Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Icariin Accelerates Fracture Healing via Activation of the WNT1/β-catenin Osteogenic Signaling Pathway

Author(s): Xiao-Yun Zhang*, Yue-Ping Chen*, Chi Zhang, Xuan Zhang, Tian Xia, Jie Han, Nan Yang, Shi-Lei Song and Can-Hong Xu

Volume 21, Issue 15, 2020

Page: [1645 - 1653] Pages: 9

DOI: 10.2174/1389201021666200611121539

Price: $65

Abstract

Background: Icariin has been shown to enhance bone formation.

Objective: The present study aimed to investigate whether icariin also promotes bone fracture healing and its mechanisms.

Methods: First, we isolated and cultured rat bone marrow stromal cells (rBMSCs) with icariincontaining serum at various concentrations (0%, 2.5%, 5% and 10%) and then measured alkaline phosphatase (ALP) activity and the expression of Core-binding factor, alpha 1 (Cbfα1), bone morphogenetic protein-2 (BMP-2) and bone morphogenetic protein-4 (BMP-4) in the rBMSCs. Second, we established a model of fracture healing in rats and performed gavage treatment for 20 days. Then, we detected bone biochemical markers (ELISA kits) in the serum, fracture healing (digital radiography, DR), and osteocalcin expression (immunohistochemistry).

Results: Icariin treatment increased ALP activity and induced the expression of Cbfα1, BMP-2 and BMP-4 in rBMSCs in a dose-dependent manner. In addition, Icariin increased the serum levels of osteocalcin (OC), bone-specific alkaline phosphatase (BAP), N-terminal telopeptides of type I collagen (NTX-1), C-terminal telopeptide of type I collagen (CTX-1) and tartrate-resistant acid phosphatase 5b (TRACP-5b); promoted osteocalcin secretion at the fracture site; and accelerated fracture healing.

Conclusion: Icariin can promote the levels of bone-formation markers, accelerate fracture healing, and activate the WNT1/β-catenin osteogenic signaling pathway.

Keywords: Icariin, rat bone marrow stromal cells, fracture healing, WNT1/β-catenin, ELISA kits, osteocalcin expression.

« Previous Next »
Graphical Abstract

[1]
Dimitriou, R.; Jones, E.; McGonagle, D.; Giannoudis, P.V. Bone regeneration: Current concepts and future directions. BMC Med., 2011, 9, 66-6.
[http://dx.doi.org/10.1186/1741-7015-9-66] [PMID: 21627784]
[2]
Giannoudis, P.; Tzioupis, C.; Almalki, T.; Buckley, R. Fracture healing in osteoporotic fractures: Is it really different? A basic science perspective. Injury, 2007, 38(Suppl. 1), S90-S99.
[http://dx.doi.org/10.1016/j.injury.2007.02.014] [PMID: 17383490]
[3]
Fazzalari, N.L. Bone fracture and bone fracture repair. Osteoporos. Int., 2011, 22(6), 2003-2006.
[http://dx.doi.org/10.1007/s00198-011-1611-4] [PMID: 21523400]
[4]
Wang, W.L.; Sheu, S.Y.; Chen, Y.S.; Kao, S.T.; Fu, Y.T.; Kuo, T.F.; Chen, K.Y.; Yao, C.H. Enhanced bone tissue regeneration by porous gelatin composites loaded with the Chinese herbal decoction Danggui buxue tang. PLoS One, 2015, 10(6)e0131999
[http://dx.doi.org/10.1371/journal.pone.0131999] [PMID: 26126113]
[5]
Cheng, K.; Chen, K.M.; Ge, B.F.; Zhen, P.; Gao, Y.H.; Ma, H.P. Comparison research with icariin and genistein by anti-inflammatory reaction and angiogenesis pathway to inhibit bone loss on ovariectomized rats. Zhong Yao Cai, 2014, 37(4), 627-631.
[PMID: 25345138]
[6]
Wang, L.; Zhang, L.; Chen, Z.B.; Wu, J.Y.; Zhang, X.; Xu, Y. Icariin enhances neuronal survival after oxygen and glucose deprivation by increasing SIRT1. Eur. J. Pharmacol., 2009, 609(1-3), 40-44.
[http://dx.doi.org/10.1016/j.ejphar.2009.03.033] [PMID: 19303870]
[7]
Cheng, K.; Ge, B.F.; Chen, K.M.; Zhen, P.; Zhou, J.; Ma, X.N.; Song, P.; Ma, H.P. Oral medication of icariin enhances peak bone mineral density and bone quality in rats. Chin. J. Osteopor., 2014, 20, 120-124.
[8]
Peng, S.; Zhang, G.; He, Y.; Wang, X.; Leung, P.; Leung, K.; Qin, L. Epimedium-derived flavonoids promote osteoblastogenesis and suppress adipogenesis in bone marrow stromal cells while exerting an anabolic effect on osteoporotic bone. Bone, 2009, 45(3), 534-544.
[http://dx.doi.org/10.1016/j.bone.2009.05.022] [PMID: 19501202]
[9]
Qin, S.; Zhou, W.; Liu, S.; Chen, P.; Wu, H. Icariin stimulates the proliferation of rat bone mesenchymal stem cells via ERK and p38 MAPK signaling. Int. J. Clin. Exp. Med., 2015, 8(5), 7125-7133.
[PMID: 26221250]
[10]
Cao, H.; Zhang, Y.; Qian, W.; Guo, X.P.; Sun, C.; Zhang, L.; Cheng, X.H. Effect of icariin on fracture healing in an ovariectomized rat model of osteoporosis. Exp. Ther. Med., 2017, 13(5), 2399-2404.
[http://dx.doi.org/10.3892/etm.2017.4233] [PMID: 28565854]
[11]
Kim, K.; Dean, D.; Lu, A.; Mikos, A.G.; Fisher, J.P. Early osteogenic signal expression of rat bone marrow stromal cells is influenced by both hydroxyapatite nanoparticle content and initial cell seeding density in biodegradable nanocomposite scaffolds. Acta Biomater., 2011, 7(3), 1249-1264.
[http://dx.doi.org/10.1016/j.actbio.2010.11.007] [PMID: 21074640]
[12]
Jiang, T.S.; Cai, L.; Ji, W.Y.; Hui, Y.N.; Wang, Y.S.; Hu, D.; Zhu, J. Reconstruction of the corneal epithelium with induced marrow mesenchymal stem cells in rats. Mol. Vis., 2010, 16, 1304-1316.
[PMID: 20664793]
[13]
Sukhikh, G.T.; Malaitsev, V.V.; Bogdanova, I.M.; Dubrovina, I.V. Mesenchymal stem cells. Bull. Exp. Biol. Med., 2002, 133(2), 103-109.
[http://dx.doi.org/10.1023/A:1015560831444] [PMID: 12428273]
[14]
Huang, S.; Xu, L.; Zhang, Y.; Sun, Y.; Li, G. Systemic and local administration of allogeneic bone marrow-derived mesenchymal stem cells promotes fracture healing in rats. Cell Transplant., 2015, 24(12), 2643-2655.
[http://dx.doi.org/10.3727/096368915X687219] [PMID: 25647659]
[15]
Xu, J.H.; Yao, M.; Ye, J.; Wang, G.D.; Wang, J.; Cui, X.J.; Mo, W. Bone mass improved effect of icariin for postmenopausal osteoporosis in ovariectomy-induced rats: A meta-analysis and systematic review. Menopause, 2016, 23(10), 1152-1157.
[http://dx.doi.org/10.1097/GME.0000000000000673 ] [PMID: 27648597]
[16]
Chen, K.M.; Ge, B.F.; Ma, H.P.; Liu, X.Y.; Bai, M.H.; Wang, Y. Icariin, a flavonoid from the herb Epimedium enhances the osteogenic differentiation of rat primary bone marrow stromal cells. Pharmazie, 2005, 60(12), 939-942.
[PMID: 16398272]
[17]
Wu, Y.; Xia, L.; Zhou, Y.; Xu, Y.; Jiang, X. Icariin induces osteogenic differentiation of bone mesenchymal stem cells in a MAPK-dependent manner. Cell Prolif., 2015, 48(3), 375-384.
[http://dx.doi.org/10.1111/cpr.12185] [PMID: 25867119]
[18]
He, W.; Li, Z.L.; Cui, Y.L.; Yi, B.; Liang, C.; Wang, X.X.; Li, Y.; Wang, X. Effect of icariin on the mRNA expressions of Cbfalpha1, BMP2, BMP4 in rat osteoblasts. Beijing Da Xue Xue Bao, 2009, 41(6), 669-673.
[PMID: 20019778]
[19]
Hsieh, T.P.; Sheu, S.Y.; Sun, J.S.; Chen, M.H.; Liu, M.H. Icariin isolated from Epimedium pubescens regulates osteoblasts anabolism through BMP-2, SMAD4, and Cbfa1 expression. Phytomedicine, 2010, 17(6), 414-423.
[http://dx.doi.org/10.1016/j.phymed.2009.08.007] [PMID: 19747809]
[20]
Kojima, H.; Uemura, T. Strong and rapid induction of osteoblast differentiation by Cbfa1/Til-1 overexpression for bone regeneration. J. Biol. Chem., 2005, 280(4), 2944-2953.
[http://dx.doi.org/10.1074/jbc.M311598200] [PMID: 15537653]
[21]
Rivera, J.C.; Strohbach, C.A.; Wenke, J.C.; Rathbone, C.R. Beyond osteogenesis: An in vitro comparison of the potentials of six bone morphogenetic proteins. Front. Pharmacol., 2013, 4, 125-131.
[http://dx.doi.org/10.3389/fphar.2013.00125] [PMID: 24101902]
[22]
Froberg, M.K.; Garg, U.C.; Stroncek, D.F.; Geis, M.; McCullough, J.; Brown, D.M. Changes in serum osteocalcin and bone-specific alkaline phosphatase are associated with bone pain in donors receiving granulocyte-colony-stimulating factor for peripheral blood stem and progenitor cell collection. Transfusion, 1999, 39(4), 410-414.
[http://dx.doi.org/10.1046/j.1537-2995.1999.39499235675.x ] [PMID: 10220269]
[23]
Moghaddam, A.; Müller, U.; Roth, H.J.; Wentzensen, A.; Grützner, P.A.; Zimmermann, G. TRACP 5b and CTX as osteological markers of delayed fracture healing. Injury, 2011, 42(8), 758-764.
[http://dx.doi.org/10.1016/j.injury.2010.11.017] [PMID: 21168135]
[24]
Plantalech, L.; Guillaumont, M.; Vergnaud, P.; Leclercq, M.; Delmas, P.D. Impairment of gamma carboxylation of circulating osteocalcin (bone gla protein) in elderly women. J. Bone Miner. Res., 1991, 6(11), 1211-1216.
[http://dx.doi.org/10.1002/jbmr.5650061111] [PMID: 1666807]
[25]
Aydin, A.; Halici, Z.; Akoz, A.; Karaman, A.; Ferah, I.; Bayir, Y.; Aksakal, A.M.; Akpinar, E.; Selli, J.; Kovaci, H. Treatment with α-lipoic acid enhances the bone healing after femoral fracture model of rats. Naunyn Schmiedebergs Arch. Pharmacol., 2014, 387(11), 1025-1036.
[http://dx.doi.org/10.1007/s00210-014-1021-1] [PMID: 25038619]
[26]
Zhang, R.; Oyajobi, B.O.; Harris, S.E.; Chen, D.; Tsao, C.; Deng, H.W.; Zhao, M. Wnt/β-catenin signaling activates bone morphogenetic protein 2 expression in osteoblasts. Bone, 2013, 52(1), 145-156.
[27]
Robinson, J.A.; Chatterjee-Kishore, M.; Yaworsky, P.J.; Cullen, D.M.; Zhao, W.; Li, C.; Kharode, Y.; Sauter, L.; Babij, P.; Brown, E.L.; Hill, A.A.; Akhter, M.P.; Johnson, M.L.; Recker, R.R.; Komm, B.S.; Bex, F.J. Wnt/β-catenin signaling is a normal physiological response to mechanical loading in bone. J. Biol. Chem., 2006, 281(42), 31720-31728.
[http://dx.doi.org/10.1074/jbc.M602308200] [PMID: 16908522]
[28]
Kook, S.H.; Heo, J.S.; Lee, J.C. Crucial roles of canonical Runx2-dependent pathway on Wnt1-induced osteoblastic differentiation of human periodontal ligament fibroblasts. Mol. Cell. Biochem., 2015, 402(1-2), 213-223.
[http://dx.doi.org/10.1007/s11010-015-2329-y] [PMID: 25618247]
[29]
Bao, Q.; Chen, S.; Qin, H.; Feng, J.; Liu, H.; Liu, D.; Li, A.; Shen, Y.; Zhao, Y.; Li, J.; Zong, Z. An appropriate Wnt/β-catenin expression level during the remodeling phase is required for improved bone fracture healing in mice. Sci. Rep., 2017, 7(1), 2695.
[http://dx.doi.org/10.1038/s41598-017-02705-0] [PMID: 28578392]

Rights & Permissions Print Cite
Article Metrics
31
1
© 2024 Bentham Science Publishers | Privacy Policy