García-Pérez M (2015) Serum circulating microRNAs as biomarkers of osteoporotic fracture. Calcif Tissue Int 97:495–505CrossRefGoogle Scholar
  33. 33.
    Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D, Galibert L (1997) A homologue of the TNF receptor and its ligand enhance T cell growth and dendritic-cell function. Nature 390:175–179CrossRefGoogle Scholar
  34. 34.
    Aguda AH, Panwar P, Du X, Nguyen NT, Brayer GD, Brömme D (2014) Structural basis of collagen fiber degradation by cathepsin K. Proc Natl Acad Sci USA 111:17474–17479CrossRefGoogle Scholar
  35. 35.
    Yasuda Y, Kaleta J, Brömme D (2005) The role of cathepsins in osteoporosis and arthritis: rationale for the design of new therapeutics. Adv Drug Deliv Rev 57:973–993CrossRefGoogle Scholar
  36. 36.
    Brömme D, Lecaille F (2009) Cathepsin K inhibitors for osteoporosis and potential off-target effects. Expert Opin Investig Drugs 18:585–600CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Pharmacognosy and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Radha Madhyastha
    • 1
  • Harishkumar Madhyastha
    • 1
  • Yutthana Pengjam
    • 2
  • Queen Intan Nurrahmah
    • 1
  • Yuichi Nakajima
    • 1
  • Masugi Maruyama
    • 1
  1. 1.Department of Applied Physiology, Faculty of MedicineUniversity of MiyazakiMiyazakiJapan
  2. 2.Faculty of Medical TechnologyPrince of Songkla UniversityHatyaiThailand

Personalised recommendations