MAPKs通路在兔骨关节炎软骨细胞表达MMP-1/-13中作用的研究
摘要
背景
骨关节炎(osteoarthritiS,OA)是一种慢性、退变性关节疾病,是老年人最常见的关节疾病。OA以中老年患者多见,女性多于男性。60岁以上的人群中患病率可达50%,75岁的人群则达80%。随着老龄社会的到来,OA已成为导致老龄者病废的主要疾病之一,造成的社会负担和医疗费用在不断增加。目前研究认为,OA是由多种因素引起关节软骨退变而导致的关节疾病,其病因尚不明确,其发生与年龄、肥胖、炎症、创伤及遗传因素等有关。
众多的细胞因子在OA的发病过程中有重要的作用,其中白介素-1(IL-1)和肿瘤坏死因子-α(TNF-α)最为重要。它们通过自分泌或旁分泌的形式作用于关节滑膜细胞和软骨细胞,产生金属蛋白酶(MMPs)、一氧化氮(NO)和前列腺素E2(PGE2)等,抑制蛋白多糖和Ⅱ型胶原的合成,促进细胞外基质(ECM)降解,最终引起关节炎。虽然细胞因子学说并不能完全解释OA的病理机制,但是关节软骨的退变离不开炎症因子的作用。相关的研究表明,IL-1β和TNF-α与相应的受体结合后,可经丝裂原活化蛋白激酶(mitogen-actirated proteinkinases,MAPKs)途径和核因子-κB(nuclear factor-κB,NF-κB)途径进行细胞内信号转导,最终引起MMPs增高、自由基生成、细胞凋亡等一系列过程,从而参与了OA的发病。然而目前对IL-1β和TNF-α通过MAPKs引起MMP-1/-13具体通路研究以及它们之间的异同并不清楚。
本实验应用real-time PCR和western blot等技术,研究IL-1β和TNF-α作用于兔关节软骨细胞后MMP-1/-13的变化以及不同,进一步研究其对MAPKs各通路蛋白的影响,并应用MAPKs抑制剂和IL-1β联合作用,分别阻断各MAPKs通路,观察对MMP-1/-13的影响。通过实验明确各MAPKs通路在骨关节炎关节软骨细胞MMP-1/-13表达增高中的具体调节作用,为进一步研究在OA发病中软骨细胞MMP-1/-13增高的分子机制提供理论基础。
第一部分IL-1β和TNF-α对兔关节软骨细胞表达MMP-1/-13和NO的影响
目的体外培养兔关节软骨细胞,观察IL-1β和TNF-α对体外培养的兔关节软骨细胞MMP-1,-13和NO表达的影响,明确它们之间的不同。
材料和方法取新西兰兔关节软骨,体外分离培养关节软骨细胞并鉴定。分别用IL-1β和TNF-α作用于关节软骨细胞不同时间(8h,16h,24h,36h)。以real-time PCR技术检测MMP-1/-13mRNA的变化。另外收取细胞培养上清液,用Western blot检测MMP-1/-13蛋白变化,并用Griess反应测定NO的变化。
结果通过倒置显微镜下细胞形态学检查,甲苯胺蓝染色和Ⅱ型胶原染色,证明所培养细胞是软骨细胞。IL-1β能引起MMP-1/-13表达的增高,MMP-1随着时间延长持续增高,而MMP-13增高后维持在一高水平。TNF-α并不能引起它们的增高。IL-1β和TNF-α都可以引起NO的表达增高。
结论兔关节软骨细胞可以被成功分离和培养。IL-1β能使得MMP-1和MMP-13表达增高,但两者增高趋势不同。TNF-α并不能引起兔关节软骨细胞MMP-1/-13的增高。IL-1β和TNF-α都可以促进NO的分泌增加。
第二部分IL-1β对兔关节软骨细胞MAPKs信号通路蛋白表达的影响
目的观察IL-1β对兔关节软骨细胞MAPKs各条通路蛋白表达的影响。
材料和方法将体外培养的软骨细胞随机分为空白对照组和用IL-1β(10ng/ml)作用不同时间组(作用时间分别为15min,30min,45min,60min),用Western blot方法检测软骨细胞中ERK1/2、JNK1/2和p38通路总蛋白和活性蛋白(磷酸化蛋白)的表达。
结果在IL-1β作用下,与对照组比较,1h内各MAPKs通路总蛋白没有明显变化;而各磷酸化蛋白在作用15min后表达明显增高,p-ERK1/2增高维持至60min,p-JNK1/2在15min增高至顶峰后,开始下降,至60min时回到正常水平;p-p38增高到30min后开始下降,至60min时回到正常水平。各组与对照组比较差异有统计学意义。
结论IL-1β不能引起MAPKs通路总蛋白的变化,却能明显引起磷酸化蛋白的增高。
第三部分MAPKs通路在兔骨关节炎软骨细胞表达MMP-1/-13和NO中的作用
目的应用MAPKs各条通路阻滞剂抑制骨关节炎软骨细胞,观察对MMP-1/-13和NO的影响,明确其各条通路在MMP-1/-13表达中的作用。
材料和方法体外培养兔关节软骨细胞,设置空白对照组和IL-1β(10ng/ml)作用组,各MAPK通路阻滞剂ERK,PD98059(20μM)、JNK,SP600125(25μM)、p38,SB230585(10μM)作用细胞30min后,加入IL-1β(10ng/ml)共同作用24h,应用real-time PCR检测MMP-1/-13mRNA的变化。收取细胞培养上清液,用Griess反应测定NO的变化。
结果IL-1β作用后软骨细胞MMP-1/-13mRNA表达增高,加入阻滞剂后,MMP-1/-13表达明显下降。ERK通路阻滞剂PD98059抑制作用29.6%(MMP-1),39.2%(MMP-13);p38通路阻滞剂SB203580抑制作用47.7%(MMP-1),37.7%(MMP-13);JNK通路阻滞剂SP600125抑制作用为55.4%(MMP-1),52.2%(MMP-13)。P38通路抑制剂SB203580能明显抑制NO表达。
结论在兔骨关节炎软骨细胞MMP-1,13表达增高中,MAPKs通路起了重要的作用。对于MMP-1表达,可能是JNK和p38通路起主要作用,而MMP-13表达,起主要作用的是ERK和JNK通路。P38通路参与了IL-1β诱导的NO表达。
Background
Osteoarthritis is a chronic degenerative disease of joint and the most prevalent form of arthritis in ages.OA increase in prevalence with age and is more common in women than in men.Approximately 50 percent of persons over 60 years old and 80 percent of 75 years old persons suffer from this disease.With the coming of aging society,OA is becoming a major cause of disability in elderly people and the social burden and use of medical expense are expect to increase.OA is characterized by degeneration of articular cartilage and it's etiology is not clear. Multiple factors are involved in the pathogenesis of OA,including age, obesity,inflammation,trauma and genetic factor etc.
Multiple cytokines are known to affect the progression of OA,in which Interleukin-1(IL-1) and tumor necrosis factor-α(TNF-α) are most important cytokines.IL-1βand TNF-αcan affect synovial fibroblasts and chondrocyte through an autocrine or paracrine manner,stimulate them to secret matrix metailoproteinases(MMPs),nitric oxide(NO),prostaglandin E2(PGE2),etc.They can inhibit progeoglycan and typeⅡcollagen synthesis,cleave different components of the cartilage Extracellular matrix(ECM),induce OA in end.Though inflammatory is not enough to elucidate the mechanism of OA pathogenesis,the major events in OA pathogenesis is correlated with inflammatory cytokines.According to the previous researches,IL-1βand TNF-αcombined with their receptor in cell membranes,then activated the signal transduction pathways that regulate gene expression including increased expressiong of MMPs,free radicals generation and chondrocyteapoptosis and so on.These pathways include mitogen-activated protein kinases(MAPKs) and nuclear factor-κB(NF-κB) signaling pathways.The mechanisms through which IL-1βand TNF-αincrease the expression of MMP-1/-13 and the difference between them have not been fully elucidated.
In our study,Quantitative Polymerase Chain Reaction(Real-time PCR) and Western blot analysis are used to observe the different expression of MMP-1/-13 of IL-1βand TNF-αon rabbit articular chondrocytes, evaluate the MAPKs signal pathways protein expression in chondrocytes, then use inhibitors of MAPKs to block IL-1βinduced elevated expression of MMP-1/-13.We examined and compared the signaling pathways required to induce MMP-1 and MMP-13 production,it will provide a basis for further study of MMPs up-regulating mechanism in OA.
PartⅠIL-1βand TNF-αon expression of MMP-1/-13 and NO in articular chondrocytes of rabbit
Objectives Isolated and cultivated rabbit articular chondrocytes. To observe the effect of IL-1βand TNF-αon expression of MMP-1/-13 and NO in chondrocytes,compared the difference between them.
Materials and methods Harvest articular cartilage from New Zealand rabbit knee joints to carry out rabbit chondrocytes culture and identification.IL-1β和TNF-αare used to treat chondrocytes in different time(8h,16h,24h,36).Real-time PCR were carried out to detect the expresion of MMP-1/-13mRNA in chondrocytes,collect culture supernatants to determine the expression of MMP-1/-13 protein by western blot and to detect the NO concentration with Griess method.
Results Through cell morphologic and immunocytochemistry identification by inverted microscope,cultured chondrocytes were identified.IL-1βcan induce elevated expression of MMP-1/-13,MMP-1 production accumulated as the time prolonged in 36h,MMP-13 increased and remained in a high level in 36h.TNF-αcannot stimulate either of them production from rabbit chondrocytes.Both IL-1β和TNF-αresult in increasing amounts of NO concentration.
Conclusions Isolated and cultured rabbit articular chondrocytes successfully.IL-1βcan induce production of MMP-1 and MMP-13,their increasing trend is different.TNF-αdid not induce either of them in chondrocytes.Both of IL-1βand TNF-αcan stimulate NO expression.
PartⅡIL-1βand TNF-αon expression of MAPKs signal transduction protein in articular chondrocytes of rabbit
Objective To observe the effect of IL-1βon expression of MAPks signal transduction protein in articular chondrocytes of rabbit.
Materials and methods Rabbit articular chondrocytes were cultivated in vitro and randomly divided into the control group,IL-1βtreated group in 15min,30min,45min and 60min groups.Western blot was performed on whole cell extracts to detect respective expression of total ERK1/2, JNK1/2,p38 MAPKs and active form(phosphorylation of MAPK).
Results As chondrocytes exposed to IL-1βfor 60mins,the levels of the respective total MAPKs remained constant.IL-1βtime-dependently stimulated the phosphorylation of ERK,p38 and JNK MAPKs in these cells in 15mins.The ERK phosphorylation was sustained up to 60min but phosphor-iNK was peaking at 15min and phosphor-p38 activation levels started declining by 30min,the amount of active p38 and JNK decreased by 60min.The differences among each group and the control groups had statistical significance.
Conclusions IL-1βcannot induce the expression of total protein of MAPKs,but increased the phosphor-MAPKs in early time obviously.
PartⅢEffect of MAPKs pathways on expression of MMP-1/-13 in articular chondrocytes of rabbit osteoarthritis
Objective To observe the expression of MMP-1/-13 in articular chondrocytes of osteoarthritis after inhibition of IL-1β-induced MMP-1/-13 expression by MAPKs inhibitors,to evaluate the effect of different MAPKs signal pathways.
Materials and methods Articular chondrocytes of rabbit were cultivated in vitro and randomly divided into negative control group,IL-1βtreated group,other groups were pretreated for 30min with each indicate MAPK inhibitor[ERK inhibitor PD98059(20μM);JNK inhibitor SP600125(μM);p38 inhibitor SB203580(μM)],then subsequently treated with rhIL-1β(10ng/ml) for 24h.Following each treatment,the expression of MMP-1/-13 mRNA was evaluated by real-time PCR.
Results IL-1βcan increase the expression of MMP-1/-13 and MAPKs inhibitors inhibited IL-1β-induced MMP-1/-13 expression in chondrocytes. The ERK1/2 pathway inhibitor,PD98059,attained 29.6%(MMP-1) and 39.2% (MMP-13) inhibition of MMP-1/-13 induction in chondrocytes;P38 inhibitor, SB203580 caused 47.7%reduction of MMP-1 and and 37.7%(MMP-13);Inhibitor of JNK,SP600125 achieved 55.4%suppression of MMP-1 and 52.25 of MMP-13 in chondrocytes.P38 inhibitor SB203580 can inhibit the NO expression effectively.
Conclusions These results suggest the involvement of MAPKs,in the IL-1 induction of MMPs in chondrocytes.MAPKs signal pathways play an important role in expression of articular chondrocytes of osteoarthritis. For MMP-1 expression,JNK and p38 maybe important,but to MMP-13 the important pathways are ERK and JNK.p38 is involved in the IL-1 induced NO production.
骨关节炎(osteoarthritiS,OA)是一种慢性、退变性关节疾病,是老年人最常见的关节疾病。OA以中老年患者多见,女性多于男性。60岁以上的人群中患病率可达50%,75岁的人群则达80%。随着老龄社会的到来,OA已成为导致老龄者病废的主要疾病之一,造成的社会负担和医疗费用在不断增加。目前研究认为,OA是由多种因素引起关节软骨退变而导致的关节疾病,其病因尚不明确,其发生与年龄、肥胖、炎症、创伤及遗传因素等有关。
众多的细胞因子在OA的发病过程中有重要的作用,其中白介素-1(IL-1)和肿瘤坏死因子-α(TNF-α)最为重要。它们通过自分泌或旁分泌的形式作用于关节滑膜细胞和软骨细胞,产生金属蛋白酶(MMPs)、一氧化氮(NO)和前列腺素E2(PGE2)等,抑制蛋白多糖和Ⅱ型胶原的合成,促进细胞外基质(ECM)降解,最终引起关节炎。虽然细胞因子学说并不能完全解释OA的病理机制,但是关节软骨的退变离不开炎症因子的作用。相关的研究表明,IL-1β和TNF-α与相应的受体结合后,可经丝裂原活化蛋白激酶(mitogen-actirated proteinkinases,MAPKs)途径和核因子-κB(nuclear factor-κB,NF-κB)途径进行细胞内信号转导,最终引起MMPs增高、自由基生成、细胞凋亡等一系列过程,从而参与了OA的发病。然而目前对IL-1β和TNF-α通过MAPKs引起MMP-1/-13具体通路研究以及它们之间的异同并不清楚。
本实验应用real-time PCR和western blot等技术,研究IL-1β和TNF-α作用于兔关节软骨细胞后MMP-1/-13的变化以及不同,进一步研究其对MAPKs各通路蛋白的影响,并应用MAPKs抑制剂和IL-1β联合作用,分别阻断各MAPKs通路,观察对MMP-1/-13的影响。通过实验明确各MAPKs通路在骨关节炎关节软骨细胞MMP-1/-13表达增高中的具体调节作用,为进一步研究在OA发病中软骨细胞MMP-1/-13增高的分子机制提供理论基础。
第一部分IL-1β和TNF-α对兔关节软骨细胞表达MMP-1/-13和NO的影响
目的体外培养兔关节软骨细胞,观察IL-1β和TNF-α对体外培养的兔关节软骨细胞MMP-1,-13和NO表达的影响,明确它们之间的不同。
材料和方法取新西兰兔关节软骨,体外分离培养关节软骨细胞并鉴定。分别用IL-1β和TNF-α作用于关节软骨细胞不同时间(8h,16h,24h,36h)。以real-time PCR技术检测MMP-1/-13mRNA的变化。另外收取细胞培养上清液,用Western blot检测MMP-1/-13蛋白变化,并用Griess反应测定NO的变化。
结果通过倒置显微镜下细胞形态学检查,甲苯胺蓝染色和Ⅱ型胶原染色,证明所培养细胞是软骨细胞。IL-1β能引起MMP-1/-13表达的增高,MMP-1随着时间延长持续增高,而MMP-13增高后维持在一高水平。TNF-α并不能引起它们的增高。IL-1β和TNF-α都可以引起NO的表达增高。
结论兔关节软骨细胞可以被成功分离和培养。IL-1β能使得MMP-1和MMP-13表达增高,但两者增高趋势不同。TNF-α并不能引起兔关节软骨细胞MMP-1/-13的增高。IL-1β和TNF-α都可以促进NO的分泌增加。
第二部分IL-1β对兔关节软骨细胞MAPKs信号通路蛋白表达的影响
目的观察IL-1β对兔关节软骨细胞MAPKs各条通路蛋白表达的影响。
材料和方法将体外培养的软骨细胞随机分为空白对照组和用IL-1β(10ng/ml)作用不同时间组(作用时间分别为15min,30min,45min,60min),用Western blot方法检测软骨细胞中ERK1/2、JNK1/2和p38通路总蛋白和活性蛋白(磷酸化蛋白)的表达。
结果在IL-1β作用下,与对照组比较,1h内各MAPKs通路总蛋白没有明显变化;而各磷酸化蛋白在作用15min后表达明显增高,p-ERK1/2增高维持至60min,p-JNK1/2在15min增高至顶峰后,开始下降,至60min时回到正常水平;p-p38增高到30min后开始下降,至60min时回到正常水平。各组与对照组比较差异有统计学意义。
结论IL-1β不能引起MAPKs通路总蛋白的变化,却能明显引起磷酸化蛋白的增高。
第三部分MAPKs通路在兔骨关节炎软骨细胞表达MMP-1/-13和NO中的作用
目的应用MAPKs各条通路阻滞剂抑制骨关节炎软骨细胞,观察对MMP-1/-13和NO的影响,明确其各条通路在MMP-1/-13表达中的作用。
材料和方法体外培养兔关节软骨细胞,设置空白对照组和IL-1β(10ng/ml)作用组,各MAPK通路阻滞剂ERK,PD98059(20μM)、JNK,SP600125(25μM)、p38,SB230585(10μM)作用细胞30min后,加入IL-1β(10ng/ml)共同作用24h,应用real-time PCR检测MMP-1/-13mRNA的变化。收取细胞培养上清液,用Griess反应测定NO的变化。
结果IL-1β作用后软骨细胞MMP-1/-13mRNA表达增高,加入阻滞剂后,MMP-1/-13表达明显下降。ERK通路阻滞剂PD98059抑制作用29.6%(MMP-1),39.2%(MMP-13);p38通路阻滞剂SB203580抑制作用47.7%(MMP-1),37.7%(MMP-13);JNK通路阻滞剂SP600125抑制作用为55.4%(MMP-1),52.2%(MMP-13)。P38通路抑制剂SB203580能明显抑制NO表达。
结论在兔骨关节炎软骨细胞MMP-1,13表达增高中,MAPKs通路起了重要的作用。对于MMP-1表达,可能是JNK和p38通路起主要作用,而MMP-13表达,起主要作用的是ERK和JNK通路。P38通路参与了IL-1β诱导的NO表达。
Background
Osteoarthritis is a chronic degenerative disease of joint and the most prevalent form of arthritis in ages.OA increase in prevalence with age and is more common in women than in men.Approximately 50 percent of persons over 60 years old and 80 percent of 75 years old persons suffer from this disease.With the coming of aging society,OA is becoming a major cause of disability in elderly people and the social burden and use of medical expense are expect to increase.OA is characterized by degeneration of articular cartilage and it's etiology is not clear. Multiple factors are involved in the pathogenesis of OA,including age, obesity,inflammation,trauma and genetic factor etc.
Multiple cytokines are known to affect the progression of OA,in which Interleukin-1(IL-1) and tumor necrosis factor-α(TNF-α) are most important cytokines.IL-1βand TNF-αcan affect synovial fibroblasts and chondrocyte through an autocrine or paracrine manner,stimulate them to secret matrix metailoproteinases(MMPs),nitric oxide(NO),prostaglandin E2(PGE2),etc.They can inhibit progeoglycan and typeⅡcollagen synthesis,cleave different components of the cartilage Extracellular matrix(ECM),induce OA in end.Though inflammatory is not enough to elucidate the mechanism of OA pathogenesis,the major events in OA pathogenesis is correlated with inflammatory cytokines.According to the previous researches,IL-1βand TNF-αcombined with their receptor in cell membranes,then activated the signal transduction pathways that regulate gene expression including increased expressiong of MMPs,free radicals generation and chondrocyteapoptosis and so on.These pathways include mitogen-activated protein kinases(MAPKs) and nuclear factor-κB(NF-κB) signaling pathways.The mechanisms through which IL-1βand TNF-αincrease the expression of MMP-1/-13 and the difference between them have not been fully elucidated.
In our study,Quantitative Polymerase Chain Reaction(Real-time PCR) and Western blot analysis are used to observe the different expression of MMP-1/-13 of IL-1βand TNF-αon rabbit articular chondrocytes, evaluate the MAPKs signal pathways protein expression in chondrocytes, then use inhibitors of MAPKs to block IL-1βinduced elevated expression of MMP-1/-13.We examined and compared the signaling pathways required to induce MMP-1 and MMP-13 production,it will provide a basis for further study of MMPs up-regulating mechanism in OA.
PartⅠIL-1βand TNF-αon expression of MMP-1/-13 and NO in articular chondrocytes of rabbit
Objectives Isolated and cultivated rabbit articular chondrocytes. To observe the effect of IL-1βand TNF-αon expression of MMP-1/-13 and NO in chondrocytes,compared the difference between them.
Materials and methods Harvest articular cartilage from New Zealand rabbit knee joints to carry out rabbit chondrocytes culture and identification.IL-1β和TNF-αare used to treat chondrocytes in different time(8h,16h,24h,36).Real-time PCR were carried out to detect the expresion of MMP-1/-13mRNA in chondrocytes,collect culture supernatants to determine the expression of MMP-1/-13 protein by western blot and to detect the NO concentration with Griess method.
Results Through cell morphologic and immunocytochemistry identification by inverted microscope,cultured chondrocytes were identified.IL-1βcan induce elevated expression of MMP-1/-13,MMP-1 production accumulated as the time prolonged in 36h,MMP-13 increased and remained in a high level in 36h.TNF-αcannot stimulate either of them production from rabbit chondrocytes.Both IL-1β和TNF-αresult in increasing amounts of NO concentration.
Conclusions Isolated and cultured rabbit articular chondrocytes successfully.IL-1βcan induce production of MMP-1 and MMP-13,their increasing trend is different.TNF-αdid not induce either of them in chondrocytes.Both of IL-1βand TNF-αcan stimulate NO expression.
PartⅡIL-1βand TNF-αon expression of MAPKs signal transduction protein in articular chondrocytes of rabbit
Objective To observe the effect of IL-1βon expression of MAPks signal transduction protein in articular chondrocytes of rabbit.
Materials and methods Rabbit articular chondrocytes were cultivated in vitro and randomly divided into the control group,IL-1βtreated group in 15min,30min,45min and 60min groups.Western blot was performed on whole cell extracts to detect respective expression of total ERK1/2, JNK1/2,p38 MAPKs and active form(phosphorylation of MAPK).
Results As chondrocytes exposed to IL-1βfor 60mins,the levels of the respective total MAPKs remained constant.IL-1βtime-dependently stimulated the phosphorylation of ERK,p38 and JNK MAPKs in these cells in 15mins.The ERK phosphorylation was sustained up to 60min but phosphor-iNK was peaking at 15min and phosphor-p38 activation levels started declining by 30min,the amount of active p38 and JNK decreased by 60min.The differences among each group and the control groups had statistical significance.
Conclusions IL-1βcannot induce the expression of total protein of MAPKs,but increased the phosphor-MAPKs in early time obviously.
PartⅢEffect of MAPKs pathways on expression of MMP-1/-13 in articular chondrocytes of rabbit osteoarthritis
Objective To observe the expression of MMP-1/-13 in articular chondrocytes of osteoarthritis after inhibition of IL-1β-induced MMP-1/-13 expression by MAPKs inhibitors,to evaluate the effect of different MAPKs signal pathways.
Materials and methods Articular chondrocytes of rabbit were cultivated in vitro and randomly divided into negative control group,IL-1βtreated group,other groups were pretreated for 30min with each indicate MAPK inhibitor[ERK inhibitor PD98059(20μM);JNK inhibitor SP600125(μM);p38 inhibitor SB203580(μM)],then subsequently treated with rhIL-1β(10ng/ml) for 24h.Following each treatment,the expression of MMP-1/-13 mRNA was evaluated by real-time PCR.
Results IL-1βcan increase the expression of MMP-1/-13 and MAPKs inhibitors inhibited IL-1β-induced MMP-1/-13 expression in chondrocytes. The ERK1/2 pathway inhibitor,PD98059,attained 29.6%(MMP-1) and 39.2% (MMP-13) inhibition of MMP-1/-13 induction in chondrocytes;P38 inhibitor, SB203580 caused 47.7%reduction of MMP-1 and and 37.7%(MMP-13);Inhibitor of JNK,SP600125 achieved 55.4%suppression of MMP-1 and 52.25 of MMP-13 in chondrocytes.P38 inhibitor SB203580 can inhibit the NO expression effectively.
Conclusions These results suggest the involvement of MAPKs,in the IL-1 induction of MMPs in chondrocytes.MAPKs signal pathways play an important role in expression of articular chondrocytes of osteoarthritis. For MMP-1 expression,JNK and p38 maybe important,but to MMP-13 the important pathways are ERK and JNK.p38 is involved in the IL-1 induced NO production.
引文
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