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International journal of stem cells2022; 15(3); 334-345; doi: 10.15283/ijsc22044

Modulation of Osteogenic Differentiation of Adipose-Derived Stromal Cells by Co-Treatment with 3, 4′-Dihydroxyflavone, U0126, and N-Acetyl Cysteine.

Abstract: Flavonoids form the largest group of plant phenols and have various biological and pharmacological activities. In this study, we investigated the effect of a flavonoid, 3, 4'-dihydroxyflavone (3, 4'-DHF) on osteogenic differentiation of equine adipose-derived stromal cells (eADSCs). Unassigned: Treatment of 3, 4'-DHF led to increased osteogenic differentiation of eADSCs by increasing phosphorylation of ERK and modulating Reactive Oxygen Species (ROS) generation. Although PD98059, an ERK inhibitor, suppressed osteogenic differentiation, another ERK inhibitor, U0126, apparently increased osteogenic differentiation of the 3, 4'-DHF-treated eADSCs, which may indicate that the effect of U0126 on bone morphogenetic protein signaling is involved in the regulation of 3, 4'-DHF in osteogenic differentiation of eADSCs. We revealed that 3, 4'-DHF could induce osteogenic differentiation of eADSCs by suppressing ROS generation and co-treatment of 3, 4'-DHF, U0126, and/or N-acetyl cysteine (NAC) resulted in the additive enhancement of osteogenic differentiation of eADSCs. Unassigned: Our results showed that co-treatment of 3, 4'-DHF, U0126, and/or NAC cumulatively regulated osteogenesis in eADSCs, suggesting that 3, 4'-DHF, a flavonoid, can provide a novel approach to the treatment of osteoporosis and can provide potential therapeutic applications in therapeutics and regenerative medicine for human and companion animals.
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Publication Date: 2022-06-30 PubMed ID: 35769058PubMed Central: PMC9396012DOI: 10.15283/ijsc22044Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research investigated the impact of a flavonoid called 3, 4′-Dihydroxyflavone (3, 4′-DHF) on the bone formation process in equine adipose-derived stromal cells (eADSCs). The study’s results suggest that 3, 4′-DHF can aid in osteogenesis, potentially offering novel treatment possibilities for osteoporosis.

Research Objectives and Methodology

  • The main objective of this study was to investigate the effect of a specific flavonoid, 3, 4′-Dihydroxyflavone (3, 4′-DHF), on osteogenic differentiation in equine adipose-derived stromal cells (eADSCs). Osteogenic differentiation is the process where cells develop into bone-forming cells.
  • This particular type of flavonoid was chosen due to the known biological and pharmacological properties of flavonoids, a large group of plant phenols.
  • The researchers employed in vitro testing, treating eADSCs with 3, 4′-DHF, and monitoring changes in ERK phosphorylation and Reactive Oxygen Species (ROS) generation, both important factors in bone formation.

Findings of the Research

  • The research revealed that treatment with 3, 4′-DHF enhanced the osteogenic differentiation in eADSCs by increasing the phosphorylation of ERK and regulating the generation of ROS.
  • When the researchers used PD98059, an ERK inhibitor, they noted that osteogenic differentiation was suppressed. Interestingly, a different ERK inhibitor, U0126, seemed to enhance osteogenic differentiation when used in combination with 3, 4′-DHF-treated eADSCs. These findings suggest that the specific influence of U0126 on bone morphogenetic protein signaling may be involved in 3, 4′-DHF’s regulation of osteogenic differentiation in eADSCs.
  • The researchers also found that 3, 4′-DHF was capable of inducing osteogenic differentiation by suppressing ROS generation. Additionally, the simultaneous treatment of eADSCs with 3, 4′-DHF, U0126, and N-acetyl cysteine (NAC), an antioxidant, led to further improvements in osteogenic differentiation.

Conclusions and Implications

  • The study concluded that the co-treatment of eADSCs with 3, 4′-DHF, U0126, and NAC synergistically promoted osteogenesis.
  • These findings suggest that 3, 4′-DHF, a flavonoid, could potentially offer a new approach to the treatment of osteoporosis, by encouraging the formation of bone cells.
  • Such a development could have significant potential applications in therapeutics and regenerative medicine, for both human and veterinary care, particularly in the effective treatment of bone diseases and injuries.

Cite This Article

APA
Song K, Yang GM, Han J, Gil M, Dayem AA, Kim K, Lim KM, Kang GH, Kim S, Jang SB, Vellingiri B, Cho SG. (2022). Modulation of Osteogenic Differentiation of Adipose-Derived Stromal Cells by Co-Treatment with 3, 4′-Dihydroxyflavone, U0126, and N-Acetyl Cysteine. Int J Stem Cells, 15(3), 334-345. https://doi.org/10.15283/ijsc22044

Publication

International journal of stem cells
ISSN: 2005-3606
NlmUniqueID: 101497587
Country: Korea (South)
Language: English
Volume: 15
Issue: 3
Pages: 334-345

Researcher Affiliations

Song, Kwonwoo
  • Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea.
Yang, Gwang-Mo
  • Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea.
Han, Jihae
  • Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea.
Gil, Minchan
  • Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea.
Dayem, Ahmed Abdal
  • Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea.
Kim, Kyeongseok
  • Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea.
Lim, Kyung Min
  • Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea.
Kang, Geun-Ho
  • Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea.
Kim, Sejong
  • Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea.
Jang, Soo Bin
  • Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea.
Vellingiri, Balachandar
  • Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, India.
Cho, Ssang-Goo
  • Department of Stem Cell and Regenerative Biotechnology and Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Seoul, Korea.

Conflict of Interest Statement

. The authors have no conflicting financial interest.

References

This article includes 37 references
  1. Arai M, Shibata Y, Pugdee K, Abiko Y, Ogata Y. Effects of reactive oxygen species (ROS) on antioxidant system and osteoblastic differentiation in MC3T3-E1 cells.. IUBMB Life 2007 Jan;59(1):27-33.
    doi: 10.1080/15216540601156188pubmed: 17365177google scholar: lookup
  2. Maruotti N, Corrado A, Neve A, Cantatore FP. Bisphosphonates: effects on osteoblast.. Eur J Clin Pharmacol 2012 Jul;68(7):1013-8.
    doi: 10.1007/s00228-012-1216-7pubmed: 22318756google scholar: lookup
  3. Huang Q, Gao B, Jie Q, Wei BY, Fan J, Zhang HY, Zhang JK, Li XJ, Shi J, Luo ZJ, Yang L, Liu J. Ginsenoside-Rb2 displays anti-osteoporosis effects through reducing oxidative damage and bone-resorbing cytokines during osteogenesis.. Bone 2014 Sep;66:306-14.
    doi: 10.1016/j.bone.2014.06.010pubmed: 24933344google scholar: lookup
  4. Kular J, Tickner J, Chim SM, Xu J. An overview of the regulation of bone remodelling at the cellular level.. Clin Biochem 2012 Aug;45(12):863-73.
    doi: 10.1016/j.clinbiochem.2012.03.021pubmed: 22465238google scholar: lookup
  5. Zhai YK, Guo XY, Ge BF, Zhen P, Ma XN, Zhou J, Ma HP, Xian CJ, Chen KM. Icariin stimulates the osteogenic differentiation of rat bone marrow stromal cells via activating the PI3K-AKT-eNOS-NO-cGMP-PKG.. Bone 2014 Sep;66:189-98.
    doi: 10.1016/j.bone.2014.06.016pubmed: 24956021google scholar: lookup
  6. Vidal MA, Kilroy GE, Lopez MJ, Johnson JR, Moore RM, Gimble JM. Characterization of equine adipose tissue-derived stromal cells: adipogenic and osteogenic capacity and comparison with bone marrow-derived mesenchymal stromal cells.. Vet Surg 2007 Oct;36(7):613-22.
    doi: 10.1111/j.1532-950X.2007.00313.xpubmed: 17894587google scholar: lookup
  7. Mathieu PS, Loboa EG. Cytoskeletal and focal adhesion influences on mesenchymal stem cell shape, mechanical properties, and differentiation down osteogenic, adipogenic, and chondrogenic pathways.. Tissue Eng Part B Rev 2012 Dec;18(6):436-44.
    doi: 10.1089/ten.teb.2012.0014pmc: PMC3495119pubmed: 22741572google scholar: lookup
  8. Braun J, Hack A, Weis-Klemm M, Conrad S, Treml S, Kohler K, Walliser U, Skutella T, Aicher WK. Evaluation of the osteogenic and chondrogenic differentiation capacities of equine adipose tissue-derived mesenchymal stem cells.. Am J Vet Res 2010 Oct;71(10):1228-36.
    doi: 10.2460/ajvr.71.10.1228pubmed: 20919912google scholar: lookup
  9. Zhang L, Su P, Xu C, Chen C, Liang A, Du K, Peng Y, Huang D. Melatonin inhibits adipogenesis and enhances osteogenesis of human mesenchymal stem cells by suppressing PPARγ expression and enhancing Runx2 expression.. J Pineal Res 2010 Nov;49(4):364-72.
    doi: 10.1111/j.1600-079X.2010.00803.xpubmed: 20738756google scholar: lookup
  10. Whitworth DJ, Ovchinnikov DA, Sun J, Fortuna PR, Wolvetang EJ. Generation and characterization of leukemia inhibitory factor-dependent equine induced pluripotent stem cells from adult dermal fibroblasts.. Stem Cells Dev 2014 Jul 1;23(13):1515-23.
    doi: 10.1089/scd.2013.0461pmc: PMC4066230pubmed: 24555755google scholar: lookup
  11. Sharma R, Livesey MR, Wyllie DJ, Proudfoot C, Whitelaw CB, Hay DC, Donadeu FX. Generation of functional neurons from feeder-free, keratinocyte-derived equine induced pluripotent stem cells.. Stem Cells Dev 2014 Jul 1;23(13):1524-34.
    doi: 10.1089/scd.2013.0565pubmed: 24548115google scholar: lookup
  12. Nagy K, Sung HK, Zhang P, Laflamme S, Vincent P, Agha-Mohammadi S, Woltjen K, Monetti C, Michael IP, Smith LC, Nagy A. Induced pluripotent stem cell lines derived from equine fibroblasts.. Stem Cell Rev Rep 2011 Sep;7(3):693-702.
    doi: 10.1007/s12015-011-9239-5pmc: PMC3137777pubmed: 21347602google scholar: lookup
  13. Arens AM, Barr B, Puchalski SM, Poppenga R, Kulin RM, Anderson J, Stover SM. Osteoporosis associated with pulmonary silicosis in an equine bone fragility syndrome.. Vet Pathol 2011 May;48(3):593-615.
    doi: 10.1177/0300985810385151pubmed: 21097716google scholar: lookup
  14. de Mattos Carvalho A, Alves ALG, de Oliveira PGG, Cisneros Álvarez LE, Amorim RL, Hussni CA, Deffune E. Use of adipose tissue-derived mesenchymal stem cells for experimental tendinitis therapy in equines. J Equine Vet Sci 2011;31:26–34.
    doi: 10.1016/j.jevs.2010.11.014google scholar: lookup
  15. Nixon AJ, Dahlgren LA, Haupt JL, Yeager AE, Ward DL. Effect of adipose-derived nucleated cell fractions on tendon repair in horses with collagenase-induced tendinitis.. Am J Vet Res 2008 Jul;69(7):928-37.
    doi: 10.2460/ajvr.69.7.928pubmed: 18593247google scholar: lookup
  16. Carvalho Ade M, Badial PR, Álvarez LE, Yamada AL, Borges AS, Deffune E, Hussni CA, Garcia Alves AL. Equine tendonitis therapy using mesenchymal stem cells and platelet concentrates: a randomized controlled trial.. Stem Cell Res Ther 2013 Jul 22;4(4):85.
    doi: 10.1186/scrt236pmc: PMC3854756pubmed: 23876512google scholar: lookup
  17. Conze P, van Schie HT, van Weeren R, Staszyk C, Conrad S, Skutella T, Hopster K, Rohn K, Stadler P, Geburek F. Effect of autologous adipose tissue-derived mesenchymal stem cells on neovascularization of artificial equine tendon lesions.. Regen Med 2014;9(6):743-57.
    doi: 10.2217/rme.14.55pubmed: 25431911google scholar: lookup
  18. Zhang JF, Li G, Chan CY, Meng CL, Lin MC, Chen YC, He ML, Leung PC, Kung HF. Flavonoids of Herba Epimedii regulate osteogenesis of human mesenchymal stem cells through BMP and Wnt/beta-catenin signaling pathway.. Mol Cell Endocrinol 2010 Jan 15;314(1):70-4.
    doi: 10.1016/j.mce.2009.08.012pubmed: 19703516google scholar: lookup
  19. Lee ER, Kang YJ, Kim JH, Lee HT, Cho SG. Modulation of apoptosis in HaCaT keratinocytes via differential regulation of ERK signaling pathway by flavonoids.. J Biol Chem 2005 Sep 9;280(36):31498-507.
    doi: 10.1074/jbc.M505537200pubmed: 16014620google scholar: lookup
  20. Lee ER, Kim JH, Kang YJ, Cho SG. The anti-apoptotic and anti-oxidant effect of eriodictyol on UV-induced apoptosis in keratinocytes.. Biol Pharm Bull 2007 Jan;30(1):32-7.
    doi: 10.1248/bpb.30.32pubmed: 17202655google scholar: lookup
  21. Lee ER, Kim JH, Choi HY, Jeon K, Cho SG. Cytoprotective effect of eriodictyol in UV-irradiated keratinocytes via phosphatase-dependent modulation of both the p38 MAPK and Akt signaling pathways.. Cell Physiol Biochem 2011;27(5):513-24.
    doi: 10.1159/000329973pubmed: 21691069google scholar: lookup
  22. Lee ER, Kim JY, Kang YJ, Ahn JY, Kim JH, Kim BW, Choi HY, Jeong MY, Cho SG. Interplay between PI3K/Akt and MAPK signaling pathways in DNA-damaging drug-induced apoptosis.. Biochim Biophys Acta 2006 Sep;1763(9):958-68.
    doi: 10.1016/j.bbamcr.2006.06.006pubmed: 16905201google scholar: lookup
  23. Kim BW, Lee ER, Min HM, Jeong HS, Ahn JY, Kim JH, Choi HY, Choi H, Kim EY, Park SP, Cho SG. Sustained ERK activation is involved in the kaempferol-induced apoptosis of breast cancer cells and is more evident under 3-D culture condition.. Cancer Biol Ther 2008 Jul;7(7):1080-9.
    doi: 10.4161/cbt.7.7.6164pubmed: 18443432google scholar: lookup
  24. Han D, Kim HJ, Choi HY, Kim B, Yang G, Han J, Dayem AA, Lee HR, Kim JH, Lee KM, Jeong KS, Do SH, Cho SG. 3,2'-Dihydroxyflavone-Treated Pluripotent Stem Cells Show Enhanced Proliferation, Pluripotency Marker Expression, and Neuroprotective Properties.. Cell Transplant 2015;24(8):1511-32.
    doi: 10.3727/096368914X683511pubmed: 25198120google scholar: lookup
  25. Lee KS, Kim EY, Jeon K, Cho SG, Han YJ, Yang BC, Lee SS, Ko MS, Riu KJ, Lee HT, Park SP. 3,4-Dihydroxyflavone acts as an antioxidant and antiapoptotic agent to support bovine embryo development in vitro.. J Reprod Dev 2011 Feb;57(1):127-34.
    doi: 10.1262/jrd.10-029Apubmed: 21071889google scholar: lookup
  26. Xu L, Liu Y, Hou Y, Wang K, Wong Y, Lin S, Li G. U0126 promotes osteogenesis of rat bone-marrow-derived mesenchymal stem cells by activating BMP/Smad signaling pathway.. Cell Tissue Res 2015 Feb;359(2):537-545.
    doi: 10.1007/s00441-014-2025-3pubmed: 25363751google scholar: lookup
  27. Han J, Choi HY, Dayem AA, Kim K, Yang G, Won J, Do SH, Kim JH, Jeong KS, Cho SG. Regulation of Adipogenesis Through Differential Modulation of ROS and Kinase Signaling Pathways by 3,4'-Dihydroxyflavone Treatment.. J Cell Biochem 2017 May;118(5):1065-1077.
    doi: 10.1002/jcb.25681pubmed: 27579626google scholar: lookup
  28. Panche AN, Diwan AD, Chandra SR. Flavonoids: an overview.. J Nutr Sci 2016;5:e47.
    doi: 10.1017/jns.2016.41pmc: PMC5465813pubmed: 28620474google scholar: lookup
  29. Preethi Soundarya S, Sanjay V, Haritha Menon A, Dhivya S, Selvamurugan N. Effects of flavonoids incorporated biological macromolecules based scaffolds in bone tissue engineering.. Int J Biol Macromol 2018 Apr 15;110:74-87.
    doi: 10.1016/j.ijbiomac.2017.09.014pubmed: 28893682google scholar: lookup
  30. Cheng SL, Shao JS, Charlton-Kachigian N, Loewy AP, Towler DA. MSX2 promotes osteogenesis and suppresses adipogenic differentiation of multipotent mesenchymal progenitors.. J Biol Chem 2003 Nov 14;278(46):45969-77.
    doi: 10.1074/jbc.M306972200pubmed: 12925529google scholar: lookup
  31. Hong G, Chen Z, Han X, Zhou L, Pang F, Wu R, Shen Y, He X, Hong Z, Li Z, He W, Wei Q. A novel RANKL-targeted flavonoid glycoside prevents osteoporosis through inhibiting NFATc1 and reactive oxygen species.. Clin Transl Med 2021 May;11(5):e392.
    doi: 10.1002/ctm2.392pmc: PMC8140192pubmed: 34047464google scholar: lookup
  32. Jiang J, Xiao S, Xu X, Ma H, Feng C, Jia X. Isomeric flavonoid aglycones derived from Epimedii Folium exerted different intensities in anti-osteoporosis through OPG/RANKL protein targets.. Int Immunopharmacol 2018 Sep;62:277-286.
    doi: 10.1016/j.intimp.2018.07.017pubmed: 30036771google scholar: lookup
  33. Martiniakova M, Babikova M, Mondockova V, Blahova J, Kovacova V, Omelka R. The Role of Macronutrients, Micronutrients and Flavonoid Polyphenols in the Prevention and Treatment of Osteoporosis.. Nutrients 2022 Jan 25;14(3).
    doi: 10.3390/nᐃ0523pmc: PMC8839902pubmed: 35276879google scholar: lookup
  34. Laflamme C, Curt S, Rouabhia M. Epidermal growth factor and bone morphogenetic proteins upregulate osteoblast proliferation and osteoblastic markers and inhibit bone nodule formation.. Arch Oral Biol 2010 Sep;55(9):689-701.
    doi: 10.1016/j.archoralbio.2010.06.010pubmed: 20627196google scholar: lookup
  35. Marie PJ. Fibroblast growth factor signaling controlling bone formation: an update.. Gene 2012 Apr 25;498(1):1-4.
    doi: 10.1016/j.gene.2012.01.086pubmed: 22342254google scholar: lookup
  36. Yu Y, Mu J, Fan Z, Lei G, Yan M, Wang S, Tang C, Wang Z, Yu J, Zhang G. Insulin-like growth factor 1 enhances the proliferation and osteogenic differentiation of human periodontal ligament stem cells via ERK and JNK MAPK pathways.. Histochem Cell Biol 2012 Apr;137(4):513-25.
    doi: 10.1007/s00418-011-0908-xpubmed: 22227802google scholar: lookup
  37. Lee DH, Lim BS, Lee YK, Yang HC. Effects of hydrogen peroxide (H2O2) on alkaline phosphatase activity and matrix mineralization of odontoblast and osteoblast cell lines.. Cell Biol Toxicol 2006 Jan;22(1):39-46.
    doi: 10.1007/s10565-006-0018-zpubmed: 16463018google scholar: lookup

Citations

This article has been cited 3 times.
  1. Park JH, Koh EB, Seo YJ, Oh HS, Won JY, Hwang SC, Byun JH. Tiron Has Negative Effects on Osteogenic Differentiation via Mitochondrial Dysfunction in Human Periosteum-Derived Cells. Int J Mol Sci 2022 Nov 14;23(22).
    doi: 10.3390/ijms232214040pubmed: 36430519google scholar: lookup
  2. Cheng J, Tan L, Lu X, Zheng M, Xu C, Xu W, Jiang T, Zhang C. Photosynthetic Toxicological Effects of Organic Extracts from Zanthoxylum bungeanum Leaves on Controlling the Microcystis aeruginosa Blooms. Curr Microbiol 2024 Dec 19;82(1):48.
    doi: 10.1007/s00284-024-04026-8pubmed: 39699658google scholar: lookup
  3. Zheng H, Liu J, Sun L, Meng Z. The role of N-acetylcysteine in osteogenic microenvironment for bone tissue engineering. Front Cell Dev Biol 2024;12:1435125.
    doi: 10.3389/fcell.2024.1435125pubmed: 39055649google scholar: lookup
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