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Current Molecular Pharmacology

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ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

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Research Article

Valproic acid, A Potential Inducer of Osteogenesis in Mouse Mesenchymal Stem Cells

Author(s): Narayanan Akshaya, Prakash Prasith, Balakrishnan Abinaya, Badrinath Ashwin, S.V. Chandran and Nagarajan Selvamurugan*

Volume 14, Issue 1, 2021

Published on: 13 July, 2020

Page: [27 - 35] Pages: 9

DOI: 10.2174/1874467213666200713102410

Price: $65

Abstract

Background: Recent reports have unveiled the potential of flavonoids to enhance bone formation and assuage bone resorption due to their involvement in cell signaling pathways. They also act as an effective alternative to circumvent the disadvantages associated with existing treatment methods, which has increased their scope in orthopedic research. Valproic acid (VA, 2-propylpentanoic acid) is one such flavonoid, obtained from an herbaceous plant, used in the treatment of epilepsy and various types of seizures.

Objective: In this study, the role of VA in osteogenesis and the molecular mechanisms underpinning its action in mouse mesenchymal stem cells (mMSCs) were determined.

Methods: Results: Cytotoxic studies validated VA’s amiable nature in mMSCs. Alizarin red and von Kossa staining results showed an increased deposition of calcium phosphate in VA-treated mMSCs, which confirmed the occurrence of osteoblast differentiation and mineralization at a cellular level. At the molecular level, there were increased levels of expression of Runx2, a vital bone transcription factor, and other major osteoblast differentiation marker genes in the VA-treated mMSCs. Further, VA-treatment in mMSCs upregulated mir-21 and activated the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway, which might be essential for the expression/activity of Runx2.

Conclusion: Thus, the current study confirmed the osteoinductive nature of VA at the cellular and molecular levels, opening the possibility for its application in bone therapeutics with mir-21.

Keywords: Valproic acid, runx2, mir-21, osteogenesis, mMSC, phytocompound.

Graphical Abstract

[1]
Seeman, E. Modeling and remodeling. Principles of Bone Biology; Bilezikian, J.P.; Raisz, L.G.; Martin, T.J., Eds.; Academic: New York, 2008.
[2]
Abinaya, B.; Prasith, T.P.; Ashwin, B.; Viji Chandran, S.; Selvamurugan, N. Chitosan in Surface Modification for Bone Tissue Engineering Applications. Biotechnol. J., 2019, 14(12), e1900171.
[http://dx.doi.org/10.1002/biot.201900171] [PMID: 31502754]
[3]
Balagangadharan, K.; Dhivya, S.; Selvamurugan, N. Chitosan based nanofibers in bone tissue engineering. Int. J. Biol. Macromol., 2017, 104(Pt B), 1372-1382.
[http://dx.doi.org/10.1016/j.ijbiomac.2016.12.046] [PMID: 27993655]
[4]
Dirckx, N.; Moorer, M.C.; Clemens, T.L.; Riddle, R.C. The role of osteoblasts in energy homeostasis. Nat. Rev. Endocrinol., 2019, 15(11), 651-665.
[http://dx.doi.org/10.1038/s41574-019-0246-y] [PMID: 31462768]
[5]
Hu, Z.; Zhang, L.; Wang, H.; Wang, Y.; Tan, Y.; Dang, L.; Wang, K.; Sun, Z.; Li, G.; Cao, X.; Zhang, S. Targeted silencing of miRNA-132-3p expression rescues disuse osteopenia by promoting mesenchymal stem cell osteogenic differentiation and osteogenesis in mice Stem Cell Res Ther, 2020, 58.
[http://dx.doi.org/10.1186/s13287-020-1581-6]
[6]
Feng, X.; McDonald, J.M. Disorders of bone remodeling. Annu. Rev. Pathol., 2011, 6, 121-145.
[http://dx.doi.org/10.1146/annurev-pathol-011110-130203] [PMID: 20936937]
[7]
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, 110, 74-87.
[http://dx.doi.org/10.1016/j.ijbiomac.2017.09.014] [PMID: 28893682]
[8]
Crane, J.L.; Cao, X. Function of matrix IGF-1 in coupling bone resorption and formation. J. Mol. Med. (Berl.), 2014, 92(2), 107-115.
[http://dx.doi.org/10.1007/s00109-013-1084-3] [PMID: 24068256]
[9]
Trippel, S.B. Growth Factor Regulation of Osteogenesis.Bone Regeneration and Repair; Humana Press, 2005, pp. 113-132.
[http://dx.doi.org/10.1385/1-59259-863-3:113]
[10]
Zhou, L.; Zhang, T.; Sun, S.; Yu, Y.; Wang, M. Cryptochrome 1 promotes osteogenic differentiation of human osteoblastic cells via Wnt/β-Catenin signaling. Life Sci., 2018, 212, 129-137.
[http://dx.doi.org/10.1016/j.lfs.2018.09.053] [PMID: 30290183]
[11]
Duque, G.; Rivas, D. Alendronate has an anabolic effect on bone through the differentiation of mesenchymal stem cells. J. Bone Miner. Res., 2007, 22(10), 1603-1611.
[http://dx.doi.org/10.1359/jbmr.070701] [PMID: 17605634]
[12]
Srinaath, N.; Balagangadharan, K.; Pooja, V.; Paarkavi, U.; Trishla, A.; Selvamurugan, N. Osteogenic potential of zingerone, a phenolic compound in mouse mesenchymal stem cells. Biofactors, 2019, 45(4), 575-582.
[http://dx.doi.org/10.1002/biof.1515] [PMID: 31091349]
[13]
Balagangadharan, K.; Trivedi, R.; Vairamani, M.; Selvamurugan, N. Sinapic acid-loaded chitosan nanoparticles in polycaprolactone electrospun fibers for bone regeneration in vitro and in vivo. Carbohydr. Polym., 2019, 216, 1-16.
[http://dx.doi.org/10.1016/j.carbpol.2019.04.002] [PMID: 31047045]
[14]
Shanmugam, H.; Dharun, V.N.; Biswal, B.K.; Chandran, S.V.; Vairamani, M.; Selvamurugan, N. Osteogenic stimulatory effect of heraclenin purified from bael in mouse mesenchymal stem cells in vitro. Chem. Biol. Interact., 2019, 310, 108750.
[http://dx.doi.org/10.1016/j.cbi.2019.108750] [PMID: 31319076]
[15]
Phiel, C.J.; Zhang, F.; Huang, E.Y.; Guenther, M.G.; Lazar, M.A.; Klein, P.S. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J. Biol. Chem., 2001, 276(39), 36734-36741.
[http://dx.doi.org/10.1074/jbc.M101287200] [PMID: 11473107]
[16]
Chateauvieux, S.; Morceau, F.; Dicato, M.; Diederich, M. Molecular and therapeutic potential and toxicity of valproic acid. J. Biomed. Biotechnol., 2010, 2010, 479364.
[http://dx.doi.org/10.1155/2010/479364] [PMID: 20798865]
[17]
Vimalraj, S.; Selvamurugan, N. MicroRNAs: synthesis, gene regulation and osteoblast differentiation. Curr. Issues Mol. Biol., 2013, 15(1), 7-18.
[PMID: 22581832]
[18]
Vimalraj, S.; Miranda, P.J.; Ramyakrishna, B.; Selvamurugan, N. Regulation of breast cancer and bone metastasis by microRNAs. Dis. Markers, 2013, 35(5), 369-387.
[http://dx.doi.org/10.1155/2013/451248] [PMID: 24191129]
[19]
Song, J.; Jin, E.H.; Kim, D.; Kim, K.Y.; Chun, C.H.; Jin, E.J. MicroRNA-222 regulates MMP-13 via targeting HDAC-4 during osteoarthritis pathogenesis. BBA Clin., 2014, 3, 79-89.
[http://dx.doi.org/10.1016/j.bbacli.2014.11.009] [PMID: 26673737]
[20]
Okamoto, H.; Matsumi, Y.; Hoshikawa, Y.; Takubo, K.; Ryoke, K.; Shiota, G. Involvement of microRNAs in regulation of osteoblastic differentiation in mouse induced pluripotent stem cells. PLoS One, 2012, 7(8), e43800.
[http://dx.doi.org/10.1371/journal.pone.0043800] [PMID: 22937097]
[21]
Shreya, S.; Malavika, D.; Priya, V.R.; Selvamurugan, N. Regulation of Histone Deacetylases by MicroRNAs in Bone. Curr. Protein Pept. Sci., 2019, 20(4), 356-367.
[http://dx.doi.org/10.2174/1389203720666181031143129] [PMID: 30381072]
[22]
Arumugam, B.; Vishal, M.; Shreya, S.; Malavika, D.; Rajpriya, V.; He, Z.; Partridge, N.C.; Selvamurugan, N. Parathyroid hormone-stimulation of Runx2 during osteoblast differentiation via the regulation of lnc-SUPT3H-1:16 (RUNX2-AS1:32) and miR-6797-5p. Biochimie, 2019, 158, 43-52.
[http://dx.doi.org/10.1016/j.biochi.2018.12.006] [PMID: 30562548]
[23]
Dhivya, S.; Saravanan, S.; Sastry, T.P.; Selvamurugan, N. Nanohydroxyapatite-reinforced chitosan composite hydrogel for bone tissue repair in vitro and in vivo. J. Nanobiotechnology, 2015, 13(1), 40.
[http://dx.doi.org/10.1186/s12951-015-0099-z] [PMID: 26065678]
[24]
Menon, A.H.; Soundarya, S.P.; Sanjay, V.; Chandran, S.V.; Balagangadharan, K.; Selvamurugan, N. Sustained release of chrysin from chitosan-based scaffolds promotes mesenchymal stem cell proliferation and osteoblast differentiation. Carbohydr. Polym., 2018, 195, 356-367.
[http://dx.doi.org/10.1016/j.carbpol.2018.04.115] [PMID: 29804987]
[25]
Arumugam, B.; Balagangadharan, K.; Selvamurugan, N. Syringic acid, a phenolic acid, promotes osteoblast differentiation by stimulation of Runx2 expression and targeting of Smad7 by miR-21 in mouse mesenchymal stem cells. J. Cell Commun. Signal., 2018, 12(3), 561-573.
[http://dx.doi.org/10.1007/s12079-018-0449-3] [PMID: 29350343]
[26]
Vishal, M.; Vimalraj, S.; Ajeetha, R.; Gokulnath, M.; Keerthana, R.; He, Z.; Partridge, N.C.; Selvamurugan, N. MicroRNA-590-5p Stabilizes Runx2 by Targeting Smad7 During Osteoblast Differentiation. J. Cell. Physiol., 2017, 232(2), 371-380.
[http://dx.doi.org/10.1002/jcp.25434] [PMID: 27192628]
[27]
Selvamurugan, N.; He, Z.; Rifkin, D.; Dabovic, B.; Partridge, N.C. Pulsed electromagnetic field regulates MicroRNA 21 expression to activate TGF-β signaling in human bone marrow stromal cells to enhance osteoblast differentiation. Stem Cells Int., 2017, 2017, 2450327.
[http://dx.doi.org/10.1155/2017/2450327] [PMID: 28512472]
[28]
Narayanan, A.; Srinaath, N.; Rohini, M.; Selvamurugan, N. Regulation of Runx2 by MicroRNAs in osteoblast differentiation. Life Sci., 2019, 232, 116676.
[http://dx.doi.org/10.1016/j.lfs.2019.116676] [PMID: 31340165]
[29]
Mei, Y.; Bian, C.; Li, J.; Du, Z.; Zhou, H.; Yang, Z.; Zhao, R.C. miR-21 modulates the ERK-MAPK signaling pathway by regulating SPRY2 expression during human mesenchymal stem cell differentiation. J. Cell. Biochem., 2013, 114(6), 1374-1384.
[http://dx.doi.org/10.1002/jcb.24479] [PMID: 23239100]
[30]
Hatakeyama, Y.; Hatakeyama, J.; Takahashi, A.; Oka, K.; Tsuruga, E.; Inai, T.; Sawa, Y. The effect of valproic Acid on mesenchymal pluripotent cell proliferation and differentiation in extracellular matrices Drug Target Insights, 2011.
[http://dx.doi.org/10.4137/DTI.S6534]
[31]
Schroeder, T.M.; Westendorf, J.J. Histone deacetylase inhibitors promote osteoblast maturation. J. Bone Miner. Res., 2005, 20(12), 2254-2263.
[http://dx.doi.org/10.1359/JBMR.050813] [PMID: 16294278]
[32]
McGaw, L.J.; Elgorashi, E.E.; Eloff, J.N. Cytotoxicity of African medicinal plants against normal animal and human cells.Toxicological Survey of African Medicinal Plants; Elsevier, 2014, pp. 181-233.
[http://dx.doi.org/10.1016/B978-0-12-800018-2.00008-X]
[33]
Jones, K.H.; Senft, J.A. An improved method to determine cell viability by simultaneous staining with fluorescein diacetate-propidium iodide. J. Histochem. Cytochem., 1985, 33(1), 77-79.
[http://dx.doi.org/10.1177/33.1.2578146] [PMID: 2578146]
[34]
McGrath, J.J.; Cravalho, E.G.; Huggins, C.E. An experimental comparison of intracellular ice formation and freeze-thaw survival of HeLa S-3 cells. Cryobiology, 1975, 12(6), 540-550.
[http://dx.doi.org/10.1016/0011-2240(75)90048-6] [PMID: 1192762]
[35]
Gregory, C.A.; Gunn, W.G.; Peister, A.; Prockop, D.J. An Alizarin red-based assay of mineralization by adherent cells in culture: comparison with cetylpyridinium chloride extraction. Anal. Biochem., 2004, 329(1), 77-84.
[http://dx.doi.org/10.1016/j.ab.2004.02.002] [PMID: 15136169]
[36]
Paul, H.; Reginato, A.J.; Schumacher, H.R. Alizarin red S staining as a screening test to detect calcium compounds in synovial fluid. Arthritis Rheum., 1983, 26(2), 191-200.
[http://dx.doi.org/10.1002/art.1780260211] [PMID: 6186260]
[37]
Cao, L.; Liu, W.; Zhong, Y.; Zhang, Y.; Gao, D.; He, T.; Liu, Y.; Zou, Z.; Mo, Y.; Peng, S.; Shuai, C. Linc02349 promotes osteogenesis of human umbilical cord-derived stem cells by acting as a competing endogenous RNA for miR-25-3p and miR-33b-5p; Cell Proliferat, 2020, p. 12814.
[38]
Rungby, J.; Kassem, M.; Eriksen, E.F.; Danscher, G. The von Kossa reaction for calcium deposits: silver lactate staining increases sensitivity and reduces background. Histochem. J., 1993, 25(6), 446-451.
[http://dx.doi.org/10.1007/BF00157809] [PMID: 8360080]
[39]
Komori, T. Regulation of bone development and extracellular matrix protein genes by RUNX2. Cell Tissue Res., 2010, 339(1), 189-195.
[http://dx.doi.org/10.1007/s00441-009-0832-8] [PMID: 19649655]
[40]
Golub, E.E.; Boesze-Battaglia, K. The role of alkaline phosphatase in mineralization. Curr. Opin. Orthop., 2007, 18(5), 444-448.
[http://dx.doi.org/10.1097/BCO.0b013e3282630851]
[41]
Büttner, C.; Skupin, A.; Rieber, E.P. Transcriptional activation of the type I collagen genes COL1A1 and COL1A2 in fibroblasts by interleukin-4: analysis of the functional collagen promoter sequences. J. Cell. Physiol., 2004, 198(2), 248-258.
[http://dx.doi.org/10.1002/jcp.10395] [PMID: 14603527]
[42]
D’Alessio, M.; Bernard, M.; Pretorius, P.J.; de Wet, W.; Ramirez, F. Complete nucleotide sequence of the region encompassing the first twenty-five exons of the human pro α 1(I) collagen gene (COL1A1). Gene, 1988, 67(1), 105-115.
[http://dx.doi.org/10.1016/0378-1119(88)90013-3] [PMID: 2843432]
[43]
Ganesh, S. D. Saleth Sidharthan, S. Pranavkrishna, S. Pranavadithya, R. Abhinandan, R. L. Akshaya, K. Balagangadharan, Nishitha Siddabathuni, Swathi Srinivasan, and N. Selvamurugan. An osteoinductive effect of phytol on mouse mesenchymal stem cells (C3H10T1/2) towards osteoblasts. Bioorg. Med. Chem. Lett., 2020, 127137.
[44]
Torre, E. Molecular signaling mechanisms behind polyphenol-induced bone anabolism. Phytochem. Rev., 2017, 16(6), 1183-1226.
[http://dx.doi.org/10.1007/s11101-017-9529-x] [PMID: 29200988]
[45]
Chandran, S. Viji, M. Vairamani, and N. Selvamurugan. Osteostimulatory effect of biocomposite scaffold containing phytomolecule diosmin by Integrin/FAK/ERK signaling pathway in mouse mesenchymal stem cells. Sci. Rep., 2019, 9(1), 1-13.
[http://dx.doi.org/10.1038/s41598-019-48429-1] [PMID: 30626917]
[46]
Xiao, H-H.; Gao, Q-G.; Zhang, Y.; Wong, K-C.; Dai, Y.; Yao, X-S.; Wong, M-S. Vanillic acid exerts oestrogen-like activities in osteoblast-like UMR 106 cells through MAP kinase (MEK/ERK)-mediated ER signaling pathway. J. Steroid Biochem. Mol. Biol., 2014, 144(Pt B), 382-391.
[http://dx.doi.org/10.1016/j.jsbmb.2014.08.002] [PMID: 25106917]
[47]
Song, L.; Zhao, J.; Zhang, X.; Li, H.; Zhou, Y. Icariin induces osteoblast proliferation, differentiation and mineralization through estrogen receptor-mediated ERK and JNK signal activation. Eur. J. Pharmacol., 2013, 714(1-3), 15-22.
[http://dx.doi.org/10.1016/j.ejphar.2013.05.039] [PMID: 23764463]
[48]
Franceschi, R.T.; Ge, C. Control of the Osteoblast Lineage by Mitogen-Activated Protein Kinase Signaling. Curr. Mol. Biol. Rep., 2017, 3(2), 122-132.
[http://dx.doi.org/10.1007/s40610-017-0059-5] [PMID: 29057206]
[49]
Ge, C.; Xiao, G.; Jiang, D.; Franceschi, R.T. Critical role of the extracellular signal-regulated kinase-MAPK pathway in osteoblast differentiation and skeletal development. J. Cell Biol., 2007, 176(5), 709-718.
[http://dx.doi.org/10.1083/jcb.200610046] [PMID: 17325210]

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