白藜芦醇通过SIRT1/IGF-1R/AKT通路促进退变椎间盘终板软骨细胞合成细胞外基质
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摘要
椎间盘退变是导致颈及腰背痛的常见原因。椎间盘是人体最大的缺氧组织，除了纤维环外层有血供分布外，纤维环内层及髓核无血管分布，髓核细胞所需营养物质需要通过终板软骨自椎体向髓核弥散渗透。随着年龄增长，终板软骨细胞衰老凋亡，细胞外基质合成减少，降解加速，软骨下椎体骨质增生钙化，导致弥散功能降低，不仅阻碍了椎间盘髓核所需要营养物质，如糖及氧份，同时使代谢废物如乳酸的排泄收到抑制，加重了椎间盘这个人体最大缺氧组织的营养障碍，加速并促进了椎间盘的退变。尽管椎间盘退变的确切分子机制尚不完全清楚，但是毫无疑问终板软骨细胞的退变，终板通透性降低，在椎间盘的退变过程中发挥了重要作用。因此，预防并降低终板软骨细胞的退变成为阻止椎间盘退变的潜在靶点。
2003年KT Howitz和Sinclair等[1]首次发现并报道白黎芦醇，其属于sirtuin激活复合物(sirtuin activating compounds，STACs)，而且在一系列多酚类物质对SIRT1的作用活性检测中，白黎芦醇的激活作用最强。从此Res作为SIRT1的激活因子，被广泛应用到科学研究当中。
众多学者[2-6]证实，SIRT1是哺乳动物延缓衰老、延长寿命的关键分子，在细胞周期、代谢、分化等方面发挥广泛调节作用。Dvir-Ginzberg等[7]证实人关节软骨细胞的SIRT1高表达能够促进软骨细胞外基质基因Aggrecan， collagen2a(α1) and2b(α1)， collagen9(α1)的表达。Gagarina VG等[8]证实骨性关节炎患者SIRT1可抑制软骨细胞凋亡。
既往研究表明[9-11]，IGF-1可明显地促进多种来源的关节软骨细胞分裂增殖和软骨基质的合成，刺激软骨细胞合成软骨基质特异型蛋白－II型胶原和蛋白多糖，增强成骨细胞的碱性磷酸酯酶的活性。
本研究首先探讨了不同浓度及时间的白藜芦醇对退变椎间盘终板软骨细胞表达SIRT1的影响，为后续研究提供参考；其次通过SIRT1特异性siRNA及SIRT1酶活性抑制剂尼克酰胺的阻断作用，研究了白藜芦醇促进细胞外基质合成的作用及其与SIRT的关系；并通过IGF-1R/AKT通路特异性抑制剂的阻断作用，研究了白藜芦醇在退变的终板软骨细胞中促进细胞外基质合成的作用与IGF-1R/AKT通路的关系；从而阐明了白藜芦醇对退变椎间盘终板软骨细胞抑制退变的作用及其信号通路。
1白藜芦醇对退变椎间盘终板软骨细胞SIRT1表达的影响
目的探讨不同浓度及时间的白藜芦醇对退变椎间盘终板软骨细胞表达SIRT1的影响。
方法老年患者的终板软骨细胞培养、传代， P2代细胞随机分组，分别用不同浓度及作用时间的白藜芦醇干预，终止培养后检测SIRT1蛋白及SIRT1mRNA表达水平。
结果与空白对照组相比较，白藜芦醇能够显著促进退变椎间盘终板软骨细胞表达SIRT1蛋白的最低条件为12.5μmol/L干预24小时，以及50μmol/L干预12小时（P<0.05）；能够显著上调SIRT1基因转录水平的最低条件为12.5μmol/L干预作用48小时，以及50μmol/L干预24小时（P<0.05）；在上述浓度、时间组合条件之上，白藜芦醇的作用呈现浓度、时间依赖性。
结论白藜芦醇可显著促进退变椎间盘终板软骨细胞SIRT1蛋白及mRNA表达水平，且该作用呈现浓度、时间依赖关系。
2白藜芦醇通过SIRT1途径促进退变椎间盘终板软骨细胞合成细胞外基质
目的探讨白藜芦醇干预对退变椎间盘终板软骨细胞SIRT1的影响及其与细胞外基质合成的关系。
方法老年腰椎间盘突出症患者的终板软骨细胞培养、传代， P2代细胞随机分为5组，即白藜芦醇组、二甲基亚砜对照组、白藜芦醇+尼克酰胺组、白藜芦醇+siRNA转染组及空白对照组。各组进行对应处理后检测SIRT1、COLA2、aggrecan及SIRT1mRNA表达水平。
结果白藜芦醇干预上调退变椎间盘终板软骨细胞SIRT1基因的转录水平及SIRT1蛋白的表达水平，促进细胞外基质（COLA2、aggrecan）的合成；Nam及siRNA干预分别有效抑制了SIRT1酶活性及SIRT1mRNA的表达，并抑制了细胞外基质的合成。
结论白藜芦醇可促进退变椎间盘终板软骨细胞合成软骨细胞外基质成分（Ⅱ型胶原、aggrecan），抑制椎间盘软骨终板退变，其机制与调节SIRT1基因转录及SIRT1酶活性有关。
3白藜芦醇通过IGF-1R/AKT通路促进退变椎间盘终板软骨细胞合成细胞外基质
目的探讨IGF-1R/AKT信号通路在白藜芦醇促进椎间盘软骨终板细胞合成细胞外基质的影响（Ⅱ型胶原及aggrecan）。
方法椎间盘软骨终板细胞培养，传代，P2代细胞培养12h后，随机分为5组，各组加入对应试剂培养12h后终止培养，检测IGF-1R、pIGF-1R、AKT、pAKT、COLAII、aggrecan的表达变化。
结果白藜芦醇干预后IGF-1R及AKT磷酸化水平显著增加，COLAII、aggrecan表达显著增加；分别加入AG1024及SH-5则显著抑制了胰岛素样生长因子1受体（IGF-1R）及蛋白激酶B（AKT）磷酸化激活，COLAII、aggrecan表达显著下降。
结论白藜芦醇可促进椎间盘软骨终板细胞表达软骨细胞外基质，抑制软骨终板退变，其机制与调节IGF-1R/AKT通路活性有关。
Disc degeneration is a common cause of neck and low back pain. The disc is the largesthypoxic tissue of human body.Only the outer layer of annulus fibrosus exists vasculardistribution, the inner layer of annulus fibrosus and nucleus have no vascular distribution.nutrients that the nucleus pulpous cells required are supplied by the penetration function ofendplate cartilage from the vertebral body to the nucleus pulpous. With aging, the endplatechondrocytes aged,the apoptosis increased, synthesis of extracellular matrix decreased whiledecomposition accelerated, subchondral vertebral bone calcified, leading to the dispersion functionreduced. these alterations not only hindered nutrients supply of the nucleus pulposus, such as sugarand oxygen,but also hindered the discharge of metabolic wastes, such as lactic acid, thuspromoting disc degeneration.
Although the exact molecular mechanism of disc degeneration is not fully understood, but thereis no doubt that the degeneration of the endplate cartilage cells, and finally the reduction ofpermeability plays an important role in the process of disc degeneration. Therefore, to prevent andreduce the degeneration of the endplate cartilage cells become a potential target to prevent discdegeneration.
In2003,KT Howitz and Sinclair et al[1]firstly discovered and reported that resveratrol, itbelongs to the sirtuin activation complexes (sirtuin activating compounds, STACs), and is morepotent than a series of phenols as SIRT1activator. From then on,resveratrol,as a activator of SIRT1,is widely used in scientific research.
Many scholars[2-6]have confirmed that SIRT1is a key molecule in the process of retardingaging and extending lifespan in mammalian, and plays an important regulatory role in cell cycle, metabolism, differentiation. Dvir-Ginzbergand et al[7]have confirmed that the high expression levelof SIRT1in human articular chondrocytes can promote the expression of cartilage extracellularmatrix genes, such as aggrecan, collagen2a (α1),2b (α1), collagen9(α1). Gagarina VG[8]have confirmed SIRT1could inhibit chondrocyte apoptosis in patients with osteoarthritis.
Previous studies have shown[9-11]that in a variety of sources of articular chondrocyte, IGF-1can significantly promote proliferation,stimulate the synthesis of chondrocytes specific extracellularmatrix, such as type II collagen and proteoglycan, enhance alkaline phosphatase activity of bonecells.
This study explored the expression of SIRT1by resveratrol of different concentrations and timein degeneration intervertebral disc endplate cartilage cells and provide reference for furtherresearch; then the effect of resveratrol on promoting the synthesis of extracellular matrix and itsrelationship with SIRT1was discussed by followed by SIRT1-specific siRNA and SIRT1bioactivityinhibitor nicotinamide; finally, the role of IGF-1R/AKT pathway in the resveratrol stimulation wasexplored through interference by IGF-1R/AKT pathway-specific inhibitors.
1Concentration and time-dependent induction of SIRT1on human degenerative endplatechondrocytes by resveratrol.
Objective To explore the effect of different concentrations and time of resveratrolintervention on the expression of SIRT1in human degenerative endplate chondrocytes. MethodsDegenerative disc endplate chondrocytes(DEC) were harvested from elder patient with lumbar dischernia, and then cultured. Passage2DEC were stimulated by resveratrol of differentconcentrations and Time respectively, and then expression levels of SIRT1and SIRT1mRNAwere detected by the end of stimulation. Results Compared with the expression levels in controlgroup, in order to achieve significant difference of SIRT1level, the least requirements of resveratrolwere12.5μmol/L by24hours,50μmol/L by12hours (P <0.05); in order to achieve significantdifference of SIRT1mRNA level, the least requirements of resveratrol were12.5μmol/L by48hours,50μmol/L by24hours (P <0.05).Resveratrol more than the above dose could inducesignificant difference when post-hoc analysis were conducted. Conclusion Resveratrolintervention could significantly upgrade the expression levels of SIRT1and SIRT1mRNA in human degenerative endplate chondrocytes in a concentration-and time-dependent manner.
2Resveratrol stimulate extracellular matrix synthesis of degenerative endplate chondrocytesby activating SIRT1pathway
Objective To explore the effect and mechanism of resveratrol on extracellular matrixsynthesize of degenerative endplate chondrocytes. Method Degenerative disc endplatechondrocytes(DECs),derived from elder patient with lumbar disc hernia, were randomly dividedinto5groups, namely, control group, dimethyl sulfoxide (DMSO) control group, resveratrol (Res)group, resveratrol+nicotinamide(RES+Nam) group, resveratrol+siRNA (RES+siRNA) group.DECs were stimulated with corresponding reagent for48hours. Expression levels of SIRT1, typeⅡcollagen, aggrecan and SIRT1mRNA were detected. Results100μmol/L Resveratrolintervention could increase the expression levels of both SIRT1and SIRT1mRNA,. stimulating thesynthesis of extracellular matrix. Nicotinamide and siRNA intervention effectively suppress SIRT1enzymatic activity and SIRT1mRNA expression respectively, inhibiting the synthesis ofextracellular matrix. Conclusion Resveratrol intervention could stimulate the extracellular matrixsynthesize of degenerative endplate chondrocytes via SIRT1pathway.
3Resveratrol stimulate the extracellular matrix synthesis of endplate chondrocytes viaIGF-1R/AKT pathway.
Objective To explore the effect of IGF-1R/AKT pathway on extracellular matrix synthesis ofdisc endplate chondrocytes stimulated by resveratrol Method P2generation of endplatechondrocytes were randomly divided into5groups, and stimulated with corresponding reagent for48hours. Expression levels of IGF-1R, pIGF-1R, AKT, pAKT, COLAII and aggrecan were detectedby Western blotting technique. Results Resveratrol intervention could significantly increase thephosphorylation levels of both IGFR and AKT, and stimulate the synthesis of COLAII and aggrecan.AG1024and SH-5significantly inhibit the phosphorylation of both IGFR and AKT, and inhibit thesynthesis of COLAII and aggrecan. Conclusion Resveratrol could stimulate the extracellular matrixsynthesis of disc endplate chondrocytes via IGF-1R/AKT regulatory pathway.
2003年KT Howitz和Sinclair等[1]首次发现并报道白黎芦醇，其属于sirtuin激活复合物(sirtuin activating compounds，STACs)，而且在一系列多酚类物质对SIRT1的作用活性检测中，白黎芦醇的激活作用最强。从此Res作为SIRT1的激活因子，被广泛应用到科学研究当中。
众多学者[2-6]证实，SIRT1是哺乳动物延缓衰老、延长寿命的关键分子，在细胞周期、代谢、分化等方面发挥广泛调节作用。Dvir-Ginzberg等[7]证实人关节软骨细胞的SIRT1高表达能够促进软骨细胞外基质基因Aggrecan， collagen2a(α1) and2b(α1)， collagen9(α1)的表达。Gagarina VG等[8]证实骨性关节炎患者SIRT1可抑制软骨细胞凋亡。
既往研究表明[9-11]，IGF-1可明显地促进多种来源的关节软骨细胞分裂增殖和软骨基质的合成，刺激软骨细胞合成软骨基质特异型蛋白－II型胶原和蛋白多糖，增强成骨细胞的碱性磷酸酯酶的活性。
本研究首先探讨了不同浓度及时间的白藜芦醇对退变椎间盘终板软骨细胞表达SIRT1的影响，为后续研究提供参考；其次通过SIRT1特异性siRNA及SIRT1酶活性抑制剂尼克酰胺的阻断作用，研究了白藜芦醇促进细胞外基质合成的作用及其与SIRT的关系；并通过IGF-1R/AKT通路特异性抑制剂的阻断作用，研究了白藜芦醇在退变的终板软骨细胞中促进细胞外基质合成的作用与IGF-1R/AKT通路的关系；从而阐明了白藜芦醇对退变椎间盘终板软骨细胞抑制退变的作用及其信号通路。
1白藜芦醇对退变椎间盘终板软骨细胞SIRT1表达的影响
目的探讨不同浓度及时间的白藜芦醇对退变椎间盘终板软骨细胞表达SIRT1的影响。
方法老年患者的终板软骨细胞培养、传代， P2代细胞随机分组，分别用不同浓度及作用时间的白藜芦醇干预，终止培养后检测SIRT1蛋白及SIRT1mRNA表达水平。
结果与空白对照组相比较，白藜芦醇能够显著促进退变椎间盘终板软骨细胞表达SIRT1蛋白的最低条件为12.5μmol/L干预24小时，以及50μmol/L干预12小时（P<0.05）；能够显著上调SIRT1基因转录水平的最低条件为12.5μmol/L干预作用48小时，以及50μmol/L干预24小时（P<0.05）；在上述浓度、时间组合条件之上，白藜芦醇的作用呈现浓度、时间依赖性。
结论白藜芦醇可显著促进退变椎间盘终板软骨细胞SIRT1蛋白及mRNA表达水平，且该作用呈现浓度、时间依赖关系。
2白藜芦醇通过SIRT1途径促进退变椎间盘终板软骨细胞合成细胞外基质
目的探讨白藜芦醇干预对退变椎间盘终板软骨细胞SIRT1的影响及其与细胞外基质合成的关系。
方法老年腰椎间盘突出症患者的终板软骨细胞培养、传代， P2代细胞随机分为5组，即白藜芦醇组、二甲基亚砜对照组、白藜芦醇+尼克酰胺组、白藜芦醇+siRNA转染组及空白对照组。各组进行对应处理后检测SIRT1、COLA2、aggrecan及SIRT1mRNA表达水平。
结果白藜芦醇干预上调退变椎间盘终板软骨细胞SIRT1基因的转录水平及SIRT1蛋白的表达水平，促进细胞外基质（COLA2、aggrecan）的合成；Nam及siRNA干预分别有效抑制了SIRT1酶活性及SIRT1mRNA的表达，并抑制了细胞外基质的合成。
结论白藜芦醇可促进退变椎间盘终板软骨细胞合成软骨细胞外基质成分（Ⅱ型胶原、aggrecan），抑制椎间盘软骨终板退变，其机制与调节SIRT1基因转录及SIRT1酶活性有关。
3白藜芦醇通过IGF-1R/AKT通路促进退变椎间盘终板软骨细胞合成细胞外基质
目的探讨IGF-1R/AKT信号通路在白藜芦醇促进椎间盘软骨终板细胞合成细胞外基质的影响（Ⅱ型胶原及aggrecan）。
方法椎间盘软骨终板细胞培养，传代，P2代细胞培养12h后，随机分为5组，各组加入对应试剂培养12h后终止培养，检测IGF-1R、pIGF-1R、AKT、pAKT、COLAII、aggrecan的表达变化。
结果白藜芦醇干预后IGF-1R及AKT磷酸化水平显著增加，COLAII、aggrecan表达显著增加；分别加入AG1024及SH-5则显著抑制了胰岛素样生长因子1受体（IGF-1R）及蛋白激酶B（AKT）磷酸化激活，COLAII、aggrecan表达显著下降。
结论白藜芦醇可促进椎间盘软骨终板细胞表达软骨细胞外基质，抑制软骨终板退变，其机制与调节IGF-1R/AKT通路活性有关。
Disc degeneration is a common cause of neck and low back pain. The disc is the largesthypoxic tissue of human body.Only the outer layer of annulus fibrosus exists vasculardistribution, the inner layer of annulus fibrosus and nucleus have no vascular distribution.nutrients that the nucleus pulpous cells required are supplied by the penetration function ofendplate cartilage from the vertebral body to the nucleus pulpous. With aging, the endplatechondrocytes aged,the apoptosis increased, synthesis of extracellular matrix decreased whiledecomposition accelerated, subchondral vertebral bone calcified, leading to the dispersion functionreduced. these alterations not only hindered nutrients supply of the nucleus pulposus, such as sugarand oxygen,but also hindered the discharge of metabolic wastes, such as lactic acid, thuspromoting disc degeneration.
Although the exact molecular mechanism of disc degeneration is not fully understood, but thereis no doubt that the degeneration of the endplate cartilage cells, and finally the reduction ofpermeability plays an important role in the process of disc degeneration. Therefore, to prevent andreduce the degeneration of the endplate cartilage cells become a potential target to prevent discdegeneration.
In2003,KT Howitz and Sinclair et al[1]firstly discovered and reported that resveratrol, itbelongs to the sirtuin activation complexes (sirtuin activating compounds, STACs), and is morepotent than a series of phenols as SIRT1activator. From then on,resveratrol,as a activator of SIRT1,is widely used in scientific research.
Many scholars[2-6]have confirmed that SIRT1is a key molecule in the process of retardingaging and extending lifespan in mammalian, and plays an important regulatory role in cell cycle, metabolism, differentiation. Dvir-Ginzbergand et al[7]have confirmed that the high expression levelof SIRT1in human articular chondrocytes can promote the expression of cartilage extracellularmatrix genes, such as aggrecan, collagen2a (α1),2b (α1), collagen9(α1). Gagarina VG[8]have confirmed SIRT1could inhibit chondrocyte apoptosis in patients with osteoarthritis.
Previous studies have shown[9-11]that in a variety of sources of articular chondrocyte, IGF-1can significantly promote proliferation,stimulate the synthesis of chondrocytes specific extracellularmatrix, such as type II collagen and proteoglycan, enhance alkaline phosphatase activity of bonecells.
This study explored the expression of SIRT1by resveratrol of different concentrations and timein degeneration intervertebral disc endplate cartilage cells and provide reference for furtherresearch; then the effect of resveratrol on promoting the synthesis of extracellular matrix and itsrelationship with SIRT1was discussed by followed by SIRT1-specific siRNA and SIRT1bioactivityinhibitor nicotinamide; finally, the role of IGF-1R/AKT pathway in the resveratrol stimulation wasexplored through interference by IGF-1R/AKT pathway-specific inhibitors.
1Concentration and time-dependent induction of SIRT1on human degenerative endplatechondrocytes by resveratrol.
Objective To explore the effect of different concentrations and time of resveratrolintervention on the expression of SIRT1in human degenerative endplate chondrocytes. MethodsDegenerative disc endplate chondrocytes(DEC) were harvested from elder patient with lumbar dischernia, and then cultured. Passage2DEC were stimulated by resveratrol of differentconcentrations and Time respectively, and then expression levels of SIRT1and SIRT1mRNAwere detected by the end of stimulation. Results Compared with the expression levels in controlgroup, in order to achieve significant difference of SIRT1level, the least requirements of resveratrolwere12.5μmol/L by24hours,50μmol/L by12hours (P <0.05); in order to achieve significantdifference of SIRT1mRNA level, the least requirements of resveratrol were12.5μmol/L by48hours,50μmol/L by24hours (P <0.05).Resveratrol more than the above dose could inducesignificant difference when post-hoc analysis were conducted. Conclusion Resveratrolintervention could significantly upgrade the expression levels of SIRT1and SIRT1mRNA in human degenerative endplate chondrocytes in a concentration-and time-dependent manner.
2Resveratrol stimulate extracellular matrix synthesis of degenerative endplate chondrocytesby activating SIRT1pathway
Objective To explore the effect and mechanism of resveratrol on extracellular matrixsynthesize of degenerative endplate chondrocytes. Method Degenerative disc endplatechondrocytes(DECs),derived from elder patient with lumbar disc hernia, were randomly dividedinto5groups, namely, control group, dimethyl sulfoxide (DMSO) control group, resveratrol (Res)group, resveratrol+nicotinamide(RES+Nam) group, resveratrol+siRNA (RES+siRNA) group.DECs were stimulated with corresponding reagent for48hours. Expression levels of SIRT1, typeⅡcollagen, aggrecan and SIRT1mRNA were detected. Results100μmol/L Resveratrolintervention could increase the expression levels of both SIRT1and SIRT1mRNA,. stimulating thesynthesis of extracellular matrix. Nicotinamide and siRNA intervention effectively suppress SIRT1enzymatic activity and SIRT1mRNA expression respectively, inhibiting the synthesis ofextracellular matrix. Conclusion Resveratrol intervention could stimulate the extracellular matrixsynthesize of degenerative endplate chondrocytes via SIRT1pathway.
3Resveratrol stimulate the extracellular matrix synthesis of endplate chondrocytes viaIGF-1R/AKT pathway.
Objective To explore the effect of IGF-1R/AKT pathway on extracellular matrix synthesis ofdisc endplate chondrocytes stimulated by resveratrol Method P2generation of endplatechondrocytes were randomly divided into5groups, and stimulated with corresponding reagent for48hours. Expression levels of IGF-1R, pIGF-1R, AKT, pAKT, COLAII and aggrecan were detectedby Western blotting technique. Results Resveratrol intervention could significantly increase thephosphorylation levels of both IGFR and AKT, and stimulate the synthesis of COLAII and aggrecan.AG1024and SH-5significantly inhibit the phosphorylation of both IGFR and AKT, and inhibit thesynthesis of COLAII and aggrecan. Conclusion Resveratrol could stimulate the extracellular matrixsynthesis of disc endplate chondrocytes via IGF-1R/AKT regulatory pathway.
引文
[1]Howitz KT, Bitterman KJ, Cohen HY, et al. Small molecule activators ofsirtuins extend Saccharomyces cerevisiae lifespan [J]. Nature,2003,425(6954):191-196.
[2]Hou X XS, Maitland-Toolan KA,. SIRT1regulates hepatocyte lipid metabolismthrough activating AMP-activated protein kinase [J]. J Biol Chem,2008,283(29):20015-20026.
[3]Li H, Rajendran GK, Liu N, et al. SirT1modulates the estrogen-insulin-likegrowth factor-1signaling for postnatal development of mammary gland in mice [J].Breast Cancer Res,2007,9(1): R1.
[4]Li Y, Xu W, McBurney MW, et al. SirT1inhibition reducesIGF-I/IRS-2/Ras/ERK1/2signaling and protects neurons [J]. Cell Metab,2008,8(1):38-48.
[5]Sun C, Zhang F, Ge X, et al. SIRT1improves insulin sensitivity underinsulin-resistant conditions by repressing PTP1B [J]. Cell Metab,2007,6(4):307-319.
[6]Tang BL. SIRT1, neuronal cell survival and the insulin/IGF-1aging paradox [J].Neurobiol Aging,2006,27(3):501-505.
[7]Dvir-Ginzberg M, Gagarina V, Lee EJ, et al. Regulation of cartilage-specificgene expression in human chondrocytes by SirT1and nicotinamidephosphoribosyltransferase [J]. J Biol Chem,2008,283(52):36300-36310.
[8]Gagarina V GO, Dvir-Ginzberg M. SirT1enhances survival of humanosteoarthritic chondrocytes by repressing protein tyrosine phosphatase1B andactivating the insulin-like growth factor receptor pathway [J]. Arthritis Rheum,2010,62(5):1383-1392.
[9]Starkman BG, Cravero JD, Delcarlo M, et al. IGF-I stimulation of proteoglycansynthesis by chondrocytes requires activation of the PI3-kinase pathway but not ERKMAPK [J]. Biochem J,2005,389(Pt3):723-729.
[10]Zhang M, Zhou Q, Liang QQ, et al. IGF-1regulation of type II collagen andMMP-13expression in rat endplate chondrocytes via distinct signaling pathways [J].Osteoarthritis Cartilage,2009,17(1):100-106.
[11]Veilleux N, Spector M. Effects of FGF-2and IGF-1on adult canine articularchondrocytes in type II collagen-glycosaminoglycan scaffolds in vitro [J]. OsteoarthritisCartilage,2005,13(4):278-286.
[12]Gruber HE GB, Williams C,et al. Vertebral endplate and disc changes in theaging sand rat lumbar spine: cross-sectional analyses of a large male and femalepopulation [J]. Spine,2007,23(2529-2536.
[13]Peng BG HS, Shi Q,et al. The relationship between cartilage endplatecalcification and disc degeneration: an experimental study [J]. Chin Med J,2001,114(3):308-312.
[14]Wang F, Jiang JM, Wang FL, et al. Biological characteristics of humandegenerative vertebral endplate cells [J]. Nan Fang Yi Ke Da Xue Xue Bao,2010,30(4):871-874.
[15]Alcain FJ, Villalba JM. Sirtuin activators [J]. Expert Opin Ther Pat,2009,19(4):403-414.
[16]Wood JG, Rogina B, Lavu S, et al. Sirtuin activators mimic caloric restrictionand delay ageing in metazoans [J]. Nature,2004,430(7000):686-689.
[17]Valenzano DR, Terzibasi E, Genade T, et al. Resveratrol prolongs lifespan andretards the onset of age-related markers in a short-lived vertebrate [J]. Curr Biol,2006,16(3):296-300.
[18]Bass TM, Weinkove D, Houthoofd K, et al. Effects of resveratrol on lifespan inDrosophila melanogaster and Caenorhabditis elegans [J]. Mech Ageing Dev,2007,128(10):546-552.
[19]Miller RA, Harrison DE, Astle CM, et al. Rapamycin, but not resveratrol orsimvastatin, extends life span of genetically heterogeneous mice [J]. J Gerontol A BiolSci Med Sci,2011,66(2):191-201.
[20]Spanier G, Xu H, Xia N, et al. Resveratrol reduces endothelial oxidative stressby modulating the gene expression of superoxide dismutase1(SOD1), glutathioneperoxidase1(GPx1) and NADPH oxidase subunit (Nox4)[J]. J Physiol Pharmacol,2009,60(Suppl4):111-116.
[21]Ryan MJ, Jackson JR, Hao Y, et al. Suppression of oxidative stress byresveratrol after isometric contractions in gastrocnemius muscles of aged mice [J]. JGerontol A Biol Sci Med Sci,2010,65(8):815-831.
[22]Smith JJ, Kenney RD, Gagne DJ, et al. Small molecule activators of SIRT1replicate signaling pathways triggered by calorie restriction in vivo [J]. BMC Syst Biol,2009,10(3):31.
[23]Yeung F, Hoberg JE, Ramsey CS, et al. Modulation of NF-kappaB-dependenttranscription and cell survival by the SIRT1deacetylase [J]. EMBO J,2004,23(12):2369-2380.
[24]Anekonda TS, Reddy PH. Neuronal protection by sirtuins in Alzheimer'sdisease [J]. J Neurochem,2006,96(2):305-313.
[25]Gouedard C, Barouki R, Morel Y. Induction of the paraoxonase-1geneexpression by resveratrol [J]. Arterioscler Thromb Vasc Biol,2004,24(12):2378-2383.
[26]Gehm BD, McAndrews JM, Chien PY, et al. Resveratrol, a polyphenoliccompound found in grapes and wine, is an agonist for the estrogen receptor [J]. ProcNatl Acad Sci U S A,1997,94(25):14138-14143.
[27]Manna SK, Mukhopadhyay A, Aggarwal BB. Resveratrol suppressesTNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1,and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation [J].J Immunol,2000,164(12):6509-6519.
[28]Baek SJ, Wilson LC, Eling TE. Resveratrol enhances the expression ofnon-steroidal anti-inflammatory drug-activated gene (NAG-1) by increasing theexpression of p53[J]. Carcinogenesis,2002,23(3):425-434.
[29]Ulrich S, Loitsch SM, Rau O, et al. Peroxisome proliferator-activated receptorgamma as a molecular target of resveratrol-induced modulation of polyaminemetabolism [J]. Cancer Res,2006,66(14):7348-7354.
[30]Da Violante G, Zerrouk N, Richard I, et al. Evaluation of the cytotoxicity effectof dimethyl sulfoxide (DMSO) on Caco2/TC7colon tumor cell cultures [J]. Biol PharmBull,2002,25(12):1600-1603.
[31]Pal R, Mamidi MK, Das AK, et al. Diverse effects of dimethyl sulfoxide(DMSO) on the differentiation potential of human embryonic stem cells [J]. ArchToxicol,2012,86(4):651-661.
[32]Yan Y, Gao YY, Liu BQ, et al. Resveratrol-induced cytotoxicity in humanBurkitt's lymphoma cells is coupled to the unfolded protein response [J]. BMC Cancer,2010,10(20):445-465.
[33]Zhou JH, Cheng HY, Yu ZQ, et al. Resveratrol induces apoptosis in pancreaticcancer cells [J]. Chin Med J (Engl),2011,124(11):1695-1699.
[34]Wang J, Gao JS, Chen JW, et al. Effect of resveratrol on cartilage protectionand apoptosis inhibition in experimental osteoarthritis of rabbit [J]. Rheumatol Int,2011,
[35]Wang TT, Schoene NW, Kim YS, et al. Differential effects of resveratrol andits naturally occurring methylether analogs on cell cycle and apoptosis in humanandrogen-responsive LNCaP cancer cells [J]. Mol Nutr Food Res,2010,54(3):335-344.
[36]Hsieh TC, Lu X, Guo J, et al. Differential regulation of proliferation, cell cyclecontrol and gene expression in cultured human aortic and pulmonary artery endothelialcells by resveratrol [J]. Int J Mol Med,2010,26(5):743-749.
[37]王广秀,浦佩玉,康春生等.白藜芦醇对C6鼠胶质瘤细胞抑制生长和诱导凋亡的作用[J].中华神经外科杂志,2007,23(4):313-315.
[38]周学武,陈建荣,刘桂艳等.白藜芦醇对人宫颈癌Hela细胞凋亡、增殖影响的实验研究[J].齐齐哈尔医学院学报,2008,29(20):2457-2459.
[39]Marier JF, Chen K, Prince P, et al. Production of ex vivolipopolysaccharide-induced tumor necrosis factor-alpha, interleukin-1beta, andinterleukin-6is suppressed by trans-resveratrol in a concentration-dependent manner [J].Can J Vet Res,2005,69(2):151-154.
[40]Wang Y, Leung LK. Pharmacological concentration of resveratrol suppressesaromatase in JEG-3cells [J]. Toxicol Lett,2007,173(3):175-180.
[41]Dave M, Attur M, Palmer G, et al. The antioxidant resveratrol protects againstchondrocyte apoptosis via effects on mitochondrial polarization and ATP production [J].Arthritis Rheum,2008,58(9):2786-2797.
[42]高洁生,王静,陈进伟，等.白藜芦醇对兔骨关节炎软骨细胞凋亡及bcl-2bax表达的影响; proceedings of the第十二届全国风湿病学学术会议,中国北京, F,2007[C].
[43]童敏,高戈,高洁生，等.白藜芦醇对骨关节炎模型兔关节液中一氧化氮水平的影响[J].新乡医学院学报,2007,01):49-52.
[44]王静.白藜芦醇对实验性兔骨关节炎软骨细胞凋亡及bcl-2，bax表达的影响[D];中南大学,2007.
[45]童敏,高戈,高洁生，等.白藜芦醇对兔骨关节炎模型关节软骨中COX-2表达的影响[J].江西医学院学报,2008,48(03):24-26.
[46]丁万军,刘世淸,贺斌，等.白藜芦醇对白细胞介素-1β诱导软骨细胞iNOs表达的影响[J].武汉大学学报(医学版),2010,31(04):458-461.
[47]蒋轩.白藜芦醇对实验性兔骨关节炎软骨IL-1β、iNOS蛋白表达的影响
[D];中南大学,2011.
[48]Elmali N, Esenkaya I, Harma A, et al. Effect of resveratrol in experimentalosteoarthritis in rabbits [J]. Inflamm Res,2005,54(4):158-162.
[49]Elmali N, Baysal O, Harma A, et al. Effects of resveratrol in inflammatoryarthritis [J]. Inflammation,2007,30(1-2):1-6.
[50]Shakibaei M, John T, Seifarth C, et al. Resveratrol inhibits IL-1beta-inducedstimulation of caspase-3and cleavage of PARP in human articular chondrocytes in vitro[J]. Ann N Y Acad Sci,2007,1095(1):554-563.
[51]Csaki C, Keshishzadeh N, Fischer K, et al. Regulation of inflammationsignalling by resveratrol in human chondrocytes in vitro [J]. Biochem Pharmacol,2008,75(3):677-687.
[52]Lei M, Liu SQ, Liu YL. Resveratrol protects bone marrow mesenchymal stemcell derived chondrocytes cultured on chitosan-gelatin scaffolds from the inhibitoryeffect of interleukin-1beta [J]. Acta Pharmacol Sin,2008,29(11):1350-1356.
[53]Li X, Phillips FM, An HS, et al. The action of resveratrol, a phytoestrogenfound in grapes, on the intervertebral disc [J]. Spine (Phila Pa1976),2008,33(24):2586-2595.
[54]Csaki C, Mobasheri A, Shakibaei M. Synergistic chondroprotective effects ofcurcumin and resveratrol in human articular chondrocytes: inhibition ofIL-1beta-induced NF-kappaB-mediated inflammation and apoptosis [J]. Arthritis ResTher,2009,11(6): R165.
[55]Takayama K, Ishida K, Matsushita T, et al. SIRT1regulation of apoptosis ofhuman chondrocytes [J]. Arthritis Rheum,2009,60(9):2731-2740.
[56]Liu FC, Hung LF, Wu WL, et al. Chondroprotective effects and mechanisms ofresveratrol in advanced glycation end products-stimulated chondrocytes [J]. ArthritisRes Ther,2010,12(5): R167.
[57]Shakibaei M, Mobasheri A, Buhrmann C. Curcumin synergizes withresveratrol to stimulate the MAPK signaling pathway in human articular chondrocytesin vitro [J]. Genes Nutr,2011,6(2):171-179.
[58]Zhao K, Harshaw R, Chai X, et al. Structural basis for nicotinamide cleavageand ADP-ribose transfer by NAD(+)-dependent Sir2histone/protein deacetylases [J].Proc Natl Acad Sci U S A,2004,101(23):8563-8568.
[59]Borra MT, Smith BC, Denu JM. Mechanism of human SIRT1activation byresveratrol [J]. J Biol Chem,2005,280(17):17187-17195.
[60]Beher D WJ, Cumine S, Kim KW, Lu SC, Atangan L, Wang M. Resveratrol isnot a direct activator of SIRT1enzyme activity [J]. Chem Biol Drug Des,2009,74(6):619-624.
[61]Pacholec M, Bleasdale JE, Chrunyk B, et al. SRT1720, SRT2183, SRT1460,and resveratrol are not direct activators of SIRT1[J]. J Biol Chem,2010,285(11):8340-8351.
[62]Park SJ, Ahmad F, Philp A, et al. Resveratrol ameliorates aging-relatedmetabolic phenotypes by inhibiting cAMP phosphodiesterases [J]. Cell,2012,148(3):421-433.
[63]Kang SK, Cho NS, Jang S.N-(5-Sulfanyl-idene-4,5-dihydro-1,3,4-thia-diazol-2-yl)acetamide dimethyl sulfoxidedisolvate [J]. Acta Crystallogr Sect E Struct Rep Online,2012,68(Pt1): o224.
[64]Lotz JC, Chin JR. Intervertebral disc cell death is dependent on the magnitudeand duration of spinal loading [J]. Spine (Phila Pa1976),2000,25(12):1477-1483.
[65]王飞,江建明,王凤龙，等.退变腰椎软骨终板细胞生物学特征实验研究[J].南方医科大学学报,2010,30(4):871-874.
[66]Khan AN, Lewis PN. Use of substrate analogs and mutagenesis to studysubstrate binding and catalysis in the Sir2family of NAD-dependent proteindeacetylases [J]. J Biol Chem,2006,281(17):11702-11711.
[67]Blander G GL. The Sir2family of protein deacetylases [J]. Annu Rev Biochem,2004,73(417-435.
[68]Buck SW, Gallo CM, Smith JS. Diversity in the Sir2family of proteindeacetylases [J]. J Leukoc Biol,2004,75(6):939-950.
[69]Audrito V, Vaisitti T, Rossi D, et al. Nicotinamide blocks proliferation andinduces apoptosis of chronic lymphocytic leukemia cells through activation of thep53/miR-34a/SIRT1tumor suppressor network [J]. Cancer Res,2011,71(13):4473-4483.
[70]Liu D, Gharavi R, Pitta M, et al. Nicotinamide prevents NAD+depletion andprotects neurons against excitotoxicity and cerebral ischemia: NAD+consumption bySIRT1may endanger energetically compromised neurons [J]. Neuromolecular Med,2009,11(1):28-42.
[71]Bai L, Pang WJ, Yang YJ, et al. Modulation of Sirt1by resveratrol andnicotinamide alters proliferation and differentiation of pig preadipocytes [J]. Mol CellBiochem,2008,307(1-2):129-140.
[72]Elbashir SM, Harborth J, Lendeckel W, et al. Duplexes of21-nucleotide RNAsmediate RNA interference in cultured mammalian cells [J]. Nature,2001,411(6836):494-498.
[73]Larsson E, Sander C, Marks D. mRNA turnover rate limits siRNA andmicroRNA efficacy [J]. Mol Syst Biol,2010,6(6):433.
[74]Hu N, Long H, Zhao M, et al. Aberrant expression pattern of histoneacetylation modifiers and mitigation of lupus by SIRT1-siRNA in MRL/lpr mice [J].Scand J Rheumatol,2009,38(6):464-471.
[75]Canto C, Jiang LQ, Deshmukh AS, et al. Interdependence of AMPK andSIRT1for metabolic adaptation to fasting and exercise in skeletal muscle [J]. CellMetab,2010,11(3):213-219.
[76]Fullerton MD, Steinberg GR. SIRT1takes a backseat to AMPK in theregulation of insulin sensitivity by resveratrol [J]. Diabetes,2010,59(3):551-553.
[77]Yao Y, Li H, Gu Y, et al. Inhibition of SIRT1deacetylase suppresses estrogenreceptor signaling [J]. Carcinogenesis,2010,31(3):382-387.
[78]Hong EH, Lee SJ, Kim JS, et al. Ionizing radiation induces cellular senescenceof articular chondrocytes via negative regulation of SIRT1by p38kinase [J]. J BiolChem,2010,285(2):1283-1295.
[79]Jeon S, Park JK, Bae CD, et al. NGF-induced moesin phosphorylation ismediated by the PI3K, Rac1and Akt and required for neurite formation in PC12cells[J]. Neurochem Int,2010,56(6-7):810-818.
[80]Vantler M, Huntgeburth M, Caglayan E, et al. PI3-kinase/Akt-dependentantiapoptotic signaling by the PDGF alpha receptor is negatively regulated by Srcfamily kinases [J]. FEBS Lett,2006,580(30):6769-6776.
[81]Guarani V, Potente M. SIRT1-a metabolic sensor that controls blood vesselgrowth [J]. Curr Opin Pharmacol,2010,10(2):139-145.
[82]Jin Q, Zhang F, Yan T, et al. C/EBPalpha regulates SIRT1expression duringadipogenesis [J]. Cell research,2010,20(4):470-479.
[83]Hirsch E, Costa C, Ciraolo E. Phosphoinositide3-kinases as a commonplatform for multi-hormone signaling [J]. J Endocrinol,2007,194(2):243-256.
[84]Krech T, Thiede M, Hilgenberg E, et al. Characterization of AKT independenteffects of the synthetic AKT inhibitors SH-5and SH-6using an integrated approachcombining transcriptomic profiling and signaling pathway perturbations [J]. BMCCancer,2010,10(6):287.
[85]Kang JD, Georgescu HI, McIntyre-Larkin L, et al. Herniated cervicalintervertebral discs spontaneously produce matrix metalloproteinases, nitric oxide,interleukin-6, and prostaglandin E2[J]. Spine (Phila Pa1976),1995,20(22):2373-2378.
[86]Boyd LM, Carter AJ. Injectable biomaterials and vertebral endplate treatmentfor repair and regeneration of the intervertebral disc [J]. Eur Spine J,2006,15(Suppl3):S414-421.
[87]Moore RJ. The vertebral end-plate: what do we know?[J]. Eur Spine J,2000,9(2):92-96.
[88]Ferguson SJ, Steffen T. Biomechanics of the aging spine [J]. Eur Spine J,2003,12(Suppl2): S97-S103.
[89]Panjabi MM, Chen NC, Shin EK, et al. The cortical shell architecture ofhuman cervical vertebral bodies [J]. Spine (Phila Pa1976),2001,26(22):2478-2484.
[90]Sivan SS, Tsitron E, Wachtel E, et al. Aggrecan turnover in humanintervertebral disc as determined by the racemization of aspartic acid [J]. J Biol Chem,2006,281(19):13009-13014.
[91]Roberts S, Urban JP, Evans H, et al. Transport properties of the humancartilage endplate in relation to its composition and calcification [J]. Spine (Phila Pa1976),1996,21(4):415-420.
[92]Taylor JR, Scott JE, Cribb AM, et al. Human intervertebral disc acidglycosaminoglycans [J]. Journal of anatomy,1992,180(Pt1)(137-141.
[93]Antoniou J, Goudsouzian NM, Heathfield TF, et al. The human lumbarendplate. Evidence of changes in biosynthesis and denaturation of the extracellularmatrix with growth, maturation, aging, and degeneration [J]. Spine (Phila Pa1976),1996,21(10):1153-1161.
[94]Aigner T, Gresk-otter KR, Fairbank JC, et al. Variation with age in the patternof type X collagen expression in normal and scoliotic human intervertebral discs [J].Calcif Tissue Int,1998,63(3):263-268.
[95]He HL, Wu ZH, Zhang JG, et al. Primary study on collagen X gene expressionin the apical disc of idiopathic scoliosis [J]. Zhonghua Yi Xue Za Zhi,2004,84(20):1681-1685.
[96]Nachemson A, Lewin T, Maroudas A, et al. In vitro diffusion of dye throughthe end-plates and the annulus fibrosus of human lumbar inter-vertebral discs [J]. ActaOrthop Scand,1970,41(6):589-607.
[97]Urban JP, Holm S, Maroudas A, et al. Nutrition of the intervertebral disc:effect of fluid flow on solute transport [J]. Clin Orthop Relat Res,1982,170(10):296-302.
[98]牛朋彦,熊伟,李锋,等.软骨终板通透性对体外培养大鼠髓核细胞生物学特性的影响[J].中国脊柱脊髓杂志,2011,21(7):597-602.
[99]吕刚,芮钢,王星铎,等.椎体软骨终板血管芽的形态学实验研究[J].中华骨科杂志,1998,18(12):722-724.
[100]Oki S, Matsuda Y, Shibata T, et al. Morphologic differences of the vascularbuds in the vertebral endplate: scanning electron microscopic study [J]. Spine (Phila Pa1976),1996,21(2):174-177.
[101]徐宏光,陈小虎,王弘,等.兔椎体软骨终板血管芽增龄性变化[J].中华骨科杂志,2011,31(4):351-356
[102]Annunen S, Paassilta P, Lohiniva J, et al. An allele of COL9A2associatedwith intervertebral disc disease [J]. Science,1999,285(5426):409-412.
[103]Karppinen J, Paakko E, Raina S, et al. Magnetic resonance imaging findingsin relation to the COL9A2tryptophan allele among patients with sciatica [J]. Spine(Phila Pa1976),2002,27(1):78-83.
[104]Sahlman J, Inkinen R, Hirvonen T, et al. Premature vertebral endplateossification and mild disc degeneration in mice after inactivation of one allele belongingto the Col2a1gene for Type II collagen [J]. Spine (Phila Pa1976),2001,26(23):2558-2565.
[105]Furuya S, Ohtsuki T, Yabe Y, et al. Ultrastructural study on calcification ofcartilage: comparing ICR and twy mice [J]. J Bone Miner Metab,2000,18(3):140-147.
[106]Goupille P, Mulleman D, Chevalier X. Is interleukin-1a good target fortherapeutic intervention in intervertebral disc degeneration: lessons from theosteoarthritic experience [J]. Arthritis Res Ther,2007,9(6):110.
[107]刘斌,金大地,瞿东滨,等. IL-1β、IL-6、TNF-α在兔腰椎软骨终板退变中的变化及作用[J].中国矫形外科杂志,2007,15（01):64-66.
[108]郑月焕,曹鹏,张兴凯,等.腰椎终板退行性改变与髓核内炎症因子及下腰痛相关性研究[J].国际骨科学杂志,2011,32(4):253-256.
[109]田峰,崔学生,张帅,等.转化生长因子β1及白介素-1β对终板软骨细胞的作用[J].重庆医学,2012,41(1):36-40.
[110]Ye W, Ma RF, Ding Y, et al.[Effect of interleukin-6on the chondrocytes inthe cartilage endplate of rabbits in vitro][J]. Nan Fang Yi Ke Da Xue Xue Bao,2007,27(8):1187-1189.
[111]Haschtmann D, Stoyanov JV, Gedet P, et al. Vertebral endplate traumainduces disc cell apoptosis and promotes organ degeneration in vitro [J]. Eur Spine J,2008,17(2):289-299.
[112]Ohtori S, Inoue G, Ito T, et al. Tumor necrosis factor-immunoreactive cellsand PGP9.5-immunoreactive nerve fibers in vertebral endplates of patients withdiscogenic low back Pain and Modic Type1or Type2changes on MRI [J]. Spine (PhilaPa1976),2006,31(9):1026-1031.
[113]刘斌,蔡道章. NO对软骨终板细胞代谢及细胞凋亡的影响[M].中国科协2005年学术年会论文集.2005.
[114]Stanic I, Facchini A, Borzi RM, et al. Polyamine depletion inhibits apoptosisfollowing blocking of survival pathways in human chondrocytes stimulated by tumornecrosis factor-alpha [J]. J Cell Physiol,2006,206(1):138-146.
[115]Zhang YG, Liu JT, Wang JT, et al.[Indexes of intervertebral disc degenerationin rats during the aging process][J]. Nan Fang Yi Ke Da Xue Xue Bao,2008,28(2):169-172.
[116]陈立,詹红生,应航,等.异常应力环境下兔颈椎软骨终板蛋白聚糖变化的实验研究[J].中国矫形外科杂志,2003,11(2):110-112.
[117]井夫杰,张静,詹红生.异常应力干预对兔颈软骨终板超微结构影响的实验研究[J].中国中医骨伤科杂志,2006,14(2):12-14.
[118]Xu HG, Chen XW, Wang H, et al.[Correlation between chondrocyteapoptosis of vertebral cartilage endplate and degeneration of intervertebral disc][J].Zhonghua Yi Xue Za Zhi,2008,88(3):194-197.
[119]Park JB, Lee JK, Park SJ, et al. Mitochondrial involvement in fas-mediatedapoptosis of human lumbar disc cells [J]. J Bone Joint Surg Am,2005,87(6):1338-1342.
[120]张振雨,叶伟,黄东生,等.兔软骨终板细胞凋亡与Caspase-3和Fas表达的实验研究[J].中国临床解剖学杂志,2006,24(5):553-558.
[121]Zhao QH, Tian JW, Wang L, et al.[Effect of siRNA-Cox-2on the growthinhibition and apoptosis of cartilage endplate chondrocytes][J]. Zhonghua Yi Xue ZaZhi,2011,91(15):1031-1035.
[122]Lefebvre V, Huang W, Harley VR, et al. SOX9is a potent activator of thechondrocyte-specific enhancer of the pro alpha1(II) collagen gene [J]. Molecular andCellular Biology,1997,17(4):2336-2346.
[123]Paul R, Haydon RC, Cheng H, et al. Potential use of Sox9gene therapy forintervertebral degenerative disc disease [J]. Spine (Phila Pa1976),2003,28(8):755-763.
[124]Moon SH, Nishida K, Gilbertson LG, et al. Biologic response of humanintervertebral disc cells to gene therapy cocktail [J]. Spine (Phila Pa1976),2008,33(17):1850-1855.
[125]裘淑荣,胡跃波,郝文杰,等.基因治疗兔颈椎间盘软骨终板钙化的实验研究[J].现代中西医结合杂志,2008,17(18):2775-2777.
[2]Hou X XS, Maitland-Toolan KA,. SIRT1regulates hepatocyte lipid metabolismthrough activating AMP-activated protein kinase [J]. J Biol Chem,2008,283(29):20015-20026.
[3]Li H, Rajendran GK, Liu N, et al. SirT1modulates the estrogen-insulin-likegrowth factor-1signaling for postnatal development of mammary gland in mice [J].Breast Cancer Res,2007,9(1): R1.
[4]Li Y, Xu W, McBurney MW, et al. SirT1inhibition reducesIGF-I/IRS-2/Ras/ERK1/2signaling and protects neurons [J]. Cell Metab,2008,8(1):38-48.
[5]Sun C, Zhang F, Ge X, et al. SIRT1improves insulin sensitivity underinsulin-resistant conditions by repressing PTP1B [J]. Cell Metab,2007,6(4):307-319.
[6]Tang BL. SIRT1, neuronal cell survival and the insulin/IGF-1aging paradox [J].Neurobiol Aging,2006,27(3):501-505.
[7]Dvir-Ginzberg M, Gagarina V, Lee EJ, et al. Regulation of cartilage-specificgene expression in human chondrocytes by SirT1and nicotinamidephosphoribosyltransferase [J]. J Biol Chem,2008,283(52):36300-36310.
[8]Gagarina V GO, Dvir-Ginzberg M. SirT1enhances survival of humanosteoarthritic chondrocytes by repressing protein tyrosine phosphatase1B andactivating the insulin-like growth factor receptor pathway [J]. Arthritis Rheum,2010,62(5):1383-1392.
[9]Starkman BG, Cravero JD, Delcarlo M, et al. IGF-I stimulation of proteoglycansynthesis by chondrocytes requires activation of the PI3-kinase pathway but not ERKMAPK [J]. Biochem J,2005,389(Pt3):723-729.
[10]Zhang M, Zhou Q, Liang QQ, et al. IGF-1regulation of type II collagen andMMP-13expression in rat endplate chondrocytes via distinct signaling pathways [J].Osteoarthritis Cartilage,2009,17(1):100-106.
[11]Veilleux N, Spector M. Effects of FGF-2and IGF-1on adult canine articularchondrocytes in type II collagen-glycosaminoglycan scaffolds in vitro [J]. OsteoarthritisCartilage,2005,13(4):278-286.
[12]Gruber HE GB, Williams C,et al. Vertebral endplate and disc changes in theaging sand rat lumbar spine: cross-sectional analyses of a large male and femalepopulation [J]. Spine,2007,23(2529-2536.
[13]Peng BG HS, Shi Q,et al. The relationship between cartilage endplatecalcification and disc degeneration: an experimental study [J]. Chin Med J,2001,114(3):308-312.
[14]Wang F, Jiang JM, Wang FL, et al. Biological characteristics of humandegenerative vertebral endplate cells [J]. Nan Fang Yi Ke Da Xue Xue Bao,2010,30(4):871-874.
[15]Alcain FJ, Villalba JM. Sirtuin activators [J]. Expert Opin Ther Pat,2009,19(4):403-414.
[16]Wood JG, Rogina B, Lavu S, et al. Sirtuin activators mimic caloric restrictionand delay ageing in metazoans [J]. Nature,2004,430(7000):686-689.
[17]Valenzano DR, Terzibasi E, Genade T, et al. Resveratrol prolongs lifespan andretards the onset of age-related markers in a short-lived vertebrate [J]. Curr Biol,2006,16(3):296-300.
[18]Bass TM, Weinkove D, Houthoofd K, et al. Effects of resveratrol on lifespan inDrosophila melanogaster and Caenorhabditis elegans [J]. Mech Ageing Dev,2007,128(10):546-552.
[19]Miller RA, Harrison DE, Astle CM, et al. Rapamycin, but not resveratrol orsimvastatin, extends life span of genetically heterogeneous mice [J]. J Gerontol A BiolSci Med Sci,2011,66(2):191-201.
[20]Spanier G, Xu H, Xia N, et al. Resveratrol reduces endothelial oxidative stressby modulating the gene expression of superoxide dismutase1(SOD1), glutathioneperoxidase1(GPx1) and NADPH oxidase subunit (Nox4)[J]. J Physiol Pharmacol,2009,60(Suppl4):111-116.
[21]Ryan MJ, Jackson JR, Hao Y, et al. Suppression of oxidative stress byresveratrol after isometric contractions in gastrocnemius muscles of aged mice [J]. JGerontol A Biol Sci Med Sci,2010,65(8):815-831.
[22]Smith JJ, Kenney RD, Gagne DJ, et al. Small molecule activators of SIRT1replicate signaling pathways triggered by calorie restriction in vivo [J]. BMC Syst Biol,2009,10(3):31.
[23]Yeung F, Hoberg JE, Ramsey CS, et al. Modulation of NF-kappaB-dependenttranscription and cell survival by the SIRT1deacetylase [J]. EMBO J,2004,23(12):2369-2380.
[24]Anekonda TS, Reddy PH. Neuronal protection by sirtuins in Alzheimer'sdisease [J]. J Neurochem,2006,96(2):305-313.
[25]Gouedard C, Barouki R, Morel Y. Induction of the paraoxonase-1geneexpression by resveratrol [J]. Arterioscler Thromb Vasc Biol,2004,24(12):2378-2383.
[26]Gehm BD, McAndrews JM, Chien PY, et al. Resveratrol, a polyphenoliccompound found in grapes and wine, is an agonist for the estrogen receptor [J]. ProcNatl Acad Sci U S A,1997,94(25):14138-14143.
[27]Manna SK, Mukhopadhyay A, Aggarwal BB. Resveratrol suppressesTNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1,and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation [J].J Immunol,2000,164(12):6509-6519.
[28]Baek SJ, Wilson LC, Eling TE. Resveratrol enhances the expression ofnon-steroidal anti-inflammatory drug-activated gene (NAG-1) by increasing theexpression of p53[J]. Carcinogenesis,2002,23(3):425-434.
[29]Ulrich S, Loitsch SM, Rau O, et al. Peroxisome proliferator-activated receptorgamma as a molecular target of resveratrol-induced modulation of polyaminemetabolism [J]. Cancer Res,2006,66(14):7348-7354.
[30]Da Violante G, Zerrouk N, Richard I, et al. Evaluation of the cytotoxicity effectof dimethyl sulfoxide (DMSO) on Caco2/TC7colon tumor cell cultures [J]. Biol PharmBull,2002,25(12):1600-1603.
[31]Pal R, Mamidi MK, Das AK, et al. Diverse effects of dimethyl sulfoxide(DMSO) on the differentiation potential of human embryonic stem cells [J]. ArchToxicol,2012,86(4):651-661.
[32]Yan Y, Gao YY, Liu BQ, et al. Resveratrol-induced cytotoxicity in humanBurkitt's lymphoma cells is coupled to the unfolded protein response [J]. BMC Cancer,2010,10(20):445-465.
[33]Zhou JH, Cheng HY, Yu ZQ, et al. Resveratrol induces apoptosis in pancreaticcancer cells [J]. Chin Med J (Engl),2011,124(11):1695-1699.
[34]Wang J, Gao JS, Chen JW, et al. Effect of resveratrol on cartilage protectionand apoptosis inhibition in experimental osteoarthritis of rabbit [J]. Rheumatol Int,2011,
[35]Wang TT, Schoene NW, Kim YS, et al. Differential effects of resveratrol andits naturally occurring methylether analogs on cell cycle and apoptosis in humanandrogen-responsive LNCaP cancer cells [J]. Mol Nutr Food Res,2010,54(3):335-344.
[36]Hsieh TC, Lu X, Guo J, et al. Differential regulation of proliferation, cell cyclecontrol and gene expression in cultured human aortic and pulmonary artery endothelialcells by resveratrol [J]. Int J Mol Med,2010,26(5):743-749.
[37]王广秀,浦佩玉,康春生等.白藜芦醇对C6鼠胶质瘤细胞抑制生长和诱导凋亡的作用[J].中华神经外科杂志,2007,23(4):313-315.
[38]周学武,陈建荣,刘桂艳等.白藜芦醇对人宫颈癌Hela细胞凋亡、增殖影响的实验研究[J].齐齐哈尔医学院学报,2008,29(20):2457-2459.
[39]Marier JF, Chen K, Prince P, et al. Production of ex vivolipopolysaccharide-induced tumor necrosis factor-alpha, interleukin-1beta, andinterleukin-6is suppressed by trans-resveratrol in a concentration-dependent manner [J].Can J Vet Res,2005,69(2):151-154.
[40]Wang Y, Leung LK. Pharmacological concentration of resveratrol suppressesaromatase in JEG-3cells [J]. Toxicol Lett,2007,173(3):175-180.
[41]Dave M, Attur M, Palmer G, et al. The antioxidant resveratrol protects againstchondrocyte apoptosis via effects on mitochondrial polarization and ATP production [J].Arthritis Rheum,2008,58(9):2786-2797.
[42]高洁生,王静,陈进伟，等.白藜芦醇对兔骨关节炎软骨细胞凋亡及bcl-2bax表达的影响; proceedings of the第十二届全国风湿病学学术会议,中国北京, F,2007[C].
[43]童敏,高戈,高洁生，等.白藜芦醇对骨关节炎模型兔关节液中一氧化氮水平的影响[J].新乡医学院学报,2007,01):49-52.
[44]王静.白藜芦醇对实验性兔骨关节炎软骨细胞凋亡及bcl-2，bax表达的影响[D];中南大学,2007.
[45]童敏,高戈,高洁生，等.白藜芦醇对兔骨关节炎模型关节软骨中COX-2表达的影响[J].江西医学院学报,2008,48(03):24-26.
[46]丁万军,刘世淸,贺斌，等.白藜芦醇对白细胞介素-1β诱导软骨细胞iNOs表达的影响[J].武汉大学学报(医学版),2010,31(04):458-461.
[47]蒋轩.白藜芦醇对实验性兔骨关节炎软骨IL-1β、iNOS蛋白表达的影响
[D];中南大学,2011.
[48]Elmali N, Esenkaya I, Harma A, et al. Effect of resveratrol in experimentalosteoarthritis in rabbits [J]. Inflamm Res,2005,54(4):158-162.
[49]Elmali N, Baysal O, Harma A, et al. Effects of resveratrol in inflammatoryarthritis [J]. Inflammation,2007,30(1-2):1-6.
[50]Shakibaei M, John T, Seifarth C, et al. Resveratrol inhibits IL-1beta-inducedstimulation of caspase-3and cleavage of PARP in human articular chondrocytes in vitro[J]. Ann N Y Acad Sci,2007,1095(1):554-563.
[51]Csaki C, Keshishzadeh N, Fischer K, et al. Regulation of inflammationsignalling by resveratrol in human chondrocytes in vitro [J]. Biochem Pharmacol,2008,75(3):677-687.
[52]Lei M, Liu SQ, Liu YL. Resveratrol protects bone marrow mesenchymal stemcell derived chondrocytes cultured on chitosan-gelatin scaffolds from the inhibitoryeffect of interleukin-1beta [J]. Acta Pharmacol Sin,2008,29(11):1350-1356.
[53]Li X, Phillips FM, An HS, et al. The action of resveratrol, a phytoestrogenfound in grapes, on the intervertebral disc [J]. Spine (Phila Pa1976),2008,33(24):2586-2595.
[54]Csaki C, Mobasheri A, Shakibaei M. Synergistic chondroprotective effects ofcurcumin and resveratrol in human articular chondrocytes: inhibition ofIL-1beta-induced NF-kappaB-mediated inflammation and apoptosis [J]. Arthritis ResTher,2009,11(6): R165.
[55]Takayama K, Ishida K, Matsushita T, et al. SIRT1regulation of apoptosis ofhuman chondrocytes [J]. Arthritis Rheum,2009,60(9):2731-2740.
[56]Liu FC, Hung LF, Wu WL, et al. Chondroprotective effects and mechanisms ofresveratrol in advanced glycation end products-stimulated chondrocytes [J]. ArthritisRes Ther,2010,12(5): R167.
[57]Shakibaei M, Mobasheri A, Buhrmann C. Curcumin synergizes withresveratrol to stimulate the MAPK signaling pathway in human articular chondrocytesin vitro [J]. Genes Nutr,2011,6(2):171-179.
[58]Zhao K, Harshaw R, Chai X, et al. Structural basis for nicotinamide cleavageand ADP-ribose transfer by NAD(+)-dependent Sir2histone/protein deacetylases [J].Proc Natl Acad Sci U S A,2004,101(23):8563-8568.
[59]Borra MT, Smith BC, Denu JM. Mechanism of human SIRT1activation byresveratrol [J]. J Biol Chem,2005,280(17):17187-17195.
[60]Beher D WJ, Cumine S, Kim KW, Lu SC, Atangan L, Wang M. Resveratrol isnot a direct activator of SIRT1enzyme activity [J]. Chem Biol Drug Des,2009,74(6):619-624.
[61]Pacholec M, Bleasdale JE, Chrunyk B, et al. SRT1720, SRT2183, SRT1460,and resveratrol are not direct activators of SIRT1[J]. J Biol Chem,2010,285(11):8340-8351.
[62]Park SJ, Ahmad F, Philp A, et al. Resveratrol ameliorates aging-relatedmetabolic phenotypes by inhibiting cAMP phosphodiesterases [J]. Cell,2012,148(3):421-433.
[63]Kang SK, Cho NS, Jang S.N-(5-Sulfanyl-idene-4,5-dihydro-1,3,4-thia-diazol-2-yl)acetamide dimethyl sulfoxidedisolvate [J]. Acta Crystallogr Sect E Struct Rep Online,2012,68(Pt1): o224.
[64]Lotz JC, Chin JR. Intervertebral disc cell death is dependent on the magnitudeand duration of spinal loading [J]. Spine (Phila Pa1976),2000,25(12):1477-1483.
[65]王飞,江建明,王凤龙，等.退变腰椎软骨终板细胞生物学特征实验研究[J].南方医科大学学报,2010,30(4):871-874.
[66]Khan AN, Lewis PN. Use of substrate analogs and mutagenesis to studysubstrate binding and catalysis in the Sir2family of NAD-dependent proteindeacetylases [J]. J Biol Chem,2006,281(17):11702-11711.
[67]Blander G GL. The Sir2family of protein deacetylases [J]. Annu Rev Biochem,2004,73(417-435.
[68]Buck SW, Gallo CM, Smith JS. Diversity in the Sir2family of proteindeacetylases [J]. J Leukoc Biol,2004,75(6):939-950.
[69]Audrito V, Vaisitti T, Rossi D, et al. Nicotinamide blocks proliferation andinduces apoptosis of chronic lymphocytic leukemia cells through activation of thep53/miR-34a/SIRT1tumor suppressor network [J]. Cancer Res,2011,71(13):4473-4483.
[70]Liu D, Gharavi R, Pitta M, et al. Nicotinamide prevents NAD+depletion andprotects neurons against excitotoxicity and cerebral ischemia: NAD+consumption bySIRT1may endanger energetically compromised neurons [J]. Neuromolecular Med,2009,11(1):28-42.
[71]Bai L, Pang WJ, Yang YJ, et al. Modulation of Sirt1by resveratrol andnicotinamide alters proliferation and differentiation of pig preadipocytes [J]. Mol CellBiochem,2008,307(1-2):129-140.
[72]Elbashir SM, Harborth J, Lendeckel W, et al. Duplexes of21-nucleotide RNAsmediate RNA interference in cultured mammalian cells [J]. Nature,2001,411(6836):494-498.
[73]Larsson E, Sander C, Marks D. mRNA turnover rate limits siRNA andmicroRNA efficacy [J]. Mol Syst Biol,2010,6(6):433.
[74]Hu N, Long H, Zhao M, et al. Aberrant expression pattern of histoneacetylation modifiers and mitigation of lupus by SIRT1-siRNA in MRL/lpr mice [J].Scand J Rheumatol,2009,38(6):464-471.
[75]Canto C, Jiang LQ, Deshmukh AS, et al. Interdependence of AMPK andSIRT1for metabolic adaptation to fasting and exercise in skeletal muscle [J]. CellMetab,2010,11(3):213-219.
[76]Fullerton MD, Steinberg GR. SIRT1takes a backseat to AMPK in theregulation of insulin sensitivity by resveratrol [J]. Diabetes,2010,59(3):551-553.
[77]Yao Y, Li H, Gu Y, et al. Inhibition of SIRT1deacetylase suppresses estrogenreceptor signaling [J]. Carcinogenesis,2010,31(3):382-387.
[78]Hong EH, Lee SJ, Kim JS, et al. Ionizing radiation induces cellular senescenceof articular chondrocytes via negative regulation of SIRT1by p38kinase [J]. J BiolChem,2010,285(2):1283-1295.
[79]Jeon S, Park JK, Bae CD, et al. NGF-induced moesin phosphorylation ismediated by the PI3K, Rac1and Akt and required for neurite formation in PC12cells[J]. Neurochem Int,2010,56(6-7):810-818.
[80]Vantler M, Huntgeburth M, Caglayan E, et al. PI3-kinase/Akt-dependentantiapoptotic signaling by the PDGF alpha receptor is negatively regulated by Srcfamily kinases [J]. FEBS Lett,2006,580(30):6769-6776.
[81]Guarani V, Potente M. SIRT1-a metabolic sensor that controls blood vesselgrowth [J]. Curr Opin Pharmacol,2010,10(2):139-145.
[82]Jin Q, Zhang F, Yan T, et al. C/EBPalpha regulates SIRT1expression duringadipogenesis [J]. Cell research,2010,20(4):470-479.
[83]Hirsch E, Costa C, Ciraolo E. Phosphoinositide3-kinases as a commonplatform for multi-hormone signaling [J]. J Endocrinol,2007,194(2):243-256.
[84]Krech T, Thiede M, Hilgenberg E, et al. Characterization of AKT independenteffects of the synthetic AKT inhibitors SH-5and SH-6using an integrated approachcombining transcriptomic profiling and signaling pathway perturbations [J]. BMCCancer,2010,10(6):287.
[85]Kang JD, Georgescu HI, McIntyre-Larkin L, et al. Herniated cervicalintervertebral discs spontaneously produce matrix metalloproteinases, nitric oxide,interleukin-6, and prostaglandin E2[J]. Spine (Phila Pa1976),1995,20(22):2373-2378.
[86]Boyd LM, Carter AJ. Injectable biomaterials and vertebral endplate treatmentfor repair and regeneration of the intervertebral disc [J]. Eur Spine J,2006,15(Suppl3):S414-421.
[87]Moore RJ. The vertebral end-plate: what do we know?[J]. Eur Spine J,2000,9(2):92-96.
[88]Ferguson SJ, Steffen T. Biomechanics of the aging spine [J]. Eur Spine J,2003,12(Suppl2): S97-S103.
[89]Panjabi MM, Chen NC, Shin EK, et al. The cortical shell architecture ofhuman cervical vertebral bodies [J]. Spine (Phila Pa1976),2001,26(22):2478-2484.
[90]Sivan SS, Tsitron E, Wachtel E, et al. Aggrecan turnover in humanintervertebral disc as determined by the racemization of aspartic acid [J]. J Biol Chem,2006,281(19):13009-13014.
[91]Roberts S, Urban JP, Evans H, et al. Transport properties of the humancartilage endplate in relation to its composition and calcification [J]. Spine (Phila Pa1976),1996,21(4):415-420.
[92]Taylor JR, Scott JE, Cribb AM, et al. Human intervertebral disc acidglycosaminoglycans [J]. Journal of anatomy,1992,180(Pt1)(137-141.
[93]Antoniou J, Goudsouzian NM, Heathfield TF, et al. The human lumbarendplate. Evidence of changes in biosynthesis and denaturation of the extracellularmatrix with growth, maturation, aging, and degeneration [J]. Spine (Phila Pa1976),1996,21(10):1153-1161.
[94]Aigner T, Gresk-otter KR, Fairbank JC, et al. Variation with age in the patternof type X collagen expression in normal and scoliotic human intervertebral discs [J].Calcif Tissue Int,1998,63(3):263-268.
[95]He HL, Wu ZH, Zhang JG, et al. Primary study on collagen X gene expressionin the apical disc of idiopathic scoliosis [J]. Zhonghua Yi Xue Za Zhi,2004,84(20):1681-1685.
[96]Nachemson A, Lewin T, Maroudas A, et al. In vitro diffusion of dye throughthe end-plates and the annulus fibrosus of human lumbar inter-vertebral discs [J]. ActaOrthop Scand,1970,41(6):589-607.
[97]Urban JP, Holm S, Maroudas A, et al. Nutrition of the intervertebral disc:effect of fluid flow on solute transport [J]. Clin Orthop Relat Res,1982,170(10):296-302.
[98]牛朋彦,熊伟,李锋,等.软骨终板通透性对体外培养大鼠髓核细胞生物学特性的影响[J].中国脊柱脊髓杂志,2011,21(7):597-602.
[99]吕刚,芮钢,王星铎,等.椎体软骨终板血管芽的形态学实验研究[J].中华骨科杂志,1998,18(12):722-724.
[100]Oki S, Matsuda Y, Shibata T, et al. Morphologic differences of the vascularbuds in the vertebral endplate: scanning electron microscopic study [J]. Spine (Phila Pa1976),1996,21(2):174-177.
[101]徐宏光,陈小虎,王弘,等.兔椎体软骨终板血管芽增龄性变化[J].中华骨科杂志,2011,31(4):351-356
[102]Annunen S, Paassilta P, Lohiniva J, et al. An allele of COL9A2associatedwith intervertebral disc disease [J]. Science,1999,285(5426):409-412.
[103]Karppinen J, Paakko E, Raina S, et al. Magnetic resonance imaging findingsin relation to the COL9A2tryptophan allele among patients with sciatica [J]. Spine(Phila Pa1976),2002,27(1):78-83.
[104]Sahlman J, Inkinen R, Hirvonen T, et al. Premature vertebral endplateossification and mild disc degeneration in mice after inactivation of one allele belongingto the Col2a1gene for Type II collagen [J]. Spine (Phila Pa1976),2001,26(23):2558-2565.
[105]Furuya S, Ohtsuki T, Yabe Y, et al. Ultrastructural study on calcification ofcartilage: comparing ICR and twy mice [J]. J Bone Miner Metab,2000,18(3):140-147.
[106]Goupille P, Mulleman D, Chevalier X. Is interleukin-1a good target fortherapeutic intervention in intervertebral disc degeneration: lessons from theosteoarthritic experience [J]. Arthritis Res Ther,2007,9(6):110.
[107]刘斌,金大地,瞿东滨,等. IL-1β、IL-6、TNF-α在兔腰椎软骨终板退变中的变化及作用[J].中国矫形外科杂志,2007,15（01):64-66.
[108]郑月焕,曹鹏,张兴凯,等.腰椎终板退行性改变与髓核内炎症因子及下腰痛相关性研究[J].国际骨科学杂志,2011,32(4):253-256.
[109]田峰,崔学生,张帅,等.转化生长因子β1及白介素-1β对终板软骨细胞的作用[J].重庆医学,2012,41(1):36-40.
[110]Ye W, Ma RF, Ding Y, et al.[Effect of interleukin-6on the chondrocytes inthe cartilage endplate of rabbits in vitro][J]. Nan Fang Yi Ke Da Xue Xue Bao,2007,27(8):1187-1189.
[111]Haschtmann D, Stoyanov JV, Gedet P, et al. Vertebral endplate traumainduces disc cell apoptosis and promotes organ degeneration in vitro [J]. Eur Spine J,2008,17(2):289-299.
[112]Ohtori S, Inoue G, Ito T, et al. Tumor necrosis factor-immunoreactive cellsand PGP9.5-immunoreactive nerve fibers in vertebral endplates of patients withdiscogenic low back Pain and Modic Type1or Type2changes on MRI [J]. Spine (PhilaPa1976),2006,31(9):1026-1031.
[113]刘斌,蔡道章. NO对软骨终板细胞代谢及细胞凋亡的影响[M].中国科协2005年学术年会论文集.2005.
[114]Stanic I, Facchini A, Borzi RM, et al. Polyamine depletion inhibits apoptosisfollowing blocking of survival pathways in human chondrocytes stimulated by tumornecrosis factor-alpha [J]. J Cell Physiol,2006,206(1):138-146.
[115]Zhang YG, Liu JT, Wang JT, et al.[Indexes of intervertebral disc degenerationin rats during the aging process][J]. Nan Fang Yi Ke Da Xue Xue Bao,2008,28(2):169-172.
[116]陈立,詹红生,应航,等.异常应力环境下兔颈椎软骨终板蛋白聚糖变化的实验研究[J].中国矫形外科杂志,2003,11(2):110-112.
[117]井夫杰,张静,詹红生.异常应力干预对兔颈软骨终板超微结构影响的实验研究[J].中国中医骨伤科杂志,2006,14(2):12-14.
[118]Xu HG, Chen XW, Wang H, et al.[Correlation between chondrocyteapoptosis of vertebral cartilage endplate and degeneration of intervertebral disc][J].Zhonghua Yi Xue Za Zhi,2008,88(3):194-197.
[119]Park JB, Lee JK, Park SJ, et al. Mitochondrial involvement in fas-mediatedapoptosis of human lumbar disc cells [J]. J Bone Joint Surg Am,2005,87(6):1338-1342.
[120]张振雨,叶伟,黄东生,等.兔软骨终板细胞凋亡与Caspase-3和Fas表达的实验研究[J].中国临床解剖学杂志,2006,24(5):553-558.
[121]Zhao QH, Tian JW, Wang L, et al.[Effect of siRNA-Cox-2on the growthinhibition and apoptosis of cartilage endplate chondrocytes][J]. Zhonghua Yi Xue ZaZhi,2011,91(15):1031-1035.
[122]Lefebvre V, Huang W, Harley VR, et al. SOX9is a potent activator of thechondrocyte-specific enhancer of the pro alpha1(II) collagen gene [J]. Molecular andCellular Biology,1997,17(4):2336-2346.
[123]Paul R, Haydon RC, Cheng H, et al. Potential use of Sox9gene therapy forintervertebral degenerative disc disease [J]. Spine (Phila Pa1976),2003,28(8):755-763.
[124]Moon SH, Nishida K, Gilbertson LG, et al. Biologic response of humanintervertebral disc cells to gene therapy cocktail [J]. Spine (Phila Pa1976),2008,33(17):1850-1855.
[125]裘淑荣,胡跃波,郝文杰,等.基因治疗兔颈椎间盘软骨终板钙化的实验研究[J].现代中西医结合杂志,2008,17(18):2775-2777.