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通讯作者:

陈克明(1968-),男,甘肃兰州人,主任技师,主要从事加速高原战创伤性骨折愈合的研究。E-mail:chenkm@lut.edu.cn

中图分类号:R96,R683

文献标识码:A

文章编号:2096-8965(2021)01-0089-06

DOI:10.12287/j.issn.2096-8965.20210113

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参考文献 13
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参考文献 17
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参考文献 18
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辛红美,许洁,汪长东.淫羊藿苷促进 MC3T3-E1 成骨分化通过Hedgehog信号通路[J].中国药理学通报,2020,36(5):616-620.
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参考文献 25
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参考文献 39
张庆宇,高福强,程立明,等.淫羊藿苷对骨微血管内皮细胞自噬及外泌体产生的影响[J].中国修复重建外科杂志,2019,33(5):568-577.
目录contents

    摘要

    近年来 , 国内外学者对中药淫羊藿主要有效成分淫羊藿苷加速骨折愈合的机制做了一系列研究,目前研究结果显示, 淫羊藿苷加速骨折愈合的机制主要是通过激活 Wnts、BMP、MAPK、ER 等相关信号通路促进 BMSCs、ASCs 的迁移归巢,进行成骨性分化为成骨细胞,同时促进成骨细胞的成熟、矿化以形成骨痂,并抑制破骨细胞的骨吸收活性。本文从淫羊藿苷对相关细胞以及对血管重建的作用方面对淫羊藿苷加速骨折愈合的作用机制做一回顾综述,以期为后续的研究提供参考。

    Abstract

    In recent years, international and domestic academics have made a series of studies on the mechanism of icariin which is the main effective component of Herba Epimedii, to accelerate fracture healing. The current research results show that the mechanism of icariin accelerating fracture healing is to promote the migration and homing of BMSCs and ASCs by activating Wnts, BMP, MAPK, ER and other related signal pathways, so as to carry out osteogenic differentiation into osteoblasts. At the same time, it can promote the maturation and mineralization of osteoblasts to form callus, and inhibit the bone resorption activity of osteoclasts. This article reviews the mechanism of icariin in accelerating fracture healing from the aspects of its effects on related cells and vascular remodeling, so as to provide reference for the follow-up research.

  • 淫羊藿性温而味甘,具有壮肾阳,强筋骨,祛风湿等功效,临床上常用于治疗肾阳虚衰导致的筋骨痿软、风湿痹痛等病证。近年来随着对中药淫羊藿的开发,国内外学者已经证实淫羊藿具有良好的抗骨质疏松的作用。淫羊藿苷(Icriin,ICA)作为中药淫羊藿的主要有效成分,具有明显的成骨活性,相关研究显示ICA可以促进骨痂的形成,在骨折愈合方面具有良好的促进作用 [1-3],本文从淫羊藿苷促进骨折愈合的细胞机制及促进血管生成机制方面,对其促进骨折愈合作用机制的研究进展情况做一综述。

  • 1 淫羊藿苷对骨髓间充质干细胞的作用及作用机制

  • 骨髓间充质干细胞(Bone Marrow Mesenchymal Stem Cells,BMSCs)作为具有多项分化潜能的干细胞,在骨折愈合的阶段中发挥着重要的作用, BMSCs通过增殖分化以促进受损部位的修复 [4]。近年来,国内外学者通过探究淫羊藿苷对BMSCs的作用发现ICA可以加速BMSCs迁移归巢至受损部位,并促进其进一步增殖以及成骨性分化,进而促进骨折的愈合。

  • 1.1 淫羊藿苷促进骨髓间充质干细胞迁移归巢

  • 骨损伤修复是一个复杂的过程,其机制主要表现为干细胞归巢到受损部位和干细胞增殖,因此,招募和归巢内源性干细胞对改善和修复受损的组织是一种极为有效的修复方法 [5]。BMSCs具有自我不断更新的特性和分化出多种细胞的功能,在适当条件下可分化为成骨细胞和脂肪细胞以及内皮细胞等多种细胞。作为成骨细胞的前体细胞,BMSCs不仅能调节正常的骨骼细胞平衡,也在骨折修复中起着重要作用 [6]。骨髓抽吸物中只有约0.001%~0.01%的BMSCs,而且大多数都处于静止期,故促进BMSCs迁移以及激活BMSCs进入细胞周期进行增殖、分化成为重中之重 [5]。研究发现趋化因子受体4[Chemokine(C-X-C motif) Receptor 4, CXCR4]在干细胞归巢过程中具有重要调节作用, CXCR4通过在BMSCs中表达而提升骨髓间充质干细胞的迁移速率。而ICA可通过激活雌激素受体(Estrogen Receptor,ER)介导的缺氧诱导因子1β(Hypoxia Inducible Factor-1β,HIF-1β)的表达以增强CXCR4的活性,进而促进BMSCs的迁移 [5, 7]。此外,ICA诱导的骨髓间充质干细胞迁移的机制还涉及通过激活MARK信号通路刺激肌动蛋白应力纤维的形成而促进BMSCs迁移归巢 [5, 7]

  • 1.2 淫羊藿苷促进骨髓间充质干细胞成骨分化而抑制其成脂分化

  • 研究发现,低剂量的ICA可以迫使BMSCs进入细胞周期从而进行增殖,进而诱导和促进骨髓基质干细胞进行矿化和成骨性分化 [6]。骨质疏松症(Osteoporosis,OP)患者骨髓腔内会出现脂肪浸润,而这种骨髓内脂质的形成可能是由于BMSCs成骨性分化和成脂性分化之间的平衡失调所致 [8]。 ICA在促进BMSCs增殖和成骨性分化的同时,还发挥了抑制其成脂分化的作用,这种抑制作用主要是通过激活BMSCs自噬的方式来完成 [9]。另有研究发现,ICA通过激活ER、BMP/Smads/Runx2/Osx信号通路而上调Runx2和COL-Ⅰ的表达水平,两者分别是最重要的成骨发生转录因子和骨基质蛋白 [10, 11],与此同时,对参与脂肪分化的重要转录因子PPARγ 和C/EBPα 的表达水平进行下调,以促进BMSCs进行成骨性分化和抑制BMSCs向脂肪细胞分化 [12]。Liu等发现,ICA抑制BMSCs向脂肪细胞分化的作用是通过抑制Notch1的胞内结构域(Notch1Intracellular Domain, N1ICD)而抑制Notch2信使RNA的表达,进而阻断Notch信号通路以抑制PPARγ、C/EBPα 和FABP4的信使RNA表达水平来实现的 [13]。Miao等通过研究ICA对比格犬BMSCs成骨性分化的影响发现,ICA可促进BMSCs增殖并提高其碱性磷酸酶(Alkaline Phosphates, ALP) 活性,进而诱导BMSCs成骨分化 [14]

  • 1.3 淫羊藿苷促进骨髓间充质干细胞增殖

  • ICA通过调节多种信号途径以促进BMSCs发挥增殖以及成骨性分化的作用,包括MARK、 BMP、Wnt/β-catenin等多条信号通路 [15, 16]。相关研究报告指出, ICA促进BMSCs增殖的作用与MARK信号传导通路中ERK、p38和JNK的磷酸化有关,并与MARK靶点Elk-1和c-Myc上调有关。另外,ERα 和Wnt/β-catenin信号传导通路也参与介导了ICA促进大鼠BMSCs成骨性分化的作用,同时淫羊藿苷增强PDZ结合基序TAZ的表达主要是通过ERα-Wnt/β-catenin信号通路介导的 [17, 18]。另有研究发现,ICA通过BMP2信号途径上调BMSCs中BMAL1的表达促进成骨分化 [11, 19]

  • 2 淫羊藿苷对脂肪间充质干细胞的作用及作用机制

  • 脂肪间充质干细胞(Adipose-derived Stem Cells,ASCs)是指从脂肪组织分离出来并能朝着多种表型进行分化的具有自我更新能力的间充质干细胞,相比于BMSCs具有更高的增殖能力。相关研究表明,ICA作为强效的骨诱导因子,主要通过RhoA途径激活TAZ促进ASCs增殖和成骨性分化 [20]。除此之外,ICA可直接或间接激活BMP信号,诱导相关转录因子基因表达,上调骨基质基因,最终促进脂肪间充质干细胞成骨性分化 [21]

  • 3 淫羊藿苷对成骨细胞的作用及作用机制

  • 在骨折愈合中,成骨细胞有着至关重要的作用,在骨折以及骨缺损恢复的过程中,需要成骨细胞来建立新的骨骼,近年来研究发现,ICA可以促进成骨细胞的增殖,加速成骨细胞的成熟和矿化进程, ICA在促进成骨细胞活力的同时还抑制成骨细胞的凋亡活动 [22, 23]。相关研究结果显示,低浓度的ICA(浓度0.15~15 μM)可以促进成骨细胞在72小时孵育后的增殖和分化。同时发现,ICA可加速成骨细胞的基质矿化过程,激活成骨细胞中ALP的活性,上调成骨细胞中 β-catenin、Runx2、cyclin D1、ALP以及miRNA-21-5p的mRNA表达水平,又通过相关实验证明了Wnt/β-catenin信号通路可能参与了ICA诱导的大鼠下颌骨成骨细胞的增殖和分化 [24, 25]。另有研究发现,ICA通过miRNA53/Runx2途径在MC3T3-E1成骨细胞中发挥强大的成骨细胞分化作用 [23]。本课题组前期研究发现,ICA还可以通过激活CAMP/PKA/CREB信号轴来增强BMP2介导的C2C12细胞的成骨细胞分化,在进一步研究中发现,将成骨细胞表面的初级纤毛敲除后,这些作用会大大减弱甚至消失,这说明初级纤毛在成骨细胞分化和矿化中发挥重要的作用。更进一步的研究发现,ICA是通过成骨细胞上的功能性纤毛基底的囊和位于整体纤毛体上的p-PKA激活CAMP/PKA/CREB信号通路发挥成骨作用 [27-29]。除此之外,ICA通过促进结缔组织生长因子表达而增强BMP-2诱导成骨细胞分化,从而对成骨细胞分化进行严格的调控 [30],并通过ER途径上调成骨细胞OPG/RANKL的表达比例 [31],以及通过抑制Notch信号传导途径加快成骨细胞的分化 [32]。Li等通过探讨淫羊藿苷在骨保护素(Osteoprotegerin, OPG)基因敲除小鼠中的成骨作用及其机制发现ICA可显著刺激新骨形成,通过实时PCR检测发现ICA显著上调小鼠BMP2、BMP4、Runx2、骨钙素(Osteocalcin,OC)、Wnt1和Wnt3a的表达,与此同时ICA还显著促进了 β-catenin信号通路的直接靶基因AXIN2、DKK1、TCF1和LEF1的表达,体外研究也得出ICA通过Wnt/β-catenin-BMP信号传导通路,诱导成骨细胞的分化 [33]。另有研究也指出,ICA促进成骨细胞增殖、分化以及矿化的作用是通过激活Wnt/β-catenin和ER信号传导通路实现的 [12, 34]

  • 4 淫羊藿苷对破骨细胞的作用及作用机制

  • 破骨细胞作为参与调节骨稳态的重要多核细胞,其是由单核细胞/巨噬细胞谱系的造血干细胞分化而产生的多核细胞,RANKL作为活化因子参与破骨细胞的分化过程,而治疗破骨细胞参与的相关疾病的方法之一便是通过抑制RANKL诱导的信号传导通路进行相应的治疗,多项研究指出,ICA具有抑制破骨细胞分化和成熟及降低其骨吸收活性的作用,其机制为ICA通过抑制NF-κB信号通路的激活,从而抑制破骨细胞的形成 [35, 36]。同时, ICA对破骨细胞分化的抑制作用还可能通过调节成熟破骨细胞MAPK磷酸化来介导。除此之外,ICA可通过提高破骨细胞抑制因子(Osteoclastogenesis Inhibitory Factor,OPG)含量来抑制RANKL的激活,从而上调OPG/RANKL比值以抑制破骨细胞的分化和成熟。另一项研究表明,ICA通过抑制NF-κB信号通路的激活,阻断MCF7和MDAMB-231诱导的破骨细胞生成以及抑制参与破骨细胞形成和骨吸收的相关基因的表达,而达到抑制破骨细胞前体向破骨细胞分化的目的,另外发现ICA抑制RANKL刺激的TRAF-6的表达,并随后抑制ERK的磷酸化,但淫羊藿苷对p38、JNK和Akt活化没有影响 [37]

  • 5 淫羊藿苷促进骨折血管重建的作用及作用机制

  • 骨折后血管重建对骨折愈合有着重要作用,通过血运的恢复以保证骨折断端的营养支持,并提供相应的细胞因子以促进骨折的愈合。研究表明, ICA可以通过促进血管生长因子VEGF和ANG1的表达以促进血管的生成,其中VEGF在血管发育的早期阶段发挥作用,而ANG1作用于新生血管发育的晚期阶段 [36]。另有研究表明,VEGF是通过激活p38/MAPK信号途径刺激新生血管的生成和增强 [38]。另外,ICA还可通过促进BMSCs产生外泌体对其自噬产生抑制作用,同时促进内皮细胞的迁移和血管的生成 [39]。总之,ICA可以通过相关途径促进血管的生成,以维持骨再生,间接地促进骨折的愈合。

  • 6 总结与展望

  • 目前,已经有大量研究证实ICA可以促进骨折愈合,其机制主要是通过以下途径实现的: Wnts、BMP、MAPK、ER等相关信号通路促进BMSCs、ASCs的迁移归巢,进行成骨性分化为成骨细胞,同时促进成骨细胞的成熟、矿化以形成骨痂,并抑制破骨细胞的骨吸收活性。虽然目前对于ICA促进骨折愈合的机制研究较多,但多数仍停留在细胞层面,对于在体机制的研究还相对较少,生物机体较细胞更复杂更系统,同时骨折愈合过程也涉及包括肌肉系统、神经系统、循环系统等多系统参与的修复过程,其在体作用机制仍需进一步系统的研究。另外,值的注意的是, ICA对破骨细胞的骨吸收活性具有抑制作用,而骨折愈合后期即骨板形成塑型期是通过破骨细胞的骨吸收活性对骨痂进行塑型,如何应用ICA调控骨折修复过程中骨吸收与骨重建的平衡,也有待进一步研究。

  • 综上,本文对ICA加速骨折愈合的相关研究进行了初步的归纳与总结,以期对以后的研究起到一定的参考价值,同时更希望对骨折的临床治疗有一定的帮助,虽然目前对于ICA加速骨折愈合的细胞分子机制研究相对深入,但仍需在体实验的系统研究,更为主要的是,通过相关实验系统地评价其治疗效果,还要对其服药周期,以及给药方式进行相关的研究与分析,以期发挥其最大的临床价值。此外,由于淫羊藿苷的水溶性较差,口服利用率相对较低,将淫羊藿苷加载于生物载体材料进行局部应用,可达到局部控释给药的目的,提高生物利用率,促进骨再生,为加速骨折愈合及修复大面积骨缺损提供了新方法。

  • 参考文献

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    • [2] CAO H,ZHANG Y,QIAN W,et al.Effect of icariin on fracture healing in an ovariectomized rat model of osteoporosis[J].Experimental and Therapeutic Medicine,2017,13(5):2399-2404.

    • [3] 王惠平,何爱咏,常晓飞.不同剂量比淫羊藿苷与辛伐他汀对家兔桡骨骨折愈合的影响[J].中国组织工程研究,2013,17(15):2703-2713.

    • [4] 贾朗,黄荣忠,王愉乐,等.不同强度体外冲击波联合骨髓间充质干细胞移植对大鼠骨缺损的修复效果[J].上海交通大学学报(医学版),2016,36(12):1706-1712.

    • [5] ZHU H Y,WANG X X,HAN Y Y,et al.Icariin promotes the migration of bone marrow stromal cells via the SDF-1α/HIF-1α/CXCR4 pathway[J].Drug Design Development & Therapy,2018,12:4023-4031.

    • [6] FU S P,YANG L,HONG H,et al.Wnt/β-catenin signaling is involved in the Icariin induced proliferation of bone marrow mesenchymal stem cells[J].Journal of Traditional Chinese Medicine,2016,36(3):360-368.

    • [7] JIAO F,TANG W,HUANG H,et al.Icariin promotes the migration of BMSCs in vitro and in vivo via the MAPK signaling pathway[J].Stem Cells International,2018,2018(1):1-9.

    • [8] HUANG J M,BAO Y,XIANG W,et al.Icariin regulates the bidirectional differentiation of bone marrow mesenchymal stem cells through canonical wnt signaling pathway[J].Evidence-based Complementray and Alternative Medicine,2017,2017(1-4):8085325.

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    • [10] LUO Z,LIU M,SUN L,et al.Icariin recovers the osteogenic differentiation and bone formation of bone marrow stromal cells from a rat model of estrogen defi ciency-induced osteoporosis[J].Molecular Medicine Reports,2015,12(1):382-388.

    • [11] 訾慧,范颖,蒋宁,等.淫羊藿次苷Ⅰ及淫羊藿次苷Ⅱ 通过 BMP/Runx2/Osx 信号通路促进大鼠骨髓间充质干细胞成骨分化的实验研究[J].中国骨质疏松杂志,2019,25(5):690-695.

    • [12] LI X,PENG B,PAN Y,et al.Icariin stimulates osteogenic differentiation and suppresses adipogenic differentiation of rBMSCs via estrogen receptor signaling[J].Molecular Medicine Reports,2018,18(3):3483-3489.

    • [13] LIU H,XIONG Y,ZHU X,et al.Icariin improves osteoporosis,inhibits the expression of PPARγ,C/EBPα,FABP4 mRNA,N1ICD and jagged1 proteins,and increases Notch2 mRNA in ovariectomized rats[J].Experimental and Therapeutic Medicine,2017,13(4):1-9.

    • [14] MIAO G,ZHANG Y,HUANG Y.Effects of icariin on osteogenic differentiation of bone marrow stromal cells in beagle canine[J].International Journal of Clinical and Experimental Pathology,2017,10(8):8957-8967.

    • [15] QIN S,ZHOU W,LIU S,et al.Icariin stimulates the proliferation of rat bone mesenchymal stem cells via ERK and p38 MAPK signaling[J].International Journal of Clinical and Experimental Medicine,2015,8(5):7125-7133.

    • [16] WU Y,XIA L,ZHOU Y,et al.Icariin induces osteogenic differentiation of bone mesenchymal stem cells in a MAPK-dependent manner[J].Cell Proliferation,2015,48(3):375-384.

    • [17] WEI Q S,ZHANG J,HONG G J,et al.Icariin promotes osteogenic differentiation of rat bone marrow stromal cells by activating the ERα-Wnt/β-catenin signaling pathway[J].Biomedicine & Pharmacotherapy,2016,84:931-939.

    • [18] WEI Q S,HE M C,CHEN M H,et al.Icariin stimulates osteogenic differentiation of rat bone marrow stromal stem cells by increasing TAZ expression[J].Biomedicine & Pharmacotherapy,2017,91:581-589.

    • [19] HUANG Z,WEI H,WANG X,et al.Icariin promotes osteogenic differentiation of BMSCs by upregulating BMAL1 expression via BMP signaling[J].Molecular Medicine Reports,2020,21(3):10954.

    • [20] YE Y P,JING X Z,LI N,et al.Icariin promotes proliferation and osteogenic diff erentiation of rat adiposederived stem cells by activating the RhoA-TAZ signaling pathway[J].Biomedecine & Pharmacotherapie,2017,88:384-397.

    • [21] WU T,SHU T,KANG T,et al.Icaritin,a novel plantderived osteoinductive agent,enhances the osteogenic differentiation of human bone marrow and human adipose tissue-derived mesenchymal stem cells[J].International Journal of Molecular Medicine,2017,39(4):984-992.

    • [22] QIAN W,SU Y,ZHANG Y,et al.Secretome analysis of rat osteoblasts during icariin treatment induced osteogenesis[J].Molecular Medicine Reports,2018,17(5):6515-6525.

    • [23] 辛红美,许洁,汪长东.淫羊藿苷促进 MC3T3-E1 成骨分化通过Hedgehog信号通路[J].中国药理学通报,2020,36(5):616-620.

    • [24] WANG Y,WANG R,ZHANG F.Icariin promotes the proliferation and differentiation of osteoblasts from the rat mandible by the Wnt/β catenin signalling pathway[J].Molecular Medicine Reports,2018,18(3):3445-3450.

    • [25] LIAN F,ZHAO C,QU J,et al.Icariin attenuates titanium particle‐induced inhibition of osteogenic diff erentiation and matrix mineralization via miR-21-5p[J].Cell Biology International,2018,42(8):931-939.

    • [26] HUANG Z,CHENG C,WANG J,et al.Icariin regulates the osteoblast differentiation and cell proliferation of MC3T3E1 cells through microRNA153 by targeting runt-related transcription factor 2[J].Experimental and Therapeutic Medicine,2018,15(6):5159-5166.

    • [27] CHEN M,CUI Y,LI H,et al.Icariin promotes the osteogenic action of BMP2 by activating the cAMP signaling pathway[J].Molecules,2019,24(21):3875.

    • [28] MA X,MA C,SHI W,et al.Primary cilium is required for the stimulating effect of icaritin on osteogenic differentiation and mineralization of osteoblasts in vitro[J].Journal of Endocrinological Investigation,2017,40(4):357-366.

    • [29] SHI W,GAO Y,WANG Y,et al.The fl avonol glycoside icariin promotes bone formation in growing rats by activating the cAMP signaling pathway in primary cilia of osteoblasts[J].Journal of Biological Chemistry,2017,292(51):20883-20896.

    • [30] XU B,WANG X,WU C,et al.Flavonoid compound icariin enhances BMP-2 induced differentiation and signalling by targeting to connective tissue growth factor(CTGF)in SAMP6 osteoblasts[J].PloS One,2018,13(7):e0200367.

    • [31] SUN L J,CHONG L,WEN X H,et al.Icariin stimulates hFOB 1.19 osteoblast proliferation and differentiation via OPG/RANKL mediated by the estrogen receptor[J].Current Pharmaceutical Biotechnology,2021,22(1):168-175.

    • [32] XU Y X,LI L Y,TANG Y T,et al.Icariin promotes osteogenic differentiation by suppressing Notchsignaling[J].European Journal of Pharmacology,2019,865:172794.

    • [33] LI X F,XU H,ZHAO Y J,et al.Icariin augments bone formation and reverses the phenotypes of osteoprotegerindefi cient mice through the activation of Wnt/β-CateninBMP signaling[J].Evidence-based Complementray and Alternative Medicine,2013,2013(9):652317.

    • [34] LIU Y,HUANG L,HAO B,et al.Use of an osteoblast overload damage model to probe the effect of icariin on the proliferation,differentiation and mineralization of MC3T3-E1 cells through the Wnt/β-Catenin signalling pathway[J].Cell Physiol Biochem,2017,41(4):1605-1615.

    • [35] XU Q,CHEN G P,LIU X Q,et al.Icariin inhibits RANKL-induced osteoclastogenesis via modulation of the NF-κB and MAPK signaling pathways[J].Biochemical and Biophysical Research Communications,2019,508(3):902-906.

    • [36] WU Y,CAO L Y,XIA L,et al.Evaluation of osteogenesis and angiogenesis of icariin in local controlled release and systemic delivery for calvarial defect in ovariectomized rats[J].Rep,2017,7(1):5077.

    • [37] BUYUN K,YONG L K,BYOUNGDUCK P.Icariin abrogates osteoclast formation through the regulation of the RANKL-mediated TRAF6/NF-κB/ERK signaling pathway in Raw264.7 cells[J].Phytomedicine,2018,51:181-190.

    • [38] ZHANG Q Y,GAO F Q,CHENG L M,et al.Eff ects of icariin on autophagy and exosome production of bone microvascular endothelial cells[J].Chinese Journal of Reparative and Reconstructive Surgery,2019,33(5):568-577.

    • [39] 张庆宇,高福强,程立明,等.淫羊藿苷对骨微血管内皮细胞自噬及外泌体产生的影响[J].中国修复重建外科杂志,2019,33(5):568-577.

  • 参考文献

    • [1] KAAN GÜRBÜZ,MÜKERREM BETÜL YERER,PERIHAN GÜRBÜZ.Icariin promotes early and late stages of fracture healing in rats[J].Joint Diseases and Related Surgery,2019,30(3):282-288.

    • [2] CAO H,ZHANG Y,QIAN W,et al.Effect of icariin on fracture healing in an ovariectomized rat model of osteoporosis[J].Experimental and Therapeutic Medicine,2017,13(5):2399-2404.

    • [3] 王惠平,何爱咏,常晓飞.不同剂量比淫羊藿苷与辛伐他汀对家兔桡骨骨折愈合的影响[J].中国组织工程研究,2013,17(15):2703-2713.

    • [4] 贾朗,黄荣忠,王愉乐,等.不同强度体外冲击波联合骨髓间充质干细胞移植对大鼠骨缺损的修复效果[J].上海交通大学学报(医学版),2016,36(12):1706-1712.

    • [5] ZHU H Y,WANG X X,HAN Y Y,et al.Icariin promotes the migration of bone marrow stromal cells via the SDF-1α/HIF-1α/CXCR4 pathway[J].Drug Design Development & Therapy,2018,12:4023-4031.

    • [6] FU S P,YANG L,HONG H,et al.Wnt/β-catenin signaling is involved in the Icariin induced proliferation of bone marrow mesenchymal stem cells[J].Journal of Traditional Chinese Medicine,2016,36(3):360-368.

    • [7] JIAO F,TANG W,HUANG H,et al.Icariin promotes the migration of BMSCs in vitro and in vivo via the MAPK signaling pathway[J].Stem Cells International,2018,2018(1):1-9.

    • [8] HUANG J M,BAO Y,XIANG W,et al.Icariin regulates the bidirectional differentiation of bone marrow mesenchymal stem cells through canonical wnt signaling pathway[J].Evidence-based Complementray and Alternative Medicine,2017,2017(1-4):8085325.

    • [9] LIANG X,HOU Z,XIE Y,et al.Icariin promotes osteogenic differentiation of bone marrow stromal cells and prevents bone loss in OVX mice via activating autophagy[J].Journal of Cellular Biochemistry,2019,120(8):13121-13132.

    • [10] LUO Z,LIU M,SUN L,et al.Icariin recovers the osteogenic differentiation and bone formation of bone marrow stromal cells from a rat model of estrogen defi ciency-induced osteoporosis[J].Molecular Medicine Reports,2015,12(1):382-388.

    • [11] 訾慧,范颖,蒋宁,等.淫羊藿次苷Ⅰ及淫羊藿次苷Ⅱ 通过 BMP/Runx2/Osx 信号通路促进大鼠骨髓间充质干细胞成骨分化的实验研究[J].中国骨质疏松杂志,2019,25(5):690-695.

    • [12] LI X,PENG B,PAN Y,et al.Icariin stimulates osteogenic differentiation and suppresses adipogenic differentiation of rBMSCs via estrogen receptor signaling[J].Molecular Medicine Reports,2018,18(3):3483-3489.

    • [13] LIU H,XIONG Y,ZHU X,et al.Icariin improves osteoporosis,inhibits the expression of PPARγ,C/EBPα,FABP4 mRNA,N1ICD and jagged1 proteins,and increases Notch2 mRNA in ovariectomized rats[J].Experimental and Therapeutic Medicine,2017,13(4):1-9.

    • [14] MIAO G,ZHANG Y,HUANG Y.Effects of icariin on osteogenic differentiation of bone marrow stromal cells in beagle canine[J].International Journal of Clinical and Experimental Pathology,2017,10(8):8957-8967.

    • [15] QIN S,ZHOU W,LIU S,et al.Icariin stimulates the proliferation of rat bone mesenchymal stem cells via ERK and p38 MAPK signaling[J].International Journal of Clinical and Experimental Medicine,2015,8(5):7125-7133.

    • [16] WU Y,XIA L,ZHOU Y,et al.Icariin induces osteogenic differentiation of bone mesenchymal stem cells in a MAPK-dependent manner[J].Cell Proliferation,2015,48(3):375-384.

    • [17] WEI Q S,ZHANG J,HONG G J,et al.Icariin promotes osteogenic differentiation of rat bone marrow stromal cells by activating the ERα-Wnt/β-catenin signaling pathway[J].Biomedicine & Pharmacotherapy,2016,84:931-939.

    • [18] WEI Q S,HE M C,CHEN M H,et al.Icariin stimulates osteogenic differentiation of rat bone marrow stromal stem cells by increasing TAZ expression[J].Biomedicine & Pharmacotherapy,2017,91:581-589.

    • [19] HUANG Z,WEI H,WANG X,et al.Icariin promotes osteogenic differentiation of BMSCs by upregulating BMAL1 expression via BMP signaling[J].Molecular Medicine Reports,2020,21(3):10954.

    • [20] YE Y P,JING X Z,LI N,et al.Icariin promotes proliferation and osteogenic diff erentiation of rat adiposederived stem cells by activating the RhoA-TAZ signaling pathway[J].Biomedecine & Pharmacotherapie,2017,88:384-397.

    • [21] WU T,SHU T,KANG T,et al.Icaritin,a novel plantderived osteoinductive agent,enhances the osteogenic differentiation of human bone marrow and human adipose tissue-derived mesenchymal stem cells[J].International Journal of Molecular Medicine,2017,39(4):984-992.

    • [22] QIAN W,SU Y,ZHANG Y,et al.Secretome analysis of rat osteoblasts during icariin treatment induced osteogenesis[J].Molecular Medicine Reports,2018,17(5):6515-6525.

    • [23] 辛红美,许洁,汪长东.淫羊藿苷促进 MC3T3-E1 成骨分化通过Hedgehog信号通路[J].中国药理学通报,2020,36(5):616-620.

    • [24] WANG Y,WANG R,ZHANG F.Icariin promotes the proliferation and differentiation of osteoblasts from the rat mandible by the Wnt/β catenin signalling pathway[J].Molecular Medicine Reports,2018,18(3):3445-3450.

    • [25] LIAN F,ZHAO C,QU J,et al.Icariin attenuates titanium particle‐induced inhibition of osteogenic diff erentiation and matrix mineralization via miR-21-5p[J].Cell Biology International,2018,42(8):931-939.

    • [26] HUANG Z,CHENG C,WANG J,et al.Icariin regulates the osteoblast differentiation and cell proliferation of MC3T3E1 cells through microRNA153 by targeting runt-related transcription factor 2[J].Experimental and Therapeutic Medicine,2018,15(6):5159-5166.

    • [27] CHEN M,CUI Y,LI H,et al.Icariin promotes the osteogenic action of BMP2 by activating the cAMP signaling pathway[J].Molecules,2019,24(21):3875.

    • [28] MA X,MA C,SHI W,et al.Primary cilium is required for the stimulating effect of icaritin on osteogenic differentiation and mineralization of osteoblasts in vitro[J].Journal of Endocrinological Investigation,2017,40(4):357-366.

    • [29] SHI W,GAO Y,WANG Y,et al.The fl avonol glycoside icariin promotes bone formation in growing rats by activating the cAMP signaling pathway in primary cilia of osteoblasts[J].Journal of Biological Chemistry,2017,292(51):20883-20896.

    • [30] XU B,WANG X,WU C,et al.Flavonoid compound icariin enhances BMP-2 induced differentiation and signalling by targeting to connective tissue growth factor(CTGF)in SAMP6 osteoblasts[J].PloS One,2018,13(7):e0200367.

    • [31] SUN L J,CHONG L,WEN X H,et al.Icariin stimulates hFOB 1.19 osteoblast proliferation and differentiation via OPG/RANKL mediated by the estrogen receptor[J].Current Pharmaceutical Biotechnology,2021,22(1):168-175.

    • [32] XU Y X,LI L Y,TANG Y T,et al.Icariin promotes osteogenic differentiation by suppressing Notchsignaling[J].European Journal of Pharmacology,2019,865:172794.

    • [33] LI X F,XU H,ZHAO Y J,et al.Icariin augments bone formation and reverses the phenotypes of osteoprotegerindefi cient mice through the activation of Wnt/β-CateninBMP signaling[J].Evidence-based Complementray and Alternative Medicine,2013,2013(9):652317.

    • [34] LIU Y,HUANG L,HAO B,et al.Use of an osteoblast overload damage model to probe the effect of icariin on the proliferation,differentiation and mineralization of MC3T3-E1 cells through the Wnt/β-Catenin signalling pathway[J].Cell Physiol Biochem,2017,41(4):1605-1615.

    • [35] XU Q,CHEN G P,LIU X Q,et al.Icariin inhibits RANKL-induced osteoclastogenesis via modulation of the NF-κB and MAPK signaling pathways[J].Biochemical and Biophysical Research Communications,2019,508(3):902-906.

    • [36] WU Y,CAO L Y,XIA L,et al.Evaluation of osteogenesis and angiogenesis of icariin in local controlled release and systemic delivery for calvarial defect in ovariectomized rats[J].Rep,2017,7(1):5077.

    • [37] BUYUN K,YONG L K,BYOUNGDUCK P.Icariin abrogates osteoclast formation through the regulation of the RANKL-mediated TRAF6/NF-κB/ERK signaling pathway in Raw264.7 cells[J].Phytomedicine,2018,51:181-190.

    • [38] ZHANG Q Y,GAO F Q,CHENG L M,et al.Eff ects of icariin on autophagy and exosome production of bone microvascular endothelial cells[J].Chinese Journal of Reparative and Reconstructive Surgery,2019,33(5):568-577.

    • [39] 张庆宇,高福强,程立明,等.淫羊藿苷对骨微血管内皮细胞自噬及外泌体产生的影响[J].中国修复重建外科杂志,2019,33(5):568-577.

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