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干细胞国际

1687 - 9678 1687 - 966 x

Hindawi

10.1155 / 2022/8124085

8124085

研究文章

白藜芦醇协同促进BMP9-Induced间充质干细胞成骨分化

https://orcid.org/0000 - 0002 - 2215 - 492 x 王

Yonghui

https://orcid.org/0000 - 0001 - 8207 - 6647 夏

曹国伟

https://orcid.org/0000 - 0002 - 6904 - 5077 程ydF4y2Ba

杨

https://orcid.org/0000 - 0002 - 5127 - 148 x 江

天元

https://orcid.org/0000 - 0002 - 2526 - 8068 胡

杨ydF4y2Ba

https://orcid.org/0000 - 0003 - 1969 - 4455 高

竞争

他

Tong-Chuan

^{1

美国老年病学

新华医院

上海交通大学医学院

上海

中国

shsmu.edu.cn} ^{2

美国老年病学

上海综合医院

上海交通大学医学院

上海

中国

shsmu.edu.cn}

2022年

25 7 2022年

2022年 28 4 2022年 21 6 2022年 25 7 2022年

2022年

这是一个开放的文章在知识共享归属许可下发布的,它允许无限制的使用,分布和繁殖在任何媒介,提供最初的工作是正确的引用。

背景。间充质干细胞(msc)分化为骨细胞、脂肪细胞、软骨细胞。白藜芦醇和骨形态形成蛋白9 (BMP9)是已知的成骨诱导因素的msc、但白藜芦醇和BMP9对骨的影响是未知的。在此,我们探讨了白藜芦醇是否与BMP9合作提高成骨的感应。方法。白藜芦醇和BMP9 C3H10T1/2细胞的成骨诱导的染色和活动评估通过检测早期成骨的标记碱性磷酸酶(ALP)。此外,后期成骨的效果是衡量的信使rna和蛋白质水平成骨的标记,如骨桥蛋白(OPN)和骨钙素(OCN)。评估白藜芦醇的骨形成功能+ BMP9 在活的有机体内,我们移植BMP9-infected C3H10T1/2细胞裸体小鼠胃内的注射白藜芦醇的紧随其后。利用免疫印迹(WB)分析阐明白藜芦醇+ BMP9机制。结果。白藜芦醇不仅增强成骨的感应孤单而且改善BMP9-induced高山在3、5、7 d postinduction。早期成骨的标记(高山、Runx2 SP7)和已故的成骨的标记(OPN和OCN)显著增加白藜芦醇BMP9相结合的时候。胎儿肢体外植体培养进一步验证这些结果。的在活的有机体内骨形成实验,涉及移植BMP9-overexpressing C3H10T1/2细胞裸鼠,还证实,白藜芦醇增强BMP9-induced骨形成功能增效剂。白藜芦醇磷酸化腺苷酸(AMP)激活的蛋白激酶(AMPK)和刺激自体吞噬,但这些影响是废除了通过抑制AMPK, Beclin1使用抑制剂或核。结论。白藜芦醇结合BMP9显著提高C3H10T1/2细胞的成骨诱导激活AMPK和自噬。 SHDC SHDC2020CR3086B 上海市卫生委员会 2020年yjzx0122 上海市科学技术委员会 18 yf1415700 16 zr1422000 18411964500 20 zr1435100 中国国家自然科学基金 82071575 1。介绍<gydF4y2Ba/title> <p>在成人中,骨重塑是一个物理过程,平衡成骨细胞骨形成和破骨细胞骨吸收(<gydF4y2Baxref ref-type="bibr" rid="B1"> 1<gydF4y2Ba/xref>]。然而,当平衡与活跃的骨形成干扰,发生骨硬化,当平衡被中断与活跃的骨吸收,骨质疏松症(OP)发生。OP的特点是骨量的丧失,微观结构的解构,感受性骨折(<gydF4y2Baxref ref-type="bibr" rid="B2"> 2<gydF4y2Ba/xref>]。OP是一个世界性的健康问题影响数亿人,这造成了更为严重的健康问题,如疼痛、残疾、感染,甚至死亡。在OP,脂肪形成的骨髓为代价增加骨形成,导致骨质疏松和骨髓脂肪堆积。间充质干细胞(msc)第一次被发现是在骨髓,和他们可以进行成骨或脂肪血统的承诺。msc致力于分化成osteoprogenitor细胞,然后进入preosteoblasts,最终成为成熟的成骨细胞(<gydF4y2Baxref ref-type="bibr" rid="B3"> 3<gydF4y2Ba/xref>]。许多物理、化学和生物因素参与MSC分化。近几十年来,许多研究已经发现了大量的基本途径,参与调节msc的血统的承诺,包括转化生长因子(TGF -<gydF4y2Baitalic> β<gydF4y2Ba/italic>)/骨形成蛋白(BMP)信号,wingless-type MMTV集成网站Wnt信号,刺猬(Hh)信号,信号和纤维母细胞生长因子(FGF)信号<gydF4y2Baxref ref-type="bibr" rid="B3"> 3<gydF4y2Ba/xref>]。因此,研究成骨细胞谱系msc的承诺可能在未来为OP治疗提供重要信息。<gydF4y2Ba/p> <p>我国属于TGF -<gydF4y2Baitalic> β<gydF4y2Ba/italic>家庭,他们广泛参与调节细胞增殖、细胞分化和胚胎发育<gydF4y2Baxref ref-type="bibr" rid="B4"> 4<gydF4y2Ba/xref>]。有趣的是,BMP信号还参与胚胎skeletogenesis和维护产后骨头。14 bmp, BMP2 BMP4, BMP5, BMP7, BMP9已有广泛的研究,证明表现出高成骨活动[<gydF4y2Baxref ref-type="bibr" rid="B5"> 5<gydF4y2Ba/xref>- - - - - -<gydF4y2Baxref ref-type="bibr" rid="B9"> 9<gydF4y2Ba/xref>]。许多临床试验表明,BMP2和BMP7有前途的治疗骨折愈合和脊柱融合的潜力,表明我国有潜在的治疗应用骨疾病<gydF4y2Baxref ref-type="bibr" rid="B10"> 10<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B11"> 11<gydF4y2Ba/xref>]。此外,BMP9(也称为生长分化因子2 (GDF2))是参与肝纤维化,心脏衰竭,肿瘤,葡萄糖代谢和脂类代谢<gydF4y2Baxref ref-type="bibr" rid="B12"> 12<gydF4y2Ba/xref>- - - - - -<gydF4y2Baxref ref-type="bibr" rid="B14"> 14<gydF4y2Ba/xref>]。在msc、osteodifferentiation BMP9已经证明诱导成骨细胞分化和抑制破骨细胞分化<gydF4y2Baitalic> 在体外<gydF4y2Ba/italic>和<gydF4y2Baitalic> 在活的有机体内<gydF4y2Ba/italic>通过磷酸化Smad-dependent途径或通过Smad-independent通路(<gydF4y2Baxref ref-type="bibr" rid="B15"> 15<gydF4y2Ba/xref>]。作为一个有效的因素诱导成骨分化,发现了一个大型相声网络BMP9和Wnt /之间<gydF4y2Baitalic> β<gydF4y2Ba/italic>连环蛋白、Hh FGF, TGF -<gydF4y2Baitalic> β<gydF4y2Ba/italic>,Notch信号通路<gydF4y2Baxref ref-type="bibr" rid="B15"> 15<gydF4y2Ba/xref>- - - - - -<gydF4y2Baxref ref-type="bibr" rid="B19"> 19<gydF4y2Ba/xref>]。此外,为了进一步提高BMP9的成骨诱导,研究人员专注于联合治疗,同事BMP9和其他成骨诱导物。例如,促卵泡激素<gydF4y2Baitalic> β<gydF4y2Ba/italic>亚基、维甲酸、吸收FK506和大黄素在BMP9-induced证明发挥协同作用骨(<gydF4y2Baxref ref-type="bibr" rid="B20"> 20.<gydF4y2Ba/xref>- - - - - -<gydF4y2Baxref ref-type="bibr" rid="B23"> 23<gydF4y2Ba/xref>]。在我们之前的研究中,我们发现,褪黑激素和三碘甲状腺氨酸加强BMP9-induced成骨分化的msc (<gydF4y2Baxref ref-type="bibr" rid="B24"> 24<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B25"> 25<gydF4y2Ba/xref>]。此外,传统的OP兵团,包括磷酸盐、降钙素、选择性雌激素反应调节器,雌激素,显著减少骨折但有罕见的严重不良影响<gydF4y2Baxref ref-type="bibr" rid="B26"> 26<gydF4y2Ba/xref>]。由于多个分化和自我更新能力,MSC移植被认为是应用于骨质疏松症。上述研究发现的线索策略相结合,组成BMP9和其他成骨诱导,会产生更强的msc的成骨分化,这将是未来的一个有前途的治疗骨质疏松症。<gydF4y2Ba/p> <p>白藜芦醇,3、5、4<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>-trihydroxy-trans-stilbene,植物多酚的植物雌激素,植物抗毒素产品,如葡萄、浆果和花生。白藜芦醇有多种潜在的有益健康的影响,据报道,具有抗炎、免疫调节、抗氧化能力(<gydF4y2Baxref ref-type="bibr" rid="B27"> 27<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B28"> 28<gydF4y2Ba/xref>]。白藜芦醇可以刺激MC3T3成骨细胞的增殖和分化,抑制破骨细胞分化<gydF4y2Baxref ref-type="bibr" rid="B29"> 29日<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B30"> 30.<gydF4y2Ba/xref>]。同样的,<gydF4y2Baitalic> 在活的有机体内<gydF4y2Ba/italic>研究表明,白藜芦醇增加骨密度(BMD)切除卵巢的(OVX)雌性大鼠模型(<gydF4y2Baxref ref-type="bibr" rid="B31"> 31日<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B32"> 32<gydF4y2Ba/xref>]。人们普遍认为白藜芦醇的成骨的效果取决于其雌激素样作用和激活sirtuin-1 (SIRT1) [<gydF4y2Baxref ref-type="bibr" rid="B33"> 33<gydF4y2Ba/xref>]。进一步的研究表明,白藜芦醇可以防止成骨细胞dexamethasone-induced骨生成抑制激活腺苷酸- (AMP)激活的蛋白激酶(AMPK)的通路,它促进成骨细胞的分化OVX OP模型中通过调节自噬(<gydF4y2Baxref ref-type="bibr" rid="B34"> 34<gydF4y2Ba/xref>]。然而,白藜芦醇之间的交互和BMP9仍然未知。<gydF4y2Ba/p> <p>本研究旨在研究白藜芦醇在C3H10T1/2 BMP-induced成骨细胞的影响和潜在的分子机制。我们的研究结果显示,白藜芦醇促进BMP9-induced成骨分化通过激活AMPK /自噬信号通路。BMP9因此,白藜芦醇是一种有效的增强,表明它对OP可能导致新的治疗方法。<gydF4y2Ba/p> </sec> <sec id="sec2"> <title>2。方法<gydF4y2Ba/title> <sec id="sec2.1"> <title>2.1。细胞培养和试剂<gydF4y2Ba/title> <p>C3H10T1/2细胞购自上海生物科学研究所(上海,中国)。在杜尔贝科修改鹰的培养基培养细胞(DMEM)(美国Hyclone),含10%胎牛血清的边后卫(美国Gibco), 100 U /毫升青霉素、链霉素和100毫克/毫升(美国Gibco), 37°C的5%股份<gydF4y2Basub>2<gydF4y2Ba/sub>。美国白藜芦醇(σ)被稀释至50 mM存储在二甲亚砜(DMSO)(σ,美国)。成骨分化时诱导细胞融合达到了70%,和成骨诱导介质组成的DMEM, 10%的边后卫,10毫米<gydF4y2Baitalic> β<gydF4y2Ba/italic>甘油磷酸盐,50<gydF4y2Baitalic> μ<gydF4y2Ba/italic>g / L L-ascorbic酸,和100 nM地塞米松,取代每3 d(σ,美国)。Ad-BMP9和Ad-Green荧光蛋白(GFP)是从HanBio获得的。在感染之前,细胞被镀6-well盘子。当细胞融合达到了80%,添加Ad-BMP9或Ad-GFP和聚凝胺(Yeason,中国)8<gydF4y2Baitalic> μ<gydF4y2Ba/italic>克/<gydF4y2Baitalic> μ<gydF4y2Ba/italic>L 6 h。完全培养基中被改变了。<gydF4y2Ba/p> </sec> <sec id="sec2.2"> <title>2.2。碱性磷酸酶(ALP)活性和染色<gydF4y2Ba/title> <p>细胞被感染Ad-GFP或Ad-BMP9有或没有白藜芦醇为3,5,7 d。在指定的时间点,细胞细胞溶解里帕裂解缓冲(Beyotime,中国)和离心机<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"> <mml:mn> 12000年<gydF4y2Ba/mml:mn> <mml:mo> ×<gydF4y2Ba/mml:mo> <mml:mtext> g<gydF4y2Ba/mml:mtext> </mml:math> </inline-formula>10分钟。上层清液收集测量高山活动和蛋白质浓度和碱性磷酸酶测定BCA装备,分别(Beyotime,中国)。最后的高山活动规范化总细胞间蛋白质含量根据制造商的指示。<gydF4y2Ba/p> <p>高山染色,C3H10T1/2细胞被播种到12-well盘子,和细胞转导Ad-GFP或Ad-BMP9白藜芦醇的存在与否。7 d后成骨分化,细胞中被删除,与PBS洗了三次。细胞被固定为4%多聚甲醛(Beyotime,中国)在室温下15分钟,然后染色使用BCIP /电视台碱性磷酸酶染色鉴定装备(Beyotime,中国)根据制造商的协议。300 DMI徕卡显微镜图像被抓获。<gydF4y2Ba/p> </sec> <sec id="sec2.3"> <title>2.3。茜素红S染色<gydF4y2Ba/title> <p>茜素红染色是用来评估矩阵矿化的程度。成骨分化在C3H10T1/2诱导细胞如前所述。后14 d的感应,细胞被固定为4%多聚甲醛在室温下15分钟,用PBS洗了三次,然后沾2%茜素红S(美国σ)在室温下30分钟。300 DMI徕卡显微镜图像被抓获。<gydF4y2Ba/p> </sec> <sec id="sec2.4"> <title>2.4。免疫组织化学染色<gydF4y2Ba/title> <p>21 d后成骨分化,细胞被固定为4%多聚甲醛在室温下15分钟,洗PBS。细胞被permeabilized Triton-X 0.1%(美国σ)15分钟和阻止5% BSA 1 h (Beyotime,中国)在室温下。细胞被孵化一夜之间在4°C以下主要抗体:OCN (sc30045,圣克鲁斯生物技术)和OPN (ab91655 Abcam)。细胞被洗PBS和孵化biotin-labeled二级抗体(ABclonal,中国)在室温下1 h。细胞被沾diaminobenzidine (DAB) (Beyotime,中国)检测蛋白质,然后可视化使用显微镜(日本奥林巴斯BX51)。<gydF4y2Ba/p> </sec> <sec id="sec2.5"> <title>2.5。实时定量PCR(存在)<gydF4y2Ba/title> <p>从细胞总RNA诱导7 d是提取试剂盒(豆类、日本)如前所述<gydF4y2Baxref ref-type="bibr" rid="B35"> 35<gydF4y2Ba/xref>]。互补脱氧核糖核酸合成使用PrimeScript RT大师混合(豆类、日本)和执行中存在使用SYBR绿色主混合(Yeason,中国)。每个目标基因的相对表达水平计算使用2<gydF4y2Basup>−<gydF4y2Baitalic> ΔΔ<gydF4y2Ba/italic>Ct<gydF4y2Ba/sup>方法与GAPDH加载控制。<gydF4y2Ba/p> <p>以下引物被使用:高山,5<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M3"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>-GACTGGTACTCGGATAACGA-3<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M4"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>;高山反向,5<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M5"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>-TGCGGTTCCAGACATAGTGG-3<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M6"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>;SP7向前,5<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M7"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>-CAAAGAAGCCATACGCTGAC-3<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M8"> <mml:mo> ′<gydF4y2Ba/mml:mo> <mml:mo> ;<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>SP7反向,5<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M9"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>-GTCCATTGGTGCTTGAGAAG-3<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M10"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>;Runx2向前,5<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M11"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>-TGAGGGATGAAATGCTTGGGAACTG-3<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M12"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>;Runx2反向,5<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M13"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>-GATGATGACACTGCCACCTCTGAC-3<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M14"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>;GAPDH向前,5<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M15"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>-AGGTCGGTGTGAACGGATTTG-3<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M16"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>;GAPDH反向,5<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M17"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>-TGTAGACCATGTAGTTGAGGTCA-3<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M18"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>。<gydF4y2Ba/p> </sec> <sec id="sec2.6"> <title>2.6。免疫印迹(WB)分析<gydF4y2Ba/title> <p>细胞被播种在6-well盘子和治疗根据实验设计。总蛋白获得了与里帕细胞溶菌作用后裂解缓冲(Beyotime,中国),和清除溶解产物变性煮10分钟。然后分离蛋白质和10%钠十二烷基sulfate-polyacrylamide凝胶电泳(sds - page) (ABclonal,中国),然后转移到聚乙二烯二氟化物薄膜(PVDF)(美国微孔)。膜被封锁与快速块缓冲区(Epizyme,中国)在室温下20分钟。膜被孵化一夜之间在4°C以下主要抗体:AMPK(2532年,细胞信号技术),p-AMPK(2535年,细胞信号技术),Beclin1(3495年,细胞信号技术),p62 (sc - 28359,圣克鲁斯生物技术),LC3 (14600 - 1 - ap, Proteintech)和alpha-Tubulin (66031 - 1 - ig Proteintech)。洗后,膜被孵化与辣根过氧化物酶(合)共轭山羊anti-mouse和山羊anti-rabbit抗体(AS014 AS003, ABclonal)在室温下1 h。<gydF4y2Ba/p> </sec> <sec id="sec2.7"> <title>2.7。瞬时转染和小干扰rna (siRNAs)<gydF4y2Ba/title> <p>镀C3H10T1/2细胞与AMPK 6-well盘子然后转染<gydF4y2Baitalic> α<gydF4y2Ba/italic>1/2小干扰rna (GenePharma,中国)可以阻止或控制使用Lipofectamine 2000转染试剂(美国英杰公司)根据制造商的指示。<gydF4y2Ba/p> <p>核序列如下:AMPK<gydF4y2Baitalic> α<gydF4y2Ba/italic>核,5<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M19"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>-AAGAGAAGCAGAAGCACGACG-3<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M20"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>;控制,5<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M21"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>-AAGCCGGTATGCCGGTTAAGT-3<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M22"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>。<gydF4y2Ba/p> <p>Beclin1设计的siRNAs RiboBio(广州)。核的Beclin1序列如下:5<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M23"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>-CCTGTGGAGTGGAATGAAA-3<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M24"> <mml:mo> ′<gydF4y2Ba/mml:mo> </mml:math> </inline-formula>。<gydF4y2Ba/p> </sec> <sec id="sec2.8"> <title>2.8。胎儿肢体外植体培养<gydF4y2Ba/title> <p>胎儿肢体外植体培养基于执行先前描述的过程(<gydF4y2Baxref ref-type="bibr" rid="B24"> 24<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B25"> 25<gydF4y2Ba/xref>]。胎儿四肢被从小鼠胚胎切割(E18.5)在无菌条件下和在DMEM培养包含0.5% BSA, 50<gydF4y2Baitalic> μ<gydF4y2Ba/italic>g / mL抗坏血酸,1毫米<gydF4y2Baitalic> β<gydF4y2Ba/italic>甘油磷酸盐和100毫克/毫升青霉素和链霉素,37°C的5%股份<gydF4y2Basub>2<gydF4y2Ba/sub>。24小时后<gydF4y2Baitalic> 在体外<gydF4y2Ba/italic>文化,四肢相应治疗。媒介改变了每一个3 d和钙黄绿素(美国σ100毫米)添加到介质二维前端点。12 d的文化后,胎儿四肢的皮肤和肌肉被移除,和新骨形成是使用荧光显微镜和组织学评估。至少五肢外植体是包含在每组。300 DMI徕卡显微镜图像被抓获。<gydF4y2Ba/p> </sec> <sec id="sec2.9"> <title>2.9。C3H10T1/2植入和Microcomputed断层扫描(<斜体>μ< /斜体> CT)分析<gydF4y2Ba/title> <p>C3H10T1/2细胞的皮下植入和异位骨形成的诱导进行了如前所述[<gydF4y2Baxref ref-type="bibr" rid="B36"> 36<gydF4y2Ba/xref>]。细胞被感染Ad-GFP或Ad-BMP9 7 d,然后皮下注射(<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M25"> <mml:mn> 5<gydF4y2Ba/mml:mn> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:msup> <mml:mrow> <mml:mn> 10<gydF4y2Ba/mml:mn> </mml:mrow> <mml:mrow> <mml:mn> 6<gydF4y2Ba/mml:mn> </mml:mrow> </mml:msup> </mml:math> </inline-formula>细胞每注)成男性无胸腺的裸体小鼠(每组5;4 - 6周大;上海实验动物中心,中国)。白藜芦醇(20 mg·g - 1 / d级)或PBS intragastrically管理为5周的老鼠。小白鼠被安乐死,植入细胞收获<gydF4y2Baitalic> μ<gydF4y2Ba/italic>CT扫描(金星001;PINGSENG医疗、中国)在90千伏的电压,电子束电流0.07 mA和分辨率为20.0<gydF4y2Baitalic> μ<gydF4y2Ba/italic>m。分析了图像使用Avatar3软件(PINGSENG医疗)。两个/三维图像获取和分析评估骨量,骨密度(BMD)、骨体积/总量(BV /电视)的质量。按照指南的所有实验动物实验伦理委员会的新华医院。<gydF4y2Ba/p> </sec> <sec id="sec2.10"> <title>2.10。组织学染色<gydF4y2Ba/title> <p>样本与4%多聚甲醛固定后一夜之间,脱钙和脱水4周。样品被嵌入在石蜡(Beyotime,中国);部分(4<gydF4y2Baitalic> μ<gydF4y2Ba/italic>米)从石蜡块使用切片机(徕卡生物系统,位于德国)和苏木精和伊红染色())和马森的三色的染色如前所述<gydF4y2Baxref ref-type="bibr" rid="B37"> 37<gydF4y2Ba/xref>]。光学显微镜下观察组织学部分(日本奥林巴斯BX51)。<gydF4y2Ba/p> </sec> <sec id="sec2.11"> <title>2.11。统计分析<gydF4y2Ba/title> <p>所有的结果都表示为<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M26"> <mml:mtext> 的意思是<gydF4y2Ba/mml:mtext> <mml:mo> ±<gydF4y2Ba/mml:mo> <mml:mtext> 标准<gydF4y2Ba/mml:mtext> <mml:mtext> </mml:mtext> <mml:mtext> 偏差<gydF4y2Ba/mml:mtext> </mml:math> </inline-formula>(SD)。每个实验至少重复三次。学生的<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M27"> <mml:mi> t<gydF4y2Ba/mml:mi> </mml:math> </inline-formula>以及用于变量对比两组由GraphPad棱镜8.3.0软件(美国GraphPad)。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M28"> <mml:mi> P<gydF4y2Ba/mml:mi> </mml:math> </inline-formula>值< 0.05被认为是具有统计学意义。<gydF4y2Ba/p> </sec> </sec> <sec id="sec3"> <title>3所示。结果<gydF4y2Ba/title> <sec id="sec3.1"> <title>3.1。白藜芦醇协同促进BMP9-Induced msc的成骨分化<gydF4y2Ba/title> <p>首先,我们验证的感染效率Ad-BMP9 (BMP9)和Ad-GFP (Ctrl)运载体在C3H10T1/2细胞(数字<gydF4y2Baxref rid="fig1a" ref-type="fig"> 1(一)<gydF4y2Ba/xref>和S1A)。探讨白藜芦醇对C3H10T1/2细胞的成骨效果,高山染色和高山活动进行了分析。如数据所示<gydF4y2Baxref rid="fig1b" ref-type="fig"> 1 (b)<gydF4y2Ba/xref>和<gydF4y2Baxref rid="fig1c" ref-type="fig"> 1 (c)<gydF4y2Ba/xref>在浓度,白藜芦醇促进成骨细胞分化从5<gydF4y2Baitalic> μ<gydF4y2Ba/italic>米到50<gydF4y2Baitalic> μ<gydF4y2Ba/italic>M在天3、5、7 postinduction。在100<gydF4y2Baitalic> μ<gydF4y2Ba/italic>米,然而,白藜芦醇诱导成骨细胞细胞死亡(数据没有显示)。因此,我们选择一个白藜芦醇50浓度<gydF4y2Baitalic> μ<gydF4y2Ba/italic>米的后续实验。白藜芦醇单独促进骨生成,但其成骨的影响是增强BMP9-infected组(图<gydF4y2Baxref rid="fig1b" ref-type="fig"> 1 (b)<gydF4y2Ba/xref>)。一致,高山活动在BMP9 +白藜芦醇(BMP9 + RES)组相比BMP9-infected组(图<gydF4y2Baxref rid="fig1d" ref-type="fig"> 1 (d)<gydF4y2Ba/xref>)。因此,这些发现表明,白藜芦醇结合BMP9显著增强高山活动C3H10T1/2细胞。<gydF4y2Ba/p> <fig-group id="fig1"> <label>图1<gydF4y2Ba/label> <p>白藜芦醇增强了BMP9-induced早期成骨的标记,高山,C3H10T1/2细胞。(一)C3H10T1/2细胞感染Ad-GFP Ad-BMP9,和荧光显微镜下观察确定adenoviral感染效率感染后48 h。(b)的成骨诱导5<gydF4y2Baitalic> μ<gydF4y2Ba/italic>米,20<gydF4y2Baitalic> μ<gydF4y2Ba/italic>50米,<gydF4y2Baitalic> μ<gydF4y2Ba/italic>M白藜芦醇与Ad-GFP或Ad-BMP9由高山决定染色后7 d的成骨分化。(c) C3H10T1/2成骨分化的细胞与不同浓度的白藜芦醇(0、5、10、20、50<gydF4y2Baitalic> μ<gydF4y2Ba/italic>米)为3、5、7 d和高山定量测量活动。(d)白藜芦醇(50<gydF4y2Baitalic> μ<gydF4y2Ba/italic>米强BMP9-induced成骨分化,早期成骨的标记,高山,被高山测量活动。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M29"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M30"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M31"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.001<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>与对照组相比。<gydF4y2Basup>#<gydF4y2Ba/sup> <inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M32"> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Basup># #<gydF4y2Ba/sup> <inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M33"> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Basup># # #<gydF4y2Ba/sup> <inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M34"> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.001<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>相比之下,BMP9组。<gydF4y2Ba/p> <fig id="fig1a"> <label>(一)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.001a"></graphic> </fig> <fig id="fig1b"> <label>(b)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.001b"></graphic> </fig> <fig id="fig1c"> <label>(c)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.001c"></graphic> </fig> <fig id="fig1d"> <label>(d)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.001d"></graphic> </fig> </fig-group> </sec> <sec id="sec3.2"> <title>3.2。白藜芦醇增强BMP9-Induced表达水平和基质矿化成骨的标志<gydF4y2Ba/title> <p>进一步研究白藜芦醇的协同能力和BMP9诱导成骨、早期和晚期成骨分化指数进行了分析。信使rna表达水平的高山,Runx2 SP7 BMP9 +白藜芦醇组显著增加控制相比,白藜芦醇和BMP9组7 d后成骨诱导(图<gydF4y2Baxref rid="fig2a" ref-type="fig"> 2(一个)<gydF4y2Ba/xref>)。此外,经过14 d的成骨分化、蛋白质水平的骨桥蛋白(OPN)和骨钙素(OCN)高BMP9 +白藜芦醇组相比其他三组通过免疫组织化学染色(图所示<gydF4y2Baxref rid="fig2b" ref-type="fig"> 2 (b)<gydF4y2Ba/xref>和<gydF4y2Baxref rid="fig2c" ref-type="fig"> 2 (c)<gydF4y2Ba/xref>)。此外,茜素红S染色表明,矿物形成结节增强BMP9 +白藜芦醇组相比其他组C3H10T1/2细胞分化时21 d(图<gydF4y2Baxref rid="fig2d" ref-type="fig"> 2 (d)<gydF4y2Ba/xref>)。总之,这些结果表明,白藜芦醇结合BMP9显著提高骨在msc。<gydF4y2Ba/p> <fig-group id="fig2"> <label>图2<gydF4y2Ba/label> <p>白藜芦醇促进BMP9-induced表达式和矩阵C3H10T1/2细胞矿化成骨的标志。(a)早期成骨的标记的信使rna表达水平(高山、Runx2 SP7 mRNA)最高BMP9 +白藜芦醇组7 d后归纳。(b, c)免疫组织化学染色的成骨的标记(OCN和OPN) C3H10T1/2细胞后14 d的感应。(d)茜素红S染色21 d后C3H10T1/2细胞成骨分化。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M35"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M36"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M37"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.001<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>与对照组相比。<gydF4y2Basup>#<gydF4y2Ba/sup> <inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M38"> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Basup># #<gydF4y2Ba/sup> <inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M39"> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Basup># # #<gydF4y2Ba/sup> <inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M40"> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.001<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>相比之下,BMP9组。<gydF4y2Ba/p> <fig id="fig2a"> <label>(一)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.002a"></graphic> </fig> <fig id="fig2b"> <label>(b)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.002b"></graphic> </fig> <fig id="fig2c"> <label>(c)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.002c"></graphic> </fig> <fig id="fig2d"> <label>(d)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.002d"></graphic> </fig> </fig-group> </sec> <sec id="sec3.3"> <title>3.3。白藜芦醇和BMP9促进骨形成在小鼠胚胎肢外植体培养<gydF4y2Ba/title> <p>我们下一个旨在分析白藜芦醇的影响在发展中骨通过使用一个胎儿肢体文化分析。E18.5小鼠胚胎的四肢被孤立,分为以下四个组:GFP (Ctrl), GFP +白藜芦醇(RES) BMP9 (BMP9)和BMP9 +白藜芦醇(BMP9 + RES)。培养14 d后,钙黄绿素荧光染料是用来表明新骨形成不同的荧光强度。如图<gydF4y2Baxref rid="fig3a" ref-type="fig"> 3(一个)<gydF4y2Ba/xref>BMP9 +白藜芦醇治疗显著促进新骨形成的最强的荧光强度比其他三组。骨骺生长板的纵向生长的主要站点的长骨头。在这个网站是由软骨的增生和肥大细胞和典型的细胞外基质的合成。然后形成软骨钙化、退化和被骨组织所取代。因此,生长板软骨形成的大小将直接影响软骨内骨形成(<gydF4y2Baxref ref-type="bibr" rid="B21"> 21<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B38"> 38<gydF4y2Ba/xref>]。组织学评价使用)和马森的三色的染色显示BMP9 +白藜芦醇组有一个面积较大的小梁矩阵和生长板厚,骨形成指标(数据<gydF4y2Baxref rid="fig3b" ref-type="fig"> 3 (b)<gydF4y2Ba/xref>- - - - - -<gydF4y2Baxref rid="fig3d" ref-type="fig"> 3 (d)<gydF4y2Ba/xref>)。这些结果表明,白藜芦醇和BMP9可能协同作用加速软骨细胞肥大,随后软骨内骨形成。<gydF4y2Ba/p> <fig-group id="fig3"> <label>图3<gydF4y2Ba/label> <p>白藜芦醇促进BMP9-induced肥厚性软骨细胞的扩张区。(一)显微荧光图像的胎鼠胫骨E18.5胚胎处理Ad-GFP, Ad-GFP +白藜芦醇,Ad-BMP9或Ad-BMP9 +白藜芦醇14 d。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M41"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 5<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。(b, c)<gydF4y2Baitalic> 在体外<gydF4y2Ba/italic>成骨诱导胎鼠胫骨固定和染色)和马森的三色的染色。生长板框显示。(d)分析生长板的厚度。幻灯片进行扫描,测量的距离扩散区域的肥厚性区域增长板块,通过K-Viewer软件(KFBIO,中国)。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M42"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M43"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M44"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.001<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>与对照组相比。<gydF4y2Basup>#<gydF4y2Ba/sup> <inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M45"> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Basup># #<gydF4y2Ba/sup> <inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M46"> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Basup># # #<gydF4y2Ba/sup> <inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M47"> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.001<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>相比之下,BMP9组。<gydF4y2Ba/p> <fig id="fig3a"> <label>(一)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.003a"></graphic> </fig> <fig id="fig3b"> <label>(b)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.003b"></graphic> </fig> <fig id="fig3c"> <label>(c)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.003c"></graphic> </fig> <fig id="fig3d"> <label>(d)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.003d"></graphic> </fig> </fig-group> </sec> <sec id="sec3.4"> <title>3.4。白藜芦醇改善BMP9-Induced异位骨形成<gydF4y2Ba/title> <p>进一步证实了促进白藜芦醇对BMP9-induced骨形成的影响,我们进行了异位MSC移植<gydF4y2Baitalic> 在活的有机体内<gydF4y2Ba/italic>。我们C3H10T1/2感染细胞与Ad-GFP或Ad-BMP9 50的存在与否<gydF4y2Baitalic> μ<gydF4y2Ba/italic>L白藜芦醇对3 d然后皮下注射这些细胞注入BALB / c裸小鼠,然后老鼠遭受胃内的管理的白藜芦醇或PBS每隔2 d。5周的治疗后,小鼠牺牲,异位骨收集。如图<gydF4y2Baxref rid="fig4a" ref-type="fig"> 4(一)<gydF4y2Ba/xref>,只有BMP9和BMP9 +白藜芦醇组织群众形成更大的异位。然而,当分析矿物密度和骨体积,BMP9 +白藜芦醇组有更高的骨密度和骨体积相比其他群体(数字<gydF4y2Baxref rid="fig4b" ref-type="fig"> 4 (b)<gydF4y2Ba/xref>和<gydF4y2Baxref rid="fig4c" ref-type="fig"> 4 (c)<gydF4y2Ba/xref>)。符合<gydF4y2Baitalic> μ<gydF4y2Ba/italic>CT分析,BMP9 +白藜芦醇组有更多的骨矿物质矩阵相比BMP9组)如图所示,马森的三色的染色(图<gydF4y2Baxref rid="fig4d" ref-type="fig"> 4 (d)<gydF4y2Ba/xref>)。总的来说,这些发现表明,白藜芦醇有助于BMP-induced骨质的形成。<gydF4y2Ba/p> <fig-group id="fig4"> <label>图4<gydF4y2Ba/label> <p>白藜芦醇协同增强BMP-induced异位骨形成。(a)的宏观的图像BMP9——BMP9 + resveratrol-induced异位骨后5周。(b)<gydF4y2Baitalic> μ<gydF4y2Ba/italic>CT图像BMP9——BMP9 + resveratrol-induced异位骨。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M48"> <mml:mi> n<gydF4y2Ba/mml:mi> <mml:mo> =<gydF4y2Ba/mml:mo> <mml:mn> 4<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>。(c)定量分析异位骨的骨密度和骨体积<gydF4y2Baitalic> μ<gydF4y2Ba/italic>CT。(d))和马森paraffin-fixed异位骨的三色的染色。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M49"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M50"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M51"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.001<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>相比BMP9组。<gydF4y2Ba/p> <fig id="fig4a"> <label>(一)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.004a"></graphic> </fig> <fig id="fig4b"> <label>(b)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.004b"></graphic> </fig> <fig id="fig4c"> <label>(c)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.004c"></graphic> </fig> <fig id="fig4d"> <label>(d)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.004d"></graphic> </fig> </fig-group> </sec> <sec id="sec3.5"> <title>3.5。白藜芦醇与BMP9协同行为,推动通过AMPK-Dependent成骨分化途径<gydF4y2Ba/title> <p>白藜芦醇可以防止骨骼地塞米松、脂多糖和cadmium-induced骨质流失。白藜芦醇的成骨的能力取决于激活AMPK途径。我们承认,AMPK感应对骨形成至关重要。因此,我们假设白藜芦醇通过AMPK或ERK通路促进骨形成。与Ctrl或独自BMP9相比,AMPK磷酸化时更高的白藜芦醇是添加到Ctrl或BMP9组,和总AMPK水平组(图中保持不变<gydF4y2Baxref ref-type="fig" rid="fig5a"> 5(一个)<gydF4y2Ba/xref>)。此外,我们执行高山染色和高山活动分析评估是否白藜芦醇的成骨的效果取决于AMPK利用siAMPK<gydF4y2Baitalic> α<gydF4y2Ba/italic>。如图<gydF4y2Baxref ref-type="supplementary-material" rid="supplementary-material-1"> S2<gydF4y2Ba/xref>,siAMPK抑制蛋白质的总AMPK水平。推倒AMPK表达式后,高山染色和活动水平下降而BMP9和BMP9 +白藜芦醇组(数字<gydF4y2Baxref ref-type="fig" rid="fig5c"> 5 (c)<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="fig" rid="fig5d"> 5 (d)<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="fig" rid="fig5g"> 5 (g)<gydF4y2Ba/xref>)。为自噬调控AMPK和白藜芦醇刺激自噬报道,我们推测白藜芦醇介导通过自噬成骨的功能。我们发现,白藜芦醇的蛋白质含量显著提高LC-II Beclin1但p62蛋白质水平降低(图<gydF4y2Baxref ref-type="fig" rid="fig5b"> 5 (b)<gydF4y2Ba/xref>)。此外,mTOR信号,自噬的上游,是被暴露在白藜芦醇(图<gydF4y2Baxref ref-type="supplementary-material" rid="supplementary-material-1"> S1<gydF4y2Ba/xref>C)。高山染色和活动时减少BMP9 BMP9 +白藜芦醇组处理spautin-1 (sp 1),一个自噬抑制剂(数据<gydF4y2Baxref ref-type="fig" rid="fig5e"> 5 (e)<gydF4y2Ba/xref>和<gydF4y2Baxref ref-type="fig" rid="fig5f"> 5 (f)<gydF4y2Ba/xref>)。一致,sp 1治疗有效地抑制自噬通过减少LC-II的水平和较BMP9 Beclin1 BMP9 +白藜芦醇组(图<gydF4y2Baxref ref-type="fig" rid="fig5h"> 5 (h)<gydF4y2Ba/xref>)。此外,AMPK抑制剂、复合C, siBeclin1抑制磷酸化的AMPK(图<gydF4y2Baxref ref-type="supplementary-material" rid="supplementary-material-1"> S2<gydF4y2Ba/xref>(图)和Beclin1表达<gydF4y2Baxref ref-type="supplementary-material" rid="supplementary-material-1"> S2<gydF4y2Ba/xref>B),进一步抑制了高山染色(数字<gydF4y2Baxref ref-type="supplementary-material" rid="supplementary-material-1"> S3<gydF4y2Ba/xref>一个和<gydF4y2Baxref ref-type="supplementary-material" rid="supplementary-material-1"> S4<gydF4y2Ba/xref>)和活动(数据<gydF4y2Baxref ref-type="supplementary-material" rid="supplementary-material-1"> S3<gydF4y2Ba/xref>B和<gydF4y2Baxref ref-type="supplementary-material" rid="supplementary-material-1"> S4<gydF4y2Ba/xref>B)在BMP9 BMP9 +白藜芦醇组,分别。此外,磷酸化和自噬诱导白藜芦醇抑制了复合C BMP9和BMP9 +白藜芦醇组(图<gydF4y2Baxref ref-type="supplementary-material" rid="supplementary-material-1"> S3<gydF4y2Ba/xref>C),自噬抑制BMP9 siBeclin1转染和BMP9 +白藜芦醇组(图<gydF4y2Baxref ref-type="supplementary-material" rid="supplementary-material-1"> S4<gydF4y2Ba/xref>C)。在一起,这些结果表明,resveratrol-mediated通过AMPK /发生自噬通路成骨的影响。<gydF4y2Ba/p> <fig-group id="fig5"> <label>图5<gydF4y2Ba/label> <p>白藜芦醇促进BMP9-induced骨形成通过激活AMPK /自噬信号通路。(一)细胞溶解产物收集后感染Ad-GFP或Ad-BMP9有或没有白藜芦醇(50<gydF4y2Baitalic> μ<gydF4y2Ba/italic>米)48 h。p-AMPK的蛋白质含量和t-AMPK被世行分析测量。(b)自噬诱导是通过添加50<gydF4y2Baitalic> μ<gydF4y2Ba/italic>M白藜芦醇Ad-GFP或Ad-BMP9。LC3, Beclin1, p62自噬标记被世行评估分析。siAMPK (d, e)<gydF4y2Baitalic> α<gydF4y2Ba/italic>抑制了BMP9的高山和BMP9 + resveratrol-induced C3H10T1/2细胞的成骨分化。与siAMPK C3H10T1/2预处理后,细胞<gydF4y2Baitalic> α<gydF4y2Ba/italic>其次是成骨分化与BMP9或BMP9 +白藜芦醇7 d,高山染色(c)和高山活动化验(d)进行测量成骨的能力。(e, f) sp 1自噬抑制剂抑制成骨分化的BMP9和BMP9 +白藜芦醇组。细胞治疗的组合sp 1和白藜芦醇Ad-BMP9或Ad-BMP9 + 7 d,和高山染色(e)和高山活动化验(f)进行测量C3H10T1/2成骨诱导的细胞。(g)与siAMPK世行分析表明,预处理<gydF4y2Baitalic> α<gydF4y2Ba/italic>AMPK水平下降。与siAMPK C3H10T1/2细胞转染<gydF4y2Baitalic> α<gydF4y2Ba/italic>24小时之前治疗Ad-BMP9或Ad-BMP9 +白藜芦醇。48 h后,蛋白质溶解产物收集测量AMPK水平世行分析。(h)世行分析表明,自噬被sp 1抑制。治疗后的C3H10T1/2细胞sp 1结合Ad-BMP9或Ad-BMP9 +白藜芦醇48 h,细胞溶解产物收集测量LC3的蛋白质含量,Beclin1, p62世行分析。<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M52"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:msup> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M53"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Bainline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M54"> <mml:msup> <mml:mrow></mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> <mml:mrow> <mml:mo> ∗<gydF4y2Ba/mml:mo> </mml:mrow> </mml:mrow> </mml:msup> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.001<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>与对照组相比。<gydF4y2Basup>#<gydF4y2Ba/sup> <inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M55"> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Basup># #<gydF4y2Ba/sup> <inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M56"> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Basup># # #<gydF4y2Ba/sup> <inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M57"> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.001<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>相比之下,BMP9组。<gydF4y2Basup>&<gydF4y2Ba/sup> <inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M58"> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.05<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Basup>& &<gydF4y2Ba/sup> <inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M59"> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.01<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>,<gydF4y2Basup>&&&<gydF4y2Ba/sup> <inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M60"> <mml:mi> P<gydF4y2Ba/mml:mi> <mml:mo> <<gydF4y2Ba/mml:mo> <mml:mn> 0.001<gydF4y2Ba/mml:mn> </mml:math> </inline-formula>相比BMP9 +白藜芦醇组。<gydF4y2Ba/p> <fig id="fig5a"> <label>(一)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.005a"></graphic> </fig> <fig id="fig5b"> <label>(b)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.005b"></graphic> </fig> <fig id="fig5c"> <label>(c)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.005c"></graphic> </fig> <fig id="fig5d"> <label>(d)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.005d"></graphic> </fig> <fig id="fig5e"> <label>(e)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.005e"></graphic> </fig> <fig id="fig5f"> <label>(f)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.005f"></graphic> </fig> <fig id="fig5g"> <label>(g)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.005g"></graphic> </fig> <fig id="fig5h"> <label>(h)<gydF4y2Ba/label> <graphic xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.fig.005h"></graphic> </fig> </fig-group> </sec> </sec> <sec id="sec4"> <title>4所示。讨论<gydF4y2Ba/title> <p>在目前的研究中,我们表明,白藜芦醇与BMP9协同行为诱导骨生成的C3H10T1/2 MSC。作为已知的成骨诱导,BMP9和白藜芦醇骨生成标记的表达增加。具体来说,在50岁<gydF4y2Baitalic> μ<gydF4y2Ba/italic>米,白藜芦醇的成骨效应最强C3H10T1/2细胞。此外,当C3H10T1/2细胞被cotreated BMP9和白藜芦醇诱导骨生成比白藜芦醇或BMP9孤独,导致更高的高山活动以及更高的mRNA和蛋白表达水平的骨形成相关标记。的<gydF4y2Baitalic> 在活的有机体内<gydF4y2Ba/italic>老鼠胚胎肢外植体培养和异位MSC移植研究还证实,最强的成骨效应引起的组合BMP9和白藜芦醇。此外,白藜芦醇磷酸化AMPK和自噬有或没有BMP9刺激,这表明白藜芦醇改善BMP9-induced成骨分化通过AMPK /自噬信号通路。此外,抑制AMPK和自噬通过治疗可以阻止或抑制剂显著减毒高山活动,进一步证明白藜芦醇参与BMP9-induced骨通过AMPK信号通路在msc。总之,我们的结果表明,白藜芦醇具有明显的成骨的效果通过激活AMPK /自噬信号通路。<gydF4y2Ba/p> <p>BMP9研究BMP,它有一个强有力的成骨诱导效应。超表达C3H10T1/2 BMP9的C2C12, TE85, MC3T3细胞导致更高的信使rna和蛋白质水平的骨标记和高山活动早在5 d后超表达(<gydF4y2Baxref ref-type="bibr" rid="B39"> 39<gydF4y2Ba/xref>]。与其他每个位置相比,如BMP2 BMP7,治疗BMP9成骨的感应能力的更大更高水平的成骨的标记(<gydF4y2Baxref ref-type="bibr" rid="B40"> 40<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B41"> 41<gydF4y2Ba/xref>]。除了病毒载体,过度使用nonadenoviral BMP9的向量,包括重组BMP9 (rbBMP9)和肽来源于BMP9 (pBMP9),增加高山活动和成骨的标记表达式(<gydF4y2Baxref ref-type="bibr" rid="B42"> 42<gydF4y2Ba/xref>]。<gydF4y2Baitalic> 在活的有机体内<gydF4y2Ba/italic>研究进一步证明了成骨的感应能力BMP9通过肌肉注射BMP9-transduced C2C12细胞无胸腺的裸小鼠(<gydF4y2Baxref ref-type="bibr" rid="B43"> 43<gydF4y2Ba/xref>]。上述研究证明BMP9的成骨的潜力。此外,进一步的研究表明,各种化合物会增强BMP9的成骨诱导效应。例如,all-trans-retinoid酸诱导成骨分化和配合BMP2 preadipocytes诱导成骨分化,及其合作BMP9显示相同的结果通过激活BMP / Smad和Wnt /<gydF4y2Baitalic> β<gydF4y2Ba/italic>连环蛋白通路(<gydF4y2Baxref ref-type="bibr" rid="B44"> 44<gydF4y2Ba/xref>]。此外,促卵泡激素<gydF4y2Baitalic> β<gydF4y2Ba/italic>亚基也强化BMP9-induced成骨分化在小鼠胚胎成纤维细胞(<gydF4y2Baxref ref-type="bibr" rid="B20"> 20.<gydF4y2Ba/xref>]。在先前的研究中,我们发现,治疗的msc与褪黑素或三碘甲状腺氨酸显著提高BMP9-induced成骨分化(<gydF4y2Baxref ref-type="bibr" rid="B24"> 24<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B25"> 25<gydF4y2Ba/xref>]。因此,与BMP9成骨的因素的组合可能是一个有前途的战略在未来治疗OP。<gydF4y2Ba/p> <p>2014年,研究人员发现白藜芦醇在中年肥胖男性的骨头保护功能与代谢综合征(<gydF4y2Baxref ref-type="bibr" rid="B45"> 45<gydF4y2Ba/xref>];他们表明,口服1 g / d白藜芦醇的肥胖男性超过4周结果增加血清骨高山和更高的腰椎BMD。另一项研究中,招收2型糖尿病患者,进一步证实了有益的高剂量白藜芦醇对骨骼健康的影响,表现出较高的钙浓度和25-hydroxy维生素D预防骨密度和骨矿物质含量(BMC)减少相比安慰剂组(<gydF4y2Baxref ref-type="bibr" rid="B46"> 46<gydF4y2Ba/xref>]。这些结果支持<gydF4y2Baitalic> 在活的有机体内<gydF4y2Ba/italic>研究表明,白藜芦醇可以预防骨质疏松。在OVX大鼠,25 mg·公斤<gydF4y2Basup>1<gydF4y2Ba/sup>/ d和45 mg·公斤<gydF4y2Basup>1<gydF4y2Ba/sup>/ d每日剂量的白藜芦醇显著提升BMD下降,和另一个<gydF4y2Baitalic> 在活的有机体内<gydF4y2Ba/italic>研究表明,白藜芦醇能促进成骨细胞分化通过SIRT1 bmsc / NF -<gydF4y2Baitalic> Κ<gydF4y2Ba/italic>B信号通路(<gydF4y2Baxref ref-type="bibr" rid="B47"> 47<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B48"> 48<gydF4y2Ba/xref>]。另一项研究已经证实的骨保护功能白藜芦醇通过抑制osteoclastogenesis通过其抗氧化能力(<gydF4y2Baxref ref-type="bibr" rid="B49"> 49<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B50"> 50<gydF4y2Ba/xref>通过PI3K / AKT] / FoxO1信号通路。作为一个有效治疗OP在动物OP模型、李等人耦合白藜芦醇通过hydrolysable共价键与多孔聚羧酸团体-<gydF4y2Baitalic> ε<gydF4y2Ba/italic>己内酯(PCL)表面接枝丙烯酸(<gydF4y2Baxref ref-type="bibr" rid="B51"> 51<gydF4y2Ba/xref>];这些作者都使用<gydF4y2Baitalic> 在活的有机体内<gydF4y2Ba/italic>和<gydF4y2Baitalic> 在体外<gydF4y2Ba/italic>实验证明该脚手架明显促进骨生成。尽管直接保护骨质流失增加骨生成和抑制osteoclastogenesis,白藜芦醇也被证实能抑制脂肪形成的人类骨髓基质干细胞间接维持骨量(<gydF4y2Baxref ref-type="bibr" rid="B52"> 52<gydF4y2Ba/xref>]。有研究证明白藜芦醇是否有影响力的bmp诱导骨形成。例如,Kuroyanagi等人报道,白藜芦醇增强了BMP4-stimulated合成osteoprotegerin(功能)成骨细胞通过p38 / MAPK信号通路(<gydF4y2Baxref ref-type="bibr" rid="B53"> 53<gydF4y2Ba/xref>]。然而,一项研究报道,白藜芦醇不提高BMP4的影响在其他成骨的标记,高山的活动,和矿物质结节沉积。相比之下,一项研究报告了白藜芦醇不影响BMP6-induced高山活动和OCN表达式(<gydF4y2Baxref ref-type="bibr" rid="B54"> 54<gydF4y2Ba/xref>),但这项研究于2003年进行,结果表明可能是限制由于技术的局限性。根据我们的结果,白藜芦醇结合BMP9导致更高的表达成骨的标记,高山的活动,和矿物质比独自BMP9结节沉积。总之,白藜芦醇与BMP9主体性,促进骨生成的msc、这将促使干细胞移植治疗OP。<gydF4y2Ba/p> <p>AMPK heterotrimeric复杂,由分解<gydF4y2Baitalic> α<gydF4y2Ba/italic>子单元和监管<gydF4y2Baitalic> β<gydF4y2Ba/italic>和<gydF4y2Baitalic> γ<gydF4y2Ba/italic>子单元。AMPK广泛表达于各种器官,包括骨,它在成骨细胞增殖和分化中起着重要作用[<gydF4y2Baxref ref-type="bibr" rid="B55"> 55<gydF4y2Ba/xref>]。白藜芦醇报道通过SIRT1-dependent激活AMPK信号通路和SIRT1-independent通路(<gydF4y2Baxref ref-type="bibr" rid="B56"> 56<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B57"> 57<gydF4y2Ba/xref>]。尽管白藜芦醇激活AMPK信号通路在目前的研究中,它未能SIRT1激活(图<gydF4y2Baxref ref-type="supplementary-material" rid="supplementary-material-1"> S1<gydF4y2Ba/xref>B)。当AMPK被复合C或抑制转录siAMPK表达下调<gydF4y2Baitalic> α<gydF4y2Ba/italic>相比,高山染色和活动减少BMP和BMP9 +白藜芦醇组。这些结果表明,白藜芦醇促进BMP9-induced SIRT1-independent AMPK骨生成的信号通路。AMPK参与各种生理过程,包括自噬,这是一个盛典AMPK-activated过程和对msc及成骨细胞的成骨分化至关重要(<gydF4y2Baxref ref-type="bibr" rid="B58"> 58<gydF4y2Ba/xref>,<gydF4y2Baxref ref-type="bibr" rid="B59"> 59<gydF4y2Ba/xref>]。通过磷酸化的ULK1 AMPK激活自噬,自噬起始的关键(<gydF4y2Baxref ref-type="bibr" rid="B60"> 60<gydF4y2Ba/xref>]。此外,还可以诱导自噬通过磷酸化的磷脂酰肌醇3-kinase催化亚基类型3复杂和Beclin1,这对自噬体的形成至关重要<gydF4y2Baxref ref-type="bibr" rid="B61"> 61年<gydF4y2Ba/xref>]。据李et al ., AMPK刺激成骨细胞分化和矿化的自噬<gydF4y2Baxref ref-type="bibr" rid="B58"> 58<gydF4y2Ba/xref>]。李等人还显示,复合C, AMPK的抑制剂,抑制自噬和MC3T3细胞成骨分化,他们证明自噬抑制剂治疗或Beclin1沉默抑制自噬和成骨分化。因此,AMPK活化可能刺激成骨细胞分化和矿化诱导自噬。此外,白藜芦醇已被证实能促进人类牙龈间充质干细胞成骨分化(HGMSCs)通过激活AMPK和自噬<gydF4y2Baxref ref-type="bibr" rid="B56"> 56<gydF4y2Ba/xref>];治疗的HGMSCs 1<gydF4y2Baitalic> μ<gydF4y2Ba/italic>M白藜芦醇导致AMPK磷酸化和自噬小体的形成,但与sp 1治疗,一个自噬抑制剂,抑制resveratrol-induced成骨分化和HGMSCs自噬。符合上述研究,目前的研究表明,白藜芦醇诱导自噬在控制和BMP9-treated组。同样,当自噬抑制剂、sp 1或Beclin1沉默是应用于BMP9 BMP9 +白藜芦醇组,表示的成骨分化显著抑制低高山染色和活动。这些结果表明,白藜芦醇强化BMP9-induced成骨分化激活AMPK-dependent自噬的msc。<gydF4y2Ba/p> <p>本研究有几个局限性。首先,我们没有探索白藜芦醇的机制刺激AMPK磷酸化。一些研究表明,白藜芦醇epigenetically修改成骨的转录因子,如Runx2和SP7脱乙酰作用。然而,在目前的研究中,我们没有调查乙酰化Runx2 SP7。因此,目前尚不清楚是否白藜芦醇增强BMP9-induced骨通过直接脱去乙酰基Runx2 SP7。此外,白藜芦醇的表达水平没有增加SIRT1在目前的研究中,这也可能被解释成高剂量和长期的白藜芦醇治疗由于底层负反馈系统,调节过度sirtuin活动。最后,我们并没有研究白藜芦醇的影响BMP9-inhibited osteoclastogenesis。进一步的研究需要阐明的详细机制协同白藜芦醇和BMP9骨生成的函数。<gydF4y2Ba/p> </sec> <sec id="sec5"> <title>5。结论<gydF4y2Ba/title> <p>总之,目前的研究表明,白藜芦醇强化BMP9-induced骨通过激活AMPK /自噬通路。<gydF4y2Ba/p> </sec> <back> <sec sec-type="data-availability"> <title>数据可用性<gydF4y2Ba/title> <p>最初的贡献提出了在目前的研究包括在本文和补充材料。进一步询问可以针对相应的作者。<gydF4y2Ba/p> </sec> <sec> <title>伦理批准<gydF4y2Ba/title> <p>这项研究已通过新华医院的伦理委员会隶属于上海交通大学。<gydF4y2Ba/p> </sec> <sec sec-type="COI-statement"> <title>的利益冲突<gydF4y2Ba/title> <p>作者宣称没有利益冲突。<gydF4y2Ba/p> </sec> <sec> <title>作者的贡献<gydF4y2Ba/title> <p>YG, YW研究设计。YW, C夏,YC、TJ和决断力进行了实验。YW分析数据和写的手稿。YG修改了手稿,批准了最终版本,并决定提交出版的手稿。所有作者的文章和批准提交的版本。<gydF4y2Ba/p> </sec> <ack> <title>确认<gydF4y2Ba/title> <p>我们感谢博士在公元前。他(重庆生化和分子药理学重点实验室、中国)提供BMP9和GFP重组腺病毒。本研究得到了国家自然科学基金(82071575)、上海市科学技术委员会(20 zr1435100, 18411964500, 16 zr1422000, 18 yf1415700),上海市卫生委员会(2020 yjzx0122)的临床研究计划SHDC (SHDC2020CR3086B)。<gydF4y2Ba/p> </ack> <sec sec-type="supplementary-material" id="supplementary-material-1"> <title>补充材料<gydF4y2Ba/title> <supplementary-material xlink:href="//www.newsama.com/downloads/journals/sci/2022/8124085.f1.doc" id="supp-1" mimetype="application/msword"> <label>补充材料<gydF4y2Ba/label> <p>补充材料中包含额外的数据补充材料图S1, S2,图S3,和图S4是结果中描述结果和不可或缺的支持这样的结论。图S1:世行分析内源性表达BMP9 C3H10T1/2细胞后Ad-BMP9感染和Sirt1的存在与否和p-mTOR水平Ad-BMP9和白藜芦醇。图S2: WB siRNA siAMPK转染后效果分析<gydF4y2Baitalic> α<gydF4y2Ba/italic>和siBeclin1。图S3:高山分析和世行分析支持Com的结果。C是能够抑制白藜芦醇的成骨的影响。图S4:高山分析和世行分析确认siBeclin1能够抑制白藜芦醇的成骨的影响。补充图片都是额外的测试图<gydF4y2Baxref ref-type="fig" 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