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作者：吴追乐福建中医学院

学位级别：硕士

目的通过透骨消痛颗粒对骨髓间充质干细胞（BMSCs）体外抽取、分离、纯化、培养、增殖、软骨分化等基础实验,以优化软骨组织工程的种子细胞,增强软骨的自我修复功能,延缓软骨的退行性改变,达到预防与治疗骨性关节炎（OA）的目的,为中医... 详细信息

目的通过透骨消痛颗粒对骨髓间充质干细胞（BMSCs）体外抽取、分离、纯化、培养、增殖、软骨分化等基础实验,以优化软骨组织工程的种子细胞,增强软骨的自我修复功能,延缓软骨的退行性改变,达到预防与治疗骨性关节炎（OA）的目的,为中医药治疗OA提供坚实的临床基础。方法（1）抽取SD大鼠骨髓液,采用全骨髓贴壁培养法经体外分离、纯化、培养获得SD大鼠BMSCs,通过倒置相差显微镜观察其生长情况,研究BMSCs的体外生长状况。（2）取4周龄SD大鼠72只,随机分为3组,即:水提物组（48只）、醇提物组（16只）和空白对照组（8只）,再将水提物组随机分为3个亚组,即:高剂量组、中剂量（等效量）组、低剂量组,每个亚组16只。给予相对应的给药量灌胃3d,末次给药分别在1小时、2小时后进行采血,制备透骨消痛颗粒含药血清,运用透骨消痛颗粒不同含药血清浓度对获得的BMSCs进行药物干预72h,通过MTT法研究透骨消痛颗粒对BMSCs增殖的影响。（3）将第2代SD大鼠BMSCs分为空白对照组、单纯软骨诱导剂组及透骨消痛颗粒含药血清加软骨诱导剂组,采用原培养液、软骨诱导培养液(TGF-β310ug/L,Dex10-7mol/L,VitC50mg/L)及透骨消痛颗粒含药血清的软骨诱导培养液,50ml细胞培养瓶内进行培养,1、2、3周后通过倒置相差显微镜及免疫细胞化学染色等实验技术,研究透骨消痛颗粒对BMSCs诱导成软骨细胞的影响。（4）数据统计与分析:数据以均数±标准差表示,用统计软件SPSS14.0进行统计分析。结果（1）体外培养的BMSCs生长状况良好,12d可获得均质性较好的BMSCs,实验证明全骨髓贴壁培养法是分离BMSCs的一种比较理想的方法,BMSCs体外分离培养成功。（2）透骨消痛颗粒含药血清各实验组均可以促进BMSCs增殖,且各组与空白对照组相比均有非常显著性差异（P＜0.01）;在中剂量药物浓度时达到最大效应（P＜0.01）,继续增加浓度则使OD值呈现下降趋势;中剂量1小时组与2小时组相比无显著性差异（P＞0.05）。实验说明:透骨消痛颗粒刺激BMSCs增殖与药物浓度有关,水提物中剂量组的促增殖作用效应最大。（3）在TGF-β3等诱导下,软骨表型化BMSCs彼此融合,聚集生长,向三角形、多边形转变。透骨消痛颗粒组、软骨诱导剂组均有Ⅱ型胶原表达,而且透骨消痛颗粒组比软骨诱导剂组表达强,空白对照组没有Ⅱ型胶原表达。实验结果证明:透骨消痛颗粒可以有效的促进Ⅱ型胶原表达。结论（1）通过体外对SD大鼠BMSCs的抽取、分离、纯化、培养与增殖,已经建立起比较完整的BMSCs体外培养体系。（2）透骨消痛颗粒促进BMSCs增殖的同时,在诱导BMSCs向软骨细胞分化有显著的促进作用,从而增加软骨细胞的数量。（3）透骨消痛颗粒可以促进BMSCs向软骨细胞转化,优化骨组织工程的种子细胞体系,改善软骨组织的质量,延缓软骨的退变过程。

关键词：骨关节炎,膝/中药疗法间质干细胞/药物作用软骨细胞/药物作用细胞培养技术/方法细胞分化/药物作用比色法转化生长因子β 胶原Ⅱ型 @透骨消痛颗粒

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鹿茸多肽促进软骨细胞增殖机制的初步探讨

鹿茸多肽促进软骨细胞增殖机制的初步探讨

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作者：邓凌霄福建医科大学

学位级别：硕士

目的通过研究相关信号传导通路中的关键分子,如受体TPK,立早基因c-fos基因,细胞周期相关激酶等在细胞和分子水平探讨鹿茸多肽促进软骨细胞增殖的机制,为鹿茸多肽在软骨损伤组织工程修复应用提供实验依据。有利于更好的开发利用该药。研... 详细信息

目的通过研究相关信号传导通路中的关键分子,如受体TPK,立早基因c-fos基因,细胞周期相关激酶等在细胞和分子水平探讨鹿茸多肽促进软骨细胞增殖的机制,为鹿茸多肽在软骨损伤组织工程修复应用提供实验依据。有利于更好的开发利用该药。研究结果可对软骨细胞增殖相关细胞信号途径进行验证。方法1以胰酶胶原酶消化法获取兔软骨细胞进行培养。2采用相差显微镜观察其生长情况,MTT法描绘生长曲线。3以不同浓度的鹿茸多肽(PAP)刺激软骨细胞增殖,48小时后用MTT法观察细胞增殖情况。4再将实验细胞分成空白对照组,鹿茸多肽组,酪氨酸受体激酶阻断剂Genistein与PAP共同刺激的软骨细胞组和单纯Genistein组。用MTT法和流式细胞仪观察Genistein对PAP增殖情况及生长周期的影响。用免疫组化SABC法检测细胞周期蛋白cyclinA在PAP作用下的表达变化。RT-PCR法检测原癌基因c-fos mRNA表达。结果PAP作用下c-fos mRNA与cyclinA表达增加,S期的细胞比例增高,明显的促进软骨细胞增殖。Genistein作用后PAP的促增殖作用受到明显的抑制。结论鹿茸多肽可能通过酪氨酸受体蛋白激酶介导,作用下游的信号,引发立早基因c-fos表达,促进cyclinA的表达,引起更多的细胞进入有丝分裂期,从而促进软骨细胞增殖。鹿茸多肽在软骨修复组织工程中有较好的应用前景。

关键词：骨性关节炎/中药疗法软骨细胞/药物作用软骨细胞/增殖鹿茸多肽/药物作用受体酪氨酸激酶/阻滞剂原癌基因 c-fos 细胞周期蛋白 CyclinA Genistein

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鹿茸多肽对大鼠软骨细胞退变老化的影响

鹿茸多肽对大鼠软骨细胞退变老化的影响

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作者：陈晓东福建中医学院

学位级别：博士

目的：在细胞和分子水平观察体外培养的大鼠关节软骨细胞退变老化以及鹿茸多肽对这一变化的影响，并对软骨细胞复制性老化的机制以及鹿茸多肽的抗老化作用机制进行初步探讨。方法：1．采用酶消化法获取大鼠关节软骨细胞，应用台盼蓝排... 详细信息

目的：在细胞和分子水平观察体外培养的大鼠关节软骨细胞退变老化以及鹿茸多肽对这一变化的影响，并对软骨细胞复制性老化的机制以及鹿茸多肽的抗老化作用机制进行初步探讨。方法：1．采用酶消化法获取大鼠关节软骨细胞，应用台盼蓝排斥试验检测获取的软骨细胞活性。2．对软骨细胞退变老化进行观察，采用相差显微镜观察其生长情况，透射电镜观察细胞结构，阿力新蓝染色检测胞外基质硫酸GAG含量和结构，免疫细胞化学法和RT-PCR方法检测Ⅱ型胶原鉴定软骨细胞，以MTT比色法描绘生长曲线、检测生长状态，组化法检测老化相关β-半乳糖苷酶，流式细胞仪分析细胞周期和增殖指数。3．将P3软骨细胞分为空白对照组、鹿茸多肽不同浓度组、硫酸氨基葡萄糖不同浓度组进行传代培养，同时以P2代软骨细胞为对照组，进行组化检测老化相关β-半乳糖苷酶，阿力新蓝染色检测胞外基质硫酸GAG含量和结构，MTT比色检测增殖，免疫细胞化检测PCNA和Ⅱ型胶原，RT-PCR检测Ⅱ型胶原、Aggrecan蛋白，流式细胞仪分析细胞周期和增殖指数等方法，对鹿茸多肽抗软骨细胞退变老化进行分子生物学研究。4．将连续三代P2、P3、P4代软骨细胞及鹿茸多肽干预后的P4代软骨细胞进行老化机制研究。采用免疫细胞化检测p16、pRb、E2F、CyclinD、CDK4等因子表达水平，TRAP—ELISA检测端粒酶活性，进而考察软骨细胞老化过程中各因子的变化，同时考察鹿茸多肽对这一过程的作用。结果：1．酶消化法软骨细胞的分离培养可以获得大量活性优良的软骨细胞，经鉴定可以表达硫酸GAG、Ⅱ型胶原。2．从P4代开始，软骨细胞老化相关β-半乳糖苷酶表达大幅度提高，细胞停滞于G1期，增殖能力减弱，出现去分化，证明软骨细胞开始退变老化。3．鹿茸多肽可以抑制老化相关β-半乳糖苷酶的表达、促进鼠软骨细胞增殖、减少G1期细胞含量、促进软骨细胞表型等，可以抑制软骨细胞退变老化，其抗软骨细胞退变老化作用优于硫酸胺基葡萄糖。4．在软骨细胞退变老化过程中，调控细胞周期和生长的因子表达出现如下变化：p16↑—pRb↑—E2F↓—CyclinD↑—CDK4。5．鹿茸多肽可以逆向调控老化相关调控因子的表达。结论：1．酶消化法软骨细胞的分离培养可以提供良好的软骨细胞。2．体外培养软骨细胞P4代开始老化。3．鹿茸多肽具有显著的抗软骨细胞退变老化作用，其作用强于硫酸胺基葡萄糖。4．在软骨细胞退变老化过程中，老化相关调控因子出现如下变化：p16↑—pRb↑—E2F↓—CyclinD↑—CDK4↓—端粒酶↓。5．鹿茸多肽鹿茸多肽可能通过下调软骨细胞p16、pRb、CyclinD的表达、上调软骨细胞E2F、CDK4、端粒酶的表达来实现其抗软骨细胞退变老化的作用。

关键词：骨性关节炎/中药疗法软骨细胞/病理生理学软骨细胞/药物作用老化/病理生理老化/药物作用

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归芍康膝颗粒剂治疗膝骨性关节炎后MRI改变及其对IL-1α诱导后软骨细胞增殖的影响

归芍康膝颗粒剂治疗膝骨性关节炎后MRI改变及其对IL-1α诱导后软...

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作者：林越南京中医药大学

学位级别：硕士

目的:探讨中医学对骨关节炎发病机理的认识,根据中医学“肾虚血瘀”的病变机理,制定“补肾活血”治疗大法,选用千古名方“独活寄生汤”并进行化裁,拟定归芍康膝颗粒剂进行实验研究,了解归芍康膝颗粒剂对IL-1α诱导后软骨细胞增殖的影响... 详细信息

目的:探讨中医学对骨关节炎发病机理的认识,根据中医学“肾虚血瘀”的病变机理,制定“补肾活血”治疗大法,选用千古名方“独活寄生汤”并进行化裁,拟定归芍康膝颗粒剂进行实验研究,了解归芍康膝颗粒剂对IL-1α诱导后软骨细胞增殖的影响,并采用膝MRI对OA进行精确分期,定量分析病变膝关节,对关节囊积液、软骨下骨髓水肿、软骨破坏、滑膜增生及半月板损伤的程度进行综合评价,为临床治疗方案的选择提供诊断依据,为药物疗效提供客观可靠的数据,同时继续采用VAS、WOMAC骨关节炎指数,同步进行临床量化指标观察,进一步观察临床症候疗效和MRI软骨改变的关系。方法:①理论方法:采用文献学、逻辑推理、比类取象等方法。 ②实验方法:(1)取材手术后人髋关节,按常规方法培养软骨细胞;(2)MTT比色法观察归芍康膝颗粒剂对软骨细胞增殖的影响。 ③临床研究方法:采用随机平行对照的试验方法,观察例数60例(试验组和对照组各30例),疗程4周。试验组给予归芍康膝颗粒剂每日一剂,对照组给予维骨力250mg,每日3次,治疗前后两组分别评价其WOMAC指数、VAS及不良反应。同时收集膝骨关节炎患者42例,18例和24例患者服用归芍康膝颗粒剂分别于半年和一年前后行MRI检查(MRI观察包括关节囊积液、软骨下骨髓水肿、软骨破坏、滑膜增生及半月板损伤的程度)。试验结束以SPSS13.0统计软件进行统计分析。结果:①理论研究结果:祖国医学认为,骨性关节炎属“痹证”范畴,根本病机为肝肾亏虚,气血不足为本;气滞血瘀,风寒痰湿痹阻脉络为标。病理特点为本虚标实。治疗应补益和祛邪并举,补肾活血是治疗骨关节炎的大法,以益肝肾、强筋骨、补气血治其本,活血通络、散寒祛湿治其标。 ②实验研究结果:(1)成功培养软骨细胞;(2)MTT比色法观察归芍康膝颗粒剂对软骨细胞增殖的影响,结果显示:归芍康膝颗粒剂0.075 0mg/ul、0.375 0mg/ul、0.750 0mg/ul三个浓度均可显著促进IL-1α诱导后软骨细胞的增殖,较模型组明显增强,经统计学处理有显著统计学差异(P＜0.01);三个浓度之间比较,促进软骨细胞增殖的能力0.750 0＞0.3750＞0.075 0 mg/ul,经统计学处理P值均小于0.01,有显著性差异。 ③临床研究结果:(1)收集膝OA患者60例,随机分为试验组和对照组各30例,总体疗效评价归芍康膝颗粒组总有效率优于维骨力组,Ridit分析,U=1.9753,P＜0.05,有显著差异;两组WOMAC指数与治疗前相比均有下降,有极显著差异(P＜0.01),但组间比较无显著差异(P＞0.05);两组VAS与治疗前相比均有下降,有极显著差异(P＜0.01),但归芍康膝颗粒剂组止痛作用更好,两组比较有显著差异(P＜0.01);两组均未发现严重的不良反应。(2)42例膝骨0A患者,其中服用归芍康膝颗粒剂半年后复查MRI18例,一年后复查24例。观察其MRI下关节腔积液量、软骨下骨髓水肿范围、滑膜增厚及半月板退变情况。软骨破坏程度得到控制或有好转占71.4%(30/42),仍有进展的为28.6%(12/42);半月板退行性改变程度在治疗前后均无明显改变;滑膜增生在治疗中得到控制占71.4%(30/42),进展和好转各占14.3%(6/42)。结论:归芍康膝颗粒剂能改善膝骨关节炎患者的临床症状,安全,有效。实验研究证实了归芍康膝颗粒剂的软骨保护剂样作用,临床影像学方面表明该颗粒剂可促进膝关节囊积液、软骨下骨髓水肿的吸收,延缓软骨的破坏、滑膜的增厚及半月板的退变。

关键词：归芍康膝颗粒剂骨关节炎/中药疗法补肾活血法软骨细胞/药物作用细胞培养细胞增殖膝关节MRI 软骨破坏骨髓水肿 WOMAC指数 VAS指数

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骨痹康方对IL-1α诱导的人软骨细胞Ⅱ型胶原mRNA表达及WOMAC骨关节炎指数的影响研究

骨痹康方对IL-1α诱导的人软骨细胞Ⅱ型胶原mRNA表达及WOMAC骨关...

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作者：王新东南京中医药大学

学位级别：硕士

目的：探讨中医学对“骨痹”发病机理的认识，揭示验方“骨痹康”方对IL-1α诱导的人关节软骨细胞损伤模型Ⅱ型胶原mRNA表达的调控机制和对软骨细胞的保护机制；通过随机对照临床试验评价“骨痹康”方治疗膝OA的有效性和安全性，为其防... 详细信息

目的：探讨中医学对“骨痹”发病机理的认识，揭示验方“骨痹康”方对IL-1α诱导的人关节软骨细胞损伤模型Ⅱ型胶原mRNA表达的调控机制和对软骨细胞的保护机制；通过随机对照临床试验评价“骨痹康”方治疗膝OA的有效性和安全性，为其防治骨关节炎提供可靠的理论依据、实验数据和临床循证证据。方法：1 理论研究方法：采用文献学、逻辑推理、比类取象等方法，对OA发病机理的中医学认识进行探讨。2 实验方法：(1)取材手术后人关节软骨，培养软骨细胞；(2)MTT比色法观察骨痹康对正常和IL-1α诱导的软骨细胞增殖的影响；(3)RT-PCR法观察骨痹康对IL-1α诱导的软骨细胞Ⅱ型胶原mRNA表达的影响；(4)免疫组织化学法观察骨痹康对IL-1α诱导的软骨细胞Ⅱ型胶原表达的影响。3 临床研究方法：采用随机平行对照的试验方法，入选病例随机分为试验组和对照组。试验组给予骨痹康水煎剂每日一剂，对照组给予维骨力2粒，每日3次，疗程4周。治疗前后两组分别评价其WOMAC指数、中医证候改善情况、关节压痛改善情况、关节肿胀改善情况、关节活动度的改善情况、起效时间、合用泰诺林的粒数和时间、不良反应、实验室安全指标的检测情况。结果：1 理论研究结果：根据导师张前德教授的学术思想，骨关节炎根本病机为“肾虚络痹”即肝肾亏虚、痰瘀阻络，病变部位在关节络脉，不外络虚、络实，络虚是肝肾不足、气血亏虚、络脉失养；络实是痰瘀互结、邪滞络脉。其中络虚为始动因素，络脉瘀滞为其病变形成的最终病理基础。临床治疗骨关节炎应考虑其临床症状和发病特点，在辨证的基础上，

关键词：骨痹康方/药理学骨关节炎/中药疗法 Ⅱ型胶原基因表达软骨细胞/药物作用细胞,培养细胞增殖 RT-PCR 免疫组织化学硫酸氨基葡萄糖 WOMAC指数临床试验

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Chondrocyte translocation response to direct current electric fields

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JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME 2000年第3期122卷 261-267页

作者： Chao, PHG Roy, R Mauck, RL Liu, W Valhmu, WB Hung, CT Columbia Univ Dept Biomed Engn Cellular Engn Lab New York NY 10027 USA Columbia Univ Dept Orthopaed Surg Orthopaed Res Lab New York NY 10032 USA

Using a custom galvanotaxis chamber and time-lapse digital video microscopy, we report the novel observation that cultured chondrocytes exhibit cathodal migration when subjected to applied direct current (DC) electric fields as low as 0.8 V/cm. The response was dose-dependent for field strengths greater than 4 V/cm. Cell migration appeared to be an active process with extension of cytoplasmic processes in the direction of movement. In some cells, field application for greater than an hour induced elongation of initially round cells accompanied by perpendicular alignment of the long axis with respect to the applied field. Antagonists of the inositol phospholipid pathway, U-73122 and neomycin, were able to inhibit cathodal migration. Cell migration toward the cathode did nor require the presence of serum during field application. However, the directed velocity was nearly threefold greater in studies performed with serum. Studies performed at physiologic temperatures (similar to 37 degreesC) revealed a twofold enhancement in migration speed compared to similar studies at room temperature (similar to 25 degreesC). Findings from the present study may help to elucidate basic mechanisms that mediate chondrocyte migration and substrate attachment. Since chondrocyte migration has been implicated in cartilage healing, the ability to direct chondrocyte movement has the potential to impact strategies for addressing cartilage healing/repair and for development of cartilage substitutes.

关键词：细胞运动/药物作用细胞运动/生理学细胞培养的/药物作用细胞培养的/生理学软骨细胞/药物作用软骨细胞/生理学电刺激雌烯类显微镜检查电视新霉素/药理学磷酸二酯酶抑制剂/药理学吡咯烷酮类动物牛

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Response of engineered cartilage tissue to biochemical agents as studied by proton magnetic resonance microscopy

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ARTHRITIS AND RHEUMATISM 2000年第7期43卷 1580-1590页

作者： Potter, K Butler, JJ Horton, WE Spencer, RGS NIA Gerontol Res Ctr Nucl Magnet Resonance Unit Intramural Res ProgramNIH Baltimore MD 21224 USA NICHHD NIH Bethesda MD 20892 USA NE Ohio Univ Coll Med Rootstown OH 44272 USA

Objective, To test the hypothesis that magnetic resonance imaging (MRI) results correlate with the biochemical composition of cartilage matrix and can therefore be used to evaluate natural tissue development and the effects of biologic interventions. Methods. Chondrocytes harvested from day-16 chick embryo sterna were inoculated into an MRI-compatible hollow-fiber bioreactor, The tissue that formed over a period of 2-4 weeks was studied biochemically, histologically, and with MRI. Besides natural development, the response of the tissue to administration of retinoic acid, interleukin-1 beta (IL-1 beta), and daily dosing with ascorbic acid was studied. Results. Tissue wet and dry weight, glycosaminoglycan (GAG) content, and collagen content all increased with development time, while tissue hydration decreased. The administration of retinoic acid resulted in a significant reduction in tissue wet weight, proteoglycan content, and cell number and an increase in hydration as compared with controls. Daily dosing with ascorbic acid increased tissue collagen content significantly compared with controls, while the administration of IL-1 beta resulted in increased proteoglycan content. The water proton longitudinal and transverse relaxation rates correlated well with GAG and collagen concentrations of the matrix as well as with tissue hydration. In contrast, the magnetization transfer value for the tissue correlated only with total collagen, Finally, the self-coefficient of water correlated with tissue diffusion hydration. Conclusion. Parameters derived from MR images obtained noninvasively can be used to quantitatively assess the composition of cartilage tissue generated in a bioreactor. We conclude that MRI is a promising modality for the assessment of certain biochemical properties of cartilage in a wide variety of settings.

关键词：抗坏血酸/药理学生物反应器软骨/化学软骨/细胞学软骨/药物作用软骨细胞/化学软骨细胞/细胞学软骨细胞/药物作用胶原/分析培养技术葡糖氨基聚糖类/分析白细胞介素1/药理学磁共振成像/方法可重复性结果胸骨/化学胸骨/细胞学胸骨/药物作用维甲酸/药理学动物鸡胚

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Mitochondrial oxidative phosphorylation is a downstream regulator of nitric oxide effects on chondrocyte matrix synthesis and mineralization

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ARTHRITIS AND RHEUMATISM 2000年第7期43卷 1560-1570页

作者： Johnson, K Jung, A Murphy, A Andreyev, A Dykens, J Terkeltaub, R Dept Vet Affairs Med Ctr San Diego CA 92161 USA Mitokor Corp San Diego CA USA Univ Calif San Diego San Diego CA 92103 USA

Objective. Increased chondrocyte nitric oxide (NO) and peroxynitrite production appears to modulate decreased matrix synthesis and increased mineralization in osteoarthritis (OA), Because NO inhibits mitochondrial respiration, this study was undertaken to directly assess the potential role of chondrocyte mitochondrial oxidative phosphorylation (OXPHOS) in matrix synthesis and mineralization, Methods. We studied cultured human articular chondrocytes and immortalized costal chondrocytes (TC28 cells). We also assessed the effects of antimycin A and oligomycin (inhibitors of mitochondrial complexes III and V, respectively) on chondrocyte mitochondrial respiration, ATP synthesis, and inorganic pyrophosphate (PPi) generation, and the mineralizing potential of released matrix vesicles (MV), Results, Articular chondrocytes and TC28 cells respired at comparable rates. Peroxynitrite and NO donors markedly suppressed respiration and ATP generation in chondrocytes, Because NO exerts multiple effects on chondrocytes, we investigated the primary functions of mitochondrial respiration and OXPHOS, To do so, we identified minimally cytotoxic doses of antimycin and oligomycin, which both induced intracellular ATP depletion (by 50-80%), attenuated collagen and proteoglycan synthesis, and blocked transforming growth factor beta from increasing intracellular ATP and elaboration of PPI, a critical inhibitor of hydroxyapatite deposition. Antimycin and oligomycin also abrogated the ability of the ATP-hydrolyzing enzyme plasma cell membrane glycoprotein 1 (PC-1) to increase chondrocyte PPI generation. Finally, MV from cells treated with antimycin or oligomycin contained less PPI and precipitated >50% more Ca-45, Conclusion. Chondrocyte mitochondrial reserve, as NO-sensitive mitochondrial respiration-mediated ATP production, appears to support matrix synthesis and PPI elaboration and to regulate MV composition and mineralizing activity. NO-induced depression of chondrocyte respiration could

关键词：腺苷三磷酸/生物合成抗霉素A/药理学钙化生理性/药物作用软骨关节/细胞学细胞系转化细胞存活/药物作用软骨细胞/细胞学软骨细胞/药物作用软骨细胞/代谢二磷酸盐类/代谢细胞外基质/药物作用细胞外基质/代谢线粒体/药物作用线粒体/代谢一氧化氮/代谢寡霉素类/药理学氧化磷酸化重组蛋白质类转化生长因子β/药理学人类

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Expression and release of insulin-like growth factor binding proteins in isolated epiphyseal growth plate chondrocytes from the ovine fetus

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JOURNAL OF CELLULAR PHYSIOLOGY 2000年第2期183卷 172-181页

作者： De los Rios, P Hill, DJ Univ Western Ontario St Josephs Hlth Ctr Lawson Res Inst London ON N6A 4V2 Canada Univ Western Ontario Dept Physiol London ON Canada Univ Western Ontario Dept Med London ON Canada Univ Western Ontario Dept Paediat London ON Canada

Insulin-like growth factor-ii (IGF-II) is an autocrine modulator of epiphyseal chondrogenesis in the fetus. The cellular availability of ICFs are influenced by the IGF-binding proteins (ICFBPs). In this study, we investigated the control of expression and release of ICFBPs from isolated epiphyseal growth plate chondrocytes from the ovine fetus by hormones and growth factors implicated in the chondrogenic process. Chondrocytes were isolated from the proliferative zone of the fetal ovine proximal tibial growth plate and maintained in monolayer culture at early passage number. Culture media conditioned by chondrocytes under basal conditions released ICFBPs of 24, 34, and 29 kDa, and a less abundant species of 39-43 kDa that were identified immunologically as IGFBP-4, IGFBP-2, IGFBP-5, and IGFBP-3, respectively. Messenger RNAs encoding each species were identified by Northern blot analysis within chondrocytes, as was mRNA encoding IGFBP-6. Exposure to ICF-I or IGF-II (13 or 26 nM) caused an increase in expression and release of 1GFBP-3. The release of 1GFBP-2 and IGFBP-5 were also potentiated without changes to steady state mRNA, and for IGFBP-5 this was due in part to a release from the cell membrane in the presence of ICF-II. Insulin (16.7 or 167 nM)selectively increased mRNA and the release of IGFBP-3, while cortisol il or 5 mu M) inhibited both mRNA and release of IGFBP-2 and ICFBP-5, Transforming growth factor-beta 1 (TGF-beta 1) (0.1 or 0.2 nM) increased the expression and release of IGFBP-3. and caused an increase in mRNAs encoding IGFBP-2 and ICFBP-5. Neither growth hormone (GH), Fibroblast growth factor-2, nor thyroxine (T-4) had any effect on IGFBP expression or release. The results suggest that IGFBP expression and release within the developing growth plate can be modulates by IGF-II and other trophic factors, thus controlling IGF availability and action. (C) 2000 Wiley-Liss, Inc.

关键词：细胞培养的软骨细胞/药物作用软骨细胞/代谢软骨细胞/分泌软骨发生/遗传学软骨发生/生理学胎儿/细胞学胎儿/代谢基因表达调控发育期/药物作用生长面/细胞学生长面/代谢生长面/分泌氢化可的松/药理学胰岛素/药理学胰岛素样生长因子结合蛋白质类/遗传学胰岛素样生长因子结合蛋白质类/分泌胰岛素样生长因子Ⅰ/药理学胰岛素样生长因子Ⅱ/药理学 RNA 信使/遗传学 RNA 信使/代谢绵羊转化生长因子β/药理学动物

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Potent and selective nonpeptide inhibitors of caspases 3 and 7 inhibit apoptosis and maintain cell functionality

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第21期275卷 16007-16014页

作者： Lee, D Long, SA Adams, JL Chan, G Vaidya, KS Francis, TA Kikly, K Winkler, JD Sung, CM Debouck, C Richardson, S Levy, MA DeWolf, WE Keller, PM Tomaszek, T Head, MS Ryan, MD Haltiwanger, RC Liang, PH Janson, CA McDevitt, PJ Johanson, K Concha, NO Chan, W Abdel-Meguid, SS Badger, AM Lark, MW Nadeau, DP Suva, LJ Gowen, M Nuttall, ME SmithKline Beecham Pharmaceut Dept Med Chem King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Biomol Discovery King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Immunol King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Immunopharmacol King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Mol Biol King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Mol Recognit King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Phys & Struct Chem King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Prot Biochem King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Biol Struct King Of Prussia PA 19406 USA SmithKline Beecham Pharmaceut Dept Bone & Cartilage Biol King Of Prussia PA 19406 USA

Caspases have been strongly implicated to play an essential role in apoptosis, A critical question regarding the role(s) of these proteases is whether selective inhibition of an effector caspase(s) will prevent cell death. We have identified potent and selective non-peptide inhibitors of the effector caspases 3 and 7, The inhibition of apoptosis and maintenance of cell functionality with a caspase 3/7-selective inhibitor is demonstrated for the first time, and suggests that targeting these two caspases alone is sufficient for blocking apoptosis, Furthermore, an x-ray co-crystal structure of the complex between recombinant human caspase 3 and an isatin sulfonamide inhibitor has been solved to 2.8-Angstrom resolution, In contrast to previously reported peptide-based caspase inhibitors, the isatin sulfonamides derive their selectivity for caspases 3 and 7 by interacting primarily with the S-2, subsite, and do not bind in the caspase primary aspartic acid binding pocket (S-1), These inhibitors blocked apoptosis in murine bone marrow neutrophils and human chondrocytes, Furthermore, in camptothecin-induced chondrocyte apoptosis, cell functionality as measured by type II collagen promoter activity is maintained, an activity considered essential for cartilage homeostasis. These data suggest that inhibiting chondrocyte cell death with a caspase 3/7-selective inhibitor may provide a novel therapeutic approach for the prevention and treatment of osteoarthritis, or other disease states characterized by excessive apoptosis.

关键词：氨基酸氯甲基酮类/药理学细胞凋亡结合部位喜树碱/药理学半胱氨酸天冬氨酸蛋白酶3 半胱氨酸天冬氨酸蛋白酶7 软骨细胞/药物作用胶原/遗传学结晶学 X线酶抑制剂/化学酶抑制剂/药理学靛红/类似物和衍生物模型分子分子结构中性白细胞/药物作用中性白细胞/酶学骨关节炎/药物疗法启动区遗传重组蛋白质类/化学磺胺类/化学磺胺类/药理学动物人类小鼠

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