白细胞介素17促进成骨细胞诱导破骨样细胞分化的作用和机制
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摘要
背景和目的
正畸牙槽骨改建的第一步是牙槽骨的吸收,成熟的破骨细胞(osteoclast,OC)是唯一行使骨吸收功能的细胞,OC的分化和成熟主要依赖于成骨细胞(osteoblasts, OB)的调控。OB通过与OC的细胞间连接以及分泌可溶性因子调控OC的分化和成熟,这些因子称为OC分化相关因子。机械力作用下,OB产生OC分化相关因子,通过多种途径和机制参与和调节OC的分化和功能。在目前发现的调节OC分化的细胞因子中,核转录因子kB受体活化因子配基(receptor activator of NF-κB ligand, RANKL)和巨噬细胞集落刺激因子(macrophage colony-stimulating factor, M-CSF)是两个关键调节因子。此外,一些炎性细胞因子也具有重要的调节作用,如白细胞介素(interleukin, IL)-1, IL-6,肿瘤坏死因子(tumor necrosis factor, TNF)-a等,能够直接或间接促进OC的分化和活化,又被称为骨吸收炎性因子。除了细胞因子,一些脂质作为信号传递分子,参与骨重建过程。其中,前列腺素(prostaglandin, PG)E2的作用非常显著,可促进OC分化和骨吸收,并调节炎症反应。在正畸牙移动的龈沟液中,PGE2的表达水平较高。本研究相关的前期实验发现,压力上调成骨细胞表达PGE2,进而上调RANKL、M-CSF的表达和下调骨保护蛋白(osteoprotegerin, OPG)的表达,从而诱导OC分化。
IL-17是一种重要的促炎性细胞因子,1993年首次由活化的T细胞(TH17)克隆而来,直到近年来人们才对其有了一定的认识。IL-17结构独特,与其他已知的蛋白和白介素的结构没有相似性,在人类和鼠类的基因组包括至少6个成员(A-F)和5个受体成员(RA-RE).而功能方面,IL-17具有强大的促炎症作用和骨吸收的作用。近年来的研究发现,IL-17可促进IL-1,TNF-a的合成,诱导IL-6和IL-8在成纤维细胞内的表达。可增强OB内TNF-α、PGF2a诱导IL-6的合成作用,IL-17可上调多种细胞内RANKL的表达而促进OC的分化。作为最新发现的骨吸收炎性因子,IL-17在多种涉及骨丢失疾病中的重要作用不断被发现和深入研究,如牙周炎,风湿性关节炎,骨关节炎等。因此,我们设想IL-17参与正畸过程中的牙槽骨的吸收,通过OB促进OC的分化和功能。但是机械力作用下IL-17在OB内的表达情况,目前国内外尚无报道,而IL-17通过什么机制参与OC的分化过程,目前尚不清楚。
因此,本研究通过检测压力作用下IL-17及其受体在OB内的表达；研究IL-17A调控OC分化相关因子在OB内的表达及其作用机制；检测IL-17调节OB诱导OC分化的作用,探讨IL-17在体外介导OB诱导OC的作用,为进一步阐明正畸牙移动和牙槽骨改建的分子生物学机制提供理论和实践依据。
实验方法
1.检测压力作用下,IL-17及其受体在OB内的表达情况.
以来自新生小鼠颅骨的细胞系-MC3T3-E1细胞作为OB,用含10%FBS的a-MEM培养。按2.0 x 104 cells/cm2的密度将细胞接种于96孔板,用含50 mM磷酸甘油和50μg/ml抗坏血酸的培养液培养7-10天,茜素红染色观察矿化结节。按相同密度将细胞接种于100 mm培养皿,待细胞融合80%,换用含1%FBS的a-MEM培养液培养12h后,开始施加压力。按实验室以往研究,采用细胞均匀加力装置施加0、1.0、2.0或3.0g/cm2(0、98、196或294Pa)的压力,加力时间分别为1h、3h、6h、9h、12h或24h。活细胞计数试剂盒检测压力对细胞生长的影响,选择对细胞生长影响小的1.0和2.0g/cm2作为实验组。加力结束后,采用实时定量RT-PCR检测IL-17家族、IL-17受体家族、IL-lα、IL-6mRNA表达情况,采用细胞免疫荧光技术和ELISA方法检测加力9h后IL-17A蛋白表达情况。
按相同密度将细胞接种于100 mm培养皿,待细胞融合80%,换用含1%FBS的a-MEM培养液培养12h后,加入0或10 ng/ml的IL-17A继续培养6h、24h或72h,实时定量RT-PCR检测IL-17受体mRNA表达情况。
2.检测IL-17A调控OC分化相关因子在OB内表达的作用及机制。
按2.0×104 cells/cm2的密度将MC3T3-E1细胞接种于100 mm培养皿,待细胞融合80%,换用含1%FBS的a-MEM培养液培养12h。分别进行以下实验。
(1)加入0、0.1、1或10ng/ml的IL-17A继续培养6h、12h、24h、48h或72h。实时定量RT-PCR检测RANKL、OPG、M-CSF、IL-lα、IL-6、TNF-α、COX-1和COX-2mRNA表达情况,ELISA方法检测PGE2、RANKL、OPG、M-CSF、IL-lα、IL-6和TNF-a蛋白表达情况。
(2)加入0或1.5 ng/ml的PGE2继续培养24h。实时定量RT-PCR检测RANKL、OPG、M-CSF、IL-lα、IL-6和TNF-a mRNA表达情况。
(3)加入0或10 ng/ml的IL-17A和／或10μ,M塞来昔布(COX-2抑制剂)继续培养24h或72h。ELISA方法检测PGE2、RANKL、OPG、M-CSF、IL-la、IL-6和TNF-α蛋白表达情况。3.检测IL-17A间接诱导破骨样细胞(osteoclast-like cells,OCL)分化的作用和机制。
按2.0 x 104 cells/cm2的密度将MC3T3-E1细胞接种于100 mm培养皿,待细胞融合80%,加入0或10 ng／ml的IL-17A的含1%FBS的a-MEM继续培养72h。再换用含1%FBS的a-MEM培养12h,收集细胞培养上清。按照30%的比例与含10%FBS的a-MEM混合,加入50 ng/ml的RANKL,作为条件培养液。以鼠源性单核-巨噬细胞系RAW264.7作为破骨细胞前体,用含10%FBS的a-MEM培养,2天换液一次。按1.25 x 104 cells/cm2的密度将RAW264.7细胞接种于96孔板,孵育24h后,换用条件培养液培养3,5,7或10天,抗酒石酸酸性磷酸酶(TRAP)染色鉴定和计数OCL。按1.25×104 cells/cm2的密度将RAW264.7细胞接种于6孔板,孵育24h后,换用条件培养液培养3,5,7或10天,实时定量RT-PCR和Western-blot方法分别检测组织蛋白酶K、基质金属蛋白酶(MMP)-9和碳酸酐酶(CA) II mRNA和蛋白表达情况。
按2.0 x 104 cells/cm2的密度将MC3T3-E1细胞接种于100 mm的培养皿,待细胞融合80%,加入的IL-17A (0或10 ng/ml)和／或10μM塞来昔布的含1%FBS的a-MEM继续培养72h。再换用含1%FBS的a-MEM培养12h,收集细胞培养上清。按照30%的比例与含10%FBS的a-MEM混合,加入50 ng/ml的RANKL,作为条件培养液。按1.25 x 104 cells/cm2的密度将RAW264.7细胞接种于96孔板或6孔板,孵育24h后,换用条件培养液培养7天,TRAP染色鉴定和计数OCL,实时定量RT-PCR方法检测组织蛋白酶K、MMP-9和CAIImRNA表达情况。
实验结果
1.压力作用下,IL-17及其受体在OB内的表达情况。
1.1压力作用下,IL-17家族mRNA在OB内的表达情况
在一个加力周期内,对照组和实验组的IL-17(A-F) mRNA的表达逐渐升高,6h达到最高,9h后表达逐渐降低,IL-17A mRNA的表达水平在IL-17家族中最高。与对照组相比,IL-17A.IL-17D和IL-17E mRNA的表达在1.0和2.0g/cm2的压力加载后的3h,6h,9h,12h和24h均显著增强(P<0.05或P<0.01)；IL-17B.IL-17C和IL-17F mRNA的表达在1.0或2.0 g/cm2的压力加载后的6h,9h,12h和24h均显著增强(P<0.05或P<0.01)。在细胞加力后的初期和中期(3h,6h,9h),IL-17A-F mRNA的表达随着压力的增加而增强,但在细胞加力后的后期(12h,24h),IL-17A-F mRNA在1.0 g/cm2力值加载条件下比2.0g/cm2加载条件下的表达更多。
1.2压力作用下,IL-17受体家族mRNA在OB内的表达情况
在一个加力周期内,对照组和实验组的IL-17RA、IL-17RC和IL-17RD mRNA的表达逐渐升高,9h达到最高,12h后表达逐渐降低,IL-17RB和IL-17RE mRNA的表达逐渐升高,6h达到最高,9h后表达逐渐降低。IL-17RC mRNA的表达水平在IL-17受体家族中最高。与对照组相比,IL-17RA和IL-17RE mRNA的表达在1.0和2.0g/cm2的压力加载后的6h,9h,12h和24h均显著增强(P<0.05或P1):IL-17RC和IL-17RD mRNA的表达在1.0或2.0 g/cm2的压力加载后的6h,9h和12h均显著增强(P<0.05或P<0.01)；IL-17RB mRNA的表达在1.0和2.0 g/cm2的压力加载后的3h,6h和9h均显著增强(P<0.05或P<0.01)。在细胞加力的初期和中期(3h,6h,9h),IL-17RA-RE mRNA的表达随着压力的增加而增强,但在细胞加力的后期(12h,24h),IL-17 RA-RE mRNA在1.0 g/cm2力值加载条件下比2.0g/cm2加载条件下的表达更多。
1.3压力作用下,IL-17A蛋白在OB内的表达情况
细胞加力9h后,对照组中未见IL-17A蛋白的表达；细胞加载1.0g/cm2压力的实验组,部分细胞的细胞质内呈现红色荧光,IL-17A蛋白水平为7.125 pg/ml,细胞加载2.0 g/cm2压力的实验组,部分细胞的细胞质内呈现红色荧光,IL-17A蛋白水平为9.019 pg/ml。表明随压力增加,IL-17A蛋白表达增加。
1.4 IL-17A调节IL-17受体家族mRNA在OB内的表达情况
IL-17A作用于成骨细胞后,与对照组相比,IL-17RA、IL-17RB、IL-17RC和IL-17RE mRNA的表达均有显著增加(P<0.05),但IL-17RD的表达没有显著性差异。
1.5压力作用下,IL-la和IL-6mRNA在OB内的表达情况
在一个加力周期内,对照组和实验组的IL-1a和IL-6 mRNA的表达逐渐升高。与对照组相比,IL-1αmRNA的表达在1.0或2.0g/cm2的压力加载后的6h、9h、12h和24h均显著增强(P<0.01); IL-6 mRNA的表达在1.0或2.0 g/cm2的压力加载后的9h、12h和24h均显著增强(P<0.05或P<0.01)。
2.IL-17A调控OC分化相关因子在OB内表达的作用及机制。
2.1 IL-17A调节RANKL、OPG、M-CSFmRNA和蛋白在OB内的表达情况
在IL-17A刺激作用下,与对照组相比,实验组的RANKL和M-CSF mRNA表达显著增加,OPG mRNA表达显著降低：RANKL mRNA表达在24h-72h增加了1.3-1.8倍(P<0.05或P<0.01),M-CSF mRNA表达在72h增加了1.6-1.9倍(P<0.01),OPG mRNA表达在48h-72h降低了0.8-0.9(P<0.05)。
IL-17A刺激成骨细胞72h后,与对照组相比,实验组的RANKL和M-CSF蛋白表达显著增加,OPG蛋白表达显著降低：RANKL蛋白表达增加了1.9-2.4倍(P1.2-1.4倍(P<0.05), OPG蛋白表达降低了0.7-0.8倍(P<0.05)。
2.2 IL-17A调节骨吸收炎性因子mRNA和蛋白在OB内的表达情况
对照组和实验组的IL-1αmRNA表达逐渐降低,直到48h；IL-6 mRNA表达逐渐升高到24h,48h后逐渐降低；TNF-a mRNA表达逐渐升高,直到72h。在IL-17A刺激作用下,与对照组相比,实验组的骨吸收炎性因子mRNA表达显著增加：IL-lαmRNA表达在6h-72h增加了1.3-4.3倍(P<0.05或P<0.01),IL-6mRNA表达在6h-72h增加了1.3-2.5倍(P<0.05或P<0.01),TNF-a mRNA表达在12h-72h增加了1.2-3.5倍(P<0.05或P<0.01)。
IL-17A刺激OB的24h后,与对照组相比,实验组的骨吸收炎性因子蛋白表达显著增加：IL-1a蛋白表达显著增加了1.3-1.5倍(P<0.05或P<0.01),IL-6蛋白表达显著增加了2.1-2.6倍(P<0.01),IL-17A刺激OB的72h后,TNF-a蛋白表达显著增加了1.5倍(P<0.01)。2.3 IL-17A调节COX-1和COX-2 mRNA在OB内的表达情况
对照组和实验组的COX-2 mRNA表达逐渐降低,直到48h。在IL-17A刺激作用下,与对照组相比,实验组COX-2mRNA表达在6h、12h和24h显著增加了1.2-2.4倍(P<0.01)。但COX-1的mRNA表达不受IL-17A的影响。2.4 IL-17A和／或celecoxib调节PGE2在OB内的表达情况
在IL-17A刺激作用下,与对照组相比,实验组的PGE2蛋白表达显著增加,并呈剂量依赖性的特点：在6h,24h和72h分别增加了1.06-2.19倍,1.57-2.05倍和2.75-3.50倍。在IL-17A和celecoxib共同作用的24h, celecoxib阻滞了IL-17A对PGE2的刺激作用,PGE2蛋白含量显著降低,接近于对照组的水平。表明IL-17A是通过上调COX-2的表达而增加PGE2的表达。
2.5 PGE2调节OC分化相关因子mRNA在OB内的表达情况
在PGE2作用下,与对照组相比,实验组的RANKL和M-CSF的nRNA表达显著增加(P<0.01),OPG的mRNA表达显著降低(P<0.05)；实验组的IL-1a和IL-6的mRNA表达显著增加(P<0.01),但TNF-α的]mRNA表达无显著性差异。2.6 celecoxib对IL-17A调节OC分化相关因子蛋白在OB内表达的影响作用
在IL-17A和celecoxib共同作用的72h后,celecoxib阻滞了IL-17A对RANKL、OPG和M-CSF的刺激作用,RANKL和M-CSF蛋白含量显著降低,OPG蛋白表达显著增加,接近于对照组的水平。
在IL-17A和celecoxib共同作用24h后,celecoxib阻滞了IL-17A对IL-1a和IL-6的刺激作用, IL-1a和IL-6蛋白含量显著降低,接近于对照组的水平,IL-17A和celecoxib共同作用72h后,TNF-α的蛋白表达与对照组相比无显著性差异。
3.IL-17A间接诱导oCL分化的作用。
3.1 IL-17A诱导OCL形成的作用
用IL-17A处理或未处理的条件培养液培养RAW264.7细胞的第3天,可见TRAP染色阳性的多核巨细胞(OCL)出现,第5天和第7天,细胞体积变大,数量增加,第10天,OCL逐渐减少。在第5天和第7天,与对照组相比,IL-17A处理的条件培养液诱导的OCL体积较大,数量显著增多,分别增加1.45倍和1.34倍(P<0.01)。3.2 IL-17A调节cathepsin K, MMP-9和CAⅡmRNA在OCL内的表达情况
用IL-17A处理或未处理的条件培养液培养RAW264.7细胞的10天内,cathepsin K, MMP-9 mRNA的表达逐渐增加,CAⅡmRNA的表达没有明显变化,只在第10天轻微增加。与对照组相比,实验组的cathepsin K mRNA的表达在第5天和7天分别增加了1.50和1.40倍(P<0.05或P<0.01),实验组的MMP-9 mRNA的表达在第7天增加了1.31倍(P<0.01)。但实验组的CAⅡmRNA的表达没有明显变化。
3.3 IL-17A调节cathepsin K, MMP-9和CAⅡ蛋白在OCL内的表达情况
用IL-17A处理或未处理的条件培养液培养RAW264.7细胞的第10天,cathepsin K, MMP-9和CAⅡ蛋白表达与其mRNA表达相似。与对照组相比,实验组的cathepsin K的蛋白表达增加了1.35倍(P<0.01),实验组的MMP-9的蛋白表达增加了1.42倍(P<0.01)。而实验组的CAⅡ的蛋白表达没有明显变化。
3.4 celecoxib对IL-17A诱导OCL形成的影响作用
用IL-17A处理或未处理的条件培养液培养RAW264.7细胞的第7天,与对照组相比,IL-17A处理的条件培养液诱导的OCL体积较大,数量显著增多(P<0.01)。用IL-17A和celecoxib处理的条件培养液培养RAW264.7,OCL数量显著下降,接近于对照组的水平。celecoxib阻滞了lL-17A对OCL的间接诱导作用。
3.5 celecoxib对IL-17A调节cathepsin K和MMP-9 mRNA表达的影响作用
用IL-17A和celecoxib处理的条件培养液培养RAW264.7, cathepsin K和MMP-9mRNA显著下降(P<0.05),接近于对照组的水平。表明COX-2抑制剂阻滞了IL-17A对cathepsin K和MMP-9 mRNA表达的上调作用。
结论1.成骨细胞MC3T3-E1可在mRNA水平表达6个IL-17家族成员(IL-17A-F)和5个受体家族成员(IL-17RA-RE),并在蛋白水平表达IL-17A,因此,成骨细胞也可产生IL-17。
2.压力诱导IL-la, IL-6, IL-17及其受体的mRNA和IL-17A蛋白在成骨细胞内的表达增强,而且IL-17A在其家族成员中的表达水平最高。提示IL-17可能参与机械力诱导的牙槽骨吸收过程。
3.IL-17A显著上调RANKL和M-CSF,下调OPG的mRNA和蛋白在成骨细胞内的表达：IL-17A显著上调IL-1α, IL-6和TNF-a的mRNA和蛋白在成骨细胞内的表达,证实IL-17A在体外调控成骨细胞内的破骨细胞分化相关因子的表达。
4.IL-17A通过上调COX-2/PGE2的表达(可被celecoxib沮滞),从而调控破骨细胞分化相关因子在成骨细胞内的表达,揭示了该调控作用的机制。
5.IL-17A促进成骨细胞诱导破骨样细胞的分化,并上调cathepsin K, MMP-91的mRNA和蛋白在破骨样细胞中的表达,证实IL-17在体外促进成骨细胞诱导破骨样细胞的分化和功能。
6.IL-17A通过上调成骨细胞内COX-2/PGE2的表达(可被celecoxib阻滞),调控破骨细胞分化相关因子的表达,从而促进成骨细胞诱导破骨样细胞的分化和功能,揭示了IL-17在体外促进成骨细胞诱导破骨样细胞的分化相关的机制。
7.本研究探讨了IL-17在体外介导成骨细胞诱导破骨样细胞分化的作用,为进一步阐明正畸牙移动和牙槽骨改建的分子生物学机制提供理论和实践依据。
Background and Objective
Alveolar bone resorption is the first step of bone remodeling during orthodontic treatment and mature osteoclast (OC) is the only cell to be responsible for bone resorption. OB mediate pOC diffentiation and activation by multiple factors and ways..Those factors were called bone resorption-relative factors. Mechanical stress induces OB to produce such facorrs. Among them, Receptor activator of NF-kB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) are the two key factors inducing OC differentiation and function. Inflammatory mediators released from periodontal tissue trigger the biological process of alveolar bone resorption. Interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-αare known as born resorption-related-inflammatory cytokines and play important roles to stimulate OC differentiation and activity. Higher levels of prostaglandin E2 (PGE2) were found in the gingival crevicular fluid of teeth undergoing orthodontic movement. PGE2 is able to mediate the inflammatory response and to induce bone resorption through the stimulation of OC differentiation. In addition, the application of compressive force induces bone formation by increasing levels of PGE2 in OB. These reports suggest that PGE2 plays an important role in bone remodeling affecting bone resorption and formation via autocrine action. We recently reported that compressive force induces osteoclast differentiation by increasing M-CSF production and decreasing OPG production via PGE2 in OB.
IL-17 is a kind of inflammatory cytokines.It originally was cloned from activated T cells (Thl7 cells) but is well known until resently. It shares little or no homology with other proteins and interleukins. At least six members of the family and five subtypes of receptors (IL-17Rs) are in the human and mouse genomes. IL-17 induced inflammation and affect osteoclastic resorption indirectly via osteoblasts. Some reports indicate that IL-17 shows a synergistic effect with IL-10 and TNF-a and induces production of IL-6 in fibroblasts. In OB, there were reported that IL-17 enhanced the synthesis of TNF-a-stimulated IL-6 synthesis and prostaglandin F2a-stimulated IL-6. IL-17 stimulates bone resorption by inducing RANKL expression. So we hypothesize that IL-17 involves in and mediates the process of alveolar bone resorption via OB.However, the expression of IL-17 in OB induced by orthodonic force has not been reported.
Therefore, in the present study, we examined the effect of compressive force on the expression of IL-17 and their receptors in OB. We also examined the effect of different concertration of IL-17 on OC differentiation via OB and the indirect effect of IL-17 inducing OC formation, and investigate in vitro the roles of IL-17 inducing OCL formation via OB. This study will contribute to a better understanding of the molecular biology mechanism of orthodontic tooth movement and alveolar bone remodeling.
Methods
1. Measure the expression of mRNA and protein of IL-17s and their receptors in osteoblast during compressive force.
MC3T3-E1 cells from a mouse calvarial cell line were used as osteoblast-like cells. MC3T3-E1 cells were maintained in a-minimal essential medium containing 10% (v/v) heat-inactivated fetal bovine serum at 37℃in a humidified atmosphere of 95% air and 5% CO2. MC3T3-E1 cells were placed into 96-well tissue plates at a density of 2.0 x 104 cells/cm2 and cultured for 7-10 days in a-MEM containing 50 mMβ-glycerophosphate and 50μg/ml ascorbic acid. The presence of mineralized nodules was determined by staining with alizarin red S. For being applied the compressive force, MC3T3-E1 cells were seeded in 100-mm cell culture dishes at a density of 2.0×104 cells/cm2 and incubated until 90% confluent. The cells were then compressed continuously using a uniform compression method similar to those described previously. The cells were subjected to 1.0,2.0 or 3.0 g/cm2 (98,196 or294 Pa, respectively) compressive force for 1,3,6,9,12, or 24 h. The cell growth was measured by Cell Counting Kit after being subjected to the compressive force. Then 1.0 and 2.0g/cm2 compressive force were chosen for experiment. The expression of mRNA of IL-17s, their receptors and IL-la, IL-6 was measured by Real time RT-PCR. IL-17A protein expression after 9h was measured by immunofluorescence and ELISA.
MC3T3-E1 cells were seeded onto 100-mm cell tissue culture dishes at a density of 2 x 104cells/cm2. After overnight incubation, the cells were cultured for 6h,24h or 72 h in a-MEM with 0 or 10ng/ml IL-17A. The expression of mRNA of IL-17Rs was measured by Real time RT-PCR.
2. Measure the effect of IL-17A on PGE2 and cytokines expression in osteoblast.
MC3T3-E1 cells were seeded onto 100-mm cell tissue culture dishes at a density of 2 x 104cells/cm2. Then change the medium with 1% FBS for 12h after 80% confluent.
(1) The cells were cultured for up to 72 h in a-MEM with 0,0.1,1.0, or lOng/ml IL-17A. The expression of mRNA of COX 1, COX2, RANKL, OPG, M-CSF, IL-la, IL-6, TNF-a was measured by Real time RT-PCR. The expression of protein of PGE2, RANKL, OPG, M-CSF, IL-la, IL-6, TNF-a was measured by ELISA.
(2) The cells were cultured for up to 24 h in a-MEM with 0 or 1.5 ng/ml PGE2. The expression of mRNA of RANKL, OPG, M-CSF, IL-la, IL-6 andTNF-a was measured at 24h by RT-PCR.
(3) The cells were cultured for up to 72 h in a-MEM with 0, or 10 ng/ml IL-17A alone or in the presence of 10μM celecoxib. The expression of protein of PGE2, RANKL, OPG, M-CSF, IL-la, IL-6, TNF-a was measured by ELISA.
3. The effct of IL-17A on osteoclast-like cells differentiation via osteoblast.
MC3T3-E1 cells were seeded onto 100-mm culture dishes at a density of 2 x 104 cells cm 2 and left overnight to settle. The cells were then cultured for up to 72 h inα-MEM with 0 or 10 ng mL-1 IL-17A. The cell culture medium was changed to a-MEM without IL-17A, and the cells cultured for a further 24 h. Each sample of culture medium collected was diluted to 30% and supplemented with 50 ng mL-1 of soluble RANKL to be used as conditioned medium. RAW264.7 cells were plated into 96-well microplates at a density of 1.25 x 104 cells cm-2 and left overnight to settle. Conditioned medium plus or minus IL-17A was then added to the cells for up to 10 days. Cells were then fixed and stained on days 3,5,7, and 10 of culture using a TRAP staining kit. RAW264.7 cells were plated into 6-well microplates at a density of 1.25×104 cells cm-2 and cultured for up to 10 days in the conditioned medium. The expression of mRNA and protein of cathepsin K, MMP-9 and CAII was measured by Real time RT-PCR and Western-blot respectively.
MC3T3-E1 cells were seeded onto 100-mm culture dishes at a density of 2×104 cells cm-2 and left overnight to settle. The cells were then cultured for up to 72 h in the presence or absence of 10ng/ml IL-17A and/or 10μM celecoxib. The cell culture medium was changed to a-MEM without IL-17A and celecoxib, and the cells cultured for a further 24 h. Each sample of culture medium collected was diluted to 30% and supplemented with 50 ng mL-1 of soluble RANKL to be used as conditioned medium. RAW264.7 cells were plated into 96-well microplates or 6-well microplates at a density of 1.25×104 cells cm-2 and left overnight to settle. Conditioned medium was then added to the cells for 7 days. Osteoclastogenesis was measured by TRAP staining. The expression of protein of cathepsin K and MMP-9 was measured by Western-blot.
Results
1. The expression of mRNA and protein of IL-17s and their receptors in osteoblast during compressive force.
1.1 The expressions of IL-17s mRNA with compressive force
With or without compressive force, the expressions of IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F mRNA increased gradually until 6 h of culture, and decreased gradually after 9 h. In addition, the expression of IL-17A was the highest among IL-17s with or without compressive force. The expressions of IL-17A, IL-17D, and IL-17E mRNA increased significantly compared to the control at 1.0 and/or 2.0 g/cm2 after 3,6,9,12, and 24 h of culture. The expressions of IL-17B, IL-17C, and IL-17F increased significantly compared to the control at 1.0 and/or 2.0 g/cm2 after 6,9,12, and 24 h of culture. The expressions of IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F at 3,6, and 9 h of culture increased with the strength of the compressive force compared to the control, whereas the expression at 1.0 g/cm2 after 12 and 24 h of culture indicated a higher value than that at 2.0 g/cm2 compressive force at the same time points.
1.2 The expression of lL-17Rs mRNA with compressive force
With or without compressive force, the expressions of IL-17RA, IL-17RC, and IL-17RD mRNA increased gradually until 9 h of culture, and decreased gradually after 12 h. The expressions of IL-17RB and IL-17RE increased gradually until 6 h of culture, and decreased gradually after 9 h. In addition, the expression of IL-17RC mRNA was the highest among IL-17Rs with or without compressive force. The expressions of IL-17RA and IL-17RE increased significantly compared to the control at 1.0 and/or 2.0 g/cm2 over 6-24 h of culture. The expressions of IL-17RC and IL-17RD increased significantly compared to the control at 1.0 and/or 2.0 g/cm2 over 6-12 h of culture. The expression of IL-17RB increased significantly compared to the control at 1.0 and/or 2.0 g/cm2 over 3-9 h of culture. The expressions of IL-17RA, IL-17RB, IL-17RC, IL-17RD and IL-17RE increased with the compressive force strength compared to the control at 3,6 and 9 h of culture, whereas the expressions at 1.0 g/cm2 and 12 and 24 h of culture indicated a higher value than that at 2.0 g/cm2 compressive force at the same time points, excluding IL-17RC at 24 h.
1.3 The expression of lL-17A protein with compressive force
IL-17A protein was not detected after 9h of compressive force stimulation in control group. Red fluorescence was detected in the cytoplasm of part of cells in the compressive force stimulating group.IL-17A protein level is 7.125pg/ml With 1.0 g/cm2 compressive force and 9.019pg/ml with 2.0 g/cm2 compressive force.
1.4 The expression of IL-17 Rs protein with IL-17A stimulation
MC3T3-E1 cells were cultured with or without 10 ng/ml IL-17A for up to 72 h. Compared to the control, the gene expression of IL-17RA, IL-17RB, IL-17RC, and IL-17RE increased significantly in the presence of 10 ng/ml IL-17A after culture for 6, 24, or 72 h, whereas the expression of IL-17RD was not affected.
1.5 The expression of lL-1αand IL-6 mRNA with compressive force
With or without compressive force, the expressions of IL-la and IL-6 mRNA increased gradually. The expressions of IL-la mRNA increased significantly compared to the control at 1.0 and/or 2.0 g/cm2 after 6,9,12, and 24 h of culture(P<0.01). The expressions of IL-6 increased significantly compared to the control at 1.0 and/or 2.0 g/cm2 after 9,12, and 24 h of culture (P<0.05或P<0.01)
2. The effect of IL-17A on PGE2 and cytokines expression in osteoblast.
2.1 Effect of IL-17A on the expression of RANKL, M-CSF and OPG mRNA and protein
Compared to the control, the expression of RANKL and M-CSF increased significantly in the presence of 0.1,1.0, and/or lOng/ml IL-17A after culture for 24 and/or 72 h. On the other hand, the expression of OPG decreased significantly in the presence of 0.1,1.0, and 10ng/ml IL-17A after 72 h. The expression increased by 1.3-1.8-fold on RANKL (P>0.05 or P>0.01), by 1.6-1.9-fold on M-CSF (P>0.01) and decreased by 0.8-0.9 on OPG (P>0.05).
With the addition of IL-17A after 72h, the production of RANKL and M-CSF increased and OPG decreased significantly compared to control levels:the expression increased by 1.9-2.4-fold on RANKL (P>0.05), by 1.2-1.4-fold on M-CSF (P>0.05) and by 0.7-0.8 on OPG (P>0.05).
2.2 Effect of IL-17A on the expression of inflammatory cytokines mRNA and protein
In both the presence and absence of IL-17A, IL-la expression decreased gradually until 48 h of culture, whereas TNF-a expression increased gradually until 72 h of culture. The expression of IL-6 increased gradually until 24 h of culture and decreased after 48 h. With the addition of IL-17A, the production of each cytokine increased significantly compared to control levels at 6,12,24,48 and/or 72 h of culture:the 0xpression increased by 1.3-4.3-fold on IL-la (P<0.05 or P<0.01),1.3-2.5-fold on IL-6(P<0.05 or P<0.01) and 1.2-3.5-fold on TNF-a(P<0.05 or P<0.01).
With the addition of IL-17A after 24h or 72h, the production of IL-1α, IL-6 and TNF-a increased significantly compared to control levels:the expression increased by 1.3-1.5-fold on IL-la (P<0.05 or P<0.01), by 2.1-2.6-fold on IL-6 (P<0.01) and by 1.5-fold on TNF-a (P<0.01).
2.3Effect of IL-17A on the expression of COXs mRNA
In both the presence and absence of IL-17A, COX-2 expression decreased gradually until 48 h of culture. With the addition of IL-17A, COX-2 expression increased significantly compared to control levels at 6,12 and 24 h:the expression increased by 1.2-2.4-fold. In contrast, COX-1 expression was not affected by the addition of IL-17A and was changed depending on the culture days.
2.4 Effect of IL-17A and/or celecoxib on PGE2 production
With the addition of IL-17A, PGE2 production at 6,24, and 72 h of culture increased by 1.06-2.19,1.57-2.05, and 2.75-3.50-fold, respectively, in a dose-dependent manner in the presence of IL-17A. When celecoxib was present in the culture media, the stimulatory effect of IL-17A on PGE2 production was inhibited since the levels of PGE2 production remained similar to those in the untreated controls. These data suggest that the indirect stimulatory effect of IL-17A on PGE2 levels is dependent on COX-2 activity.
2.5 Effect of PGE2 on the production of osteoclast differention-related factors
With the addition of PGE2 after 24h, the production of RANKL and M-CSF increased significantly compared to control levels (P<0.01), whereas the production of OPG decreased significantly compared to control levels (P<0.05).
With the addition of PGE2 after 24h, the production of IL-la and IL-6 increased significantly compared to control levels (P<0.01), but the production of TNF-a was not affected.
2.6 Effect of lL-17A and celecoxib on the expression of osteoclast differention-related factors protein
When celecoxib was present in the culture with IL-17A, it appeared to block the stimulatory effect of IL-17A on the production of RANKL, M-CSF and OPG; the levels of these productions in cells treated with both IL-17A and celecoxib were similar to that in the controls without IL-17A.
When celecoxib was present in the culture with IL-17 A, it appeared to block the stimulatory effect of IL-17A on the production of IL-1 a, IL-6; the levels of these productions in cells treated with both IL-17A and celecoxib were similar to that in the controls without IL-17A. In contrast, TNF-a was not affected by the addition of celecoxib.
3. The indirect effect of IL-17A on osteoblast-like cells differentiation via osteoblast.
3.1 Indirect effects of IL-17A on TRAP staining of osteoclast-like cells
The multinucleated cell numbers increased after 3 days of culture. In both conditioned medium from IL-17A-treated and untreated cells, the number of TRAP-positive multinucleated cells increased gradually until day 7 of culture, and decreased from day 7 to 10. TRAP staining of osteoclast-like cells in the conditioned medium from IL-17-treated cells on days 5 and 7 of culture was stronger than the conditioned medium from untreated control cells. The number of TRAP-positive multinucleated cells increased significantly in the conditioned medium from IL-17A-treated cells compared to that of the controls on days 5 and 7 of culture, increasing by 1.45-and 1.34-fold, respectively.
3.2 Indirect effects of IL-17A on cathepsin K, MMP-9, and CAⅡmRNA expression
In both conditioned medium from IL-17A-treated and untreated MC3T3-E1 cells, the expression of cathepsin K and MMP-9 increased gradually until day 10 of culture, whereas CA II expression remained unchanged until day 7, eventually increasing on day 10. Cathepsin K expression in the conditioned medium from IL-17A-treated cells increased significantly by 1.50-and 1.40-fold, on days 7 and 10 of culture, respectively, compared with that of the conditioned medium from untreated control cells. In addition, MMP-9 expression in the medium from IL-17A-treated cells increased significantly by 1.31-fold compared to untreated cells on day 10 of culture. CA II expression remained unaffected by IL-17A treatment until day 10 of culture.
3.3 Indirect effects of IL-17A on cathepsin K, MMP-9, and CAⅡprotein expression
When the protein levels of cathepsin K and MMP-9 in the conditioned medium from IL-17A-treated cells were quantified, similar to the data observed from the mRNA analysis, their levels increased by 1.35-and 1.42-fold, respectively, compared with the untreated control cells. CAⅡexpression was again unaffected by indirect IL-17A treatment. Thus, the indirect effects of IL-17A on cathepsin K, MMP-9, and CAⅡmRNA expression levels were correlated with their protein levels in conditioned media.
3.4 Indirect effect of IL-17A and/or celecoxib on TRAP staining of osteoclast-like cells
TRAP staining of osteoclast-like cells in the conditioned medium from IL-17-treated MC3T3-E1 cells was significantly stronger than untreated cells. The addition of celecoxib to the IL-17A conditioned media reduced TRAP staining of osteoclast-like cells to levels identical to the untreated cells. In addition, celecoxib blocked the stimulatory indirect effect of IL-17A on the number of TRAP-positive multinucleated cells.
3.5 Indirect effects of IL-17A and/or celecoxib on cathepsin K and MMP-9 mRNA expression
The mRNA levels of both cathepsin K and MMP-9 in the conditioned medium from MC3T3-E1 cells treated with both IL-17A and celecoxib were similar to those in the controls lacking IL-17A. These data suggest that COX-2 inhibition by celecoxib inhibits the ability of IL-17A to stimulate cathepsin K and MMP-9 expression in the conditioned media.
Conclusion
1. MC3T3-E1 cells express six different IL-17 subtypes and five different IL-17R subtypes at the mRNA level and IL-17A at protein level.
2. Compressive force induces the expression of IL-la,IL-6, IL-17s and IL-17Rs in these cells, which suggests that IL-17s may be involved in the alveolar bone resorption during orthodontic tooth movement.
3. IL-17A increased the mRNA and protein expression of RANKL and M-CSF, decreased expression of OPG in dose-dependent way. IL-17A also stimulates the expression of bone resorption-related inflammatory cytokines. It indicates that IL-17A in vitro regulates bone resorption-related cytokines expression in osteoblast.
4. IL-17A stimulates bone resorption-related cytokines expression through an autocrine mechanism involving celecoxib-blocked PGs by increasing COX-2 expression, mainly PGE2, in osteoblasts.
5. IL-17A stimulates not only the differentiation of RAW264.7 cells into osteoclast-like cells but also the expression of cathepsin K and MMP-9 in osteoclast-like cells. It indicates that IL-17A in vitro indirectly stimulates the differentiation and function of osteoclast-like cells via osteoblasts.
6. IL-17A stimulates osteoclast-like cells differentiation through an autocrine mechanism involving celecoxib-blocked PGs by increasing COX-2 expression, mainly PGE2, in osteoblasts.
7. This study will contrubuteto a better understanding of molecule mechanism of bone remodeling during tooth movement.
正畸牙槽骨改建的第一步是牙槽骨的吸收,成熟的破骨细胞(osteoclast,OC)是唯一行使骨吸收功能的细胞,OC的分化和成熟主要依赖于成骨细胞(osteoblasts, OB)的调控。OB通过与OC的细胞间连接以及分泌可溶性因子调控OC的分化和成熟,这些因子称为OC分化相关因子。机械力作用下,OB产生OC分化相关因子,通过多种途径和机制参与和调节OC的分化和功能。在目前发现的调节OC分化的细胞因子中,核转录因子kB受体活化因子配基(receptor activator of NF-κB ligand, RANKL)和巨噬细胞集落刺激因子(macrophage colony-stimulating factor, M-CSF)是两个关键调节因子。此外,一些炎性细胞因子也具有重要的调节作用,如白细胞介素(interleukin, IL)-1, IL-6,肿瘤坏死因子(tumor necrosis factor, TNF)-a等,能够直接或间接促进OC的分化和活化,又被称为骨吸收炎性因子。除了细胞因子,一些脂质作为信号传递分子,参与骨重建过程。其中,前列腺素(prostaglandin, PG)E2的作用非常显著,可促进OC分化和骨吸收,并调节炎症反应。在正畸牙移动的龈沟液中,PGE2的表达水平较高。本研究相关的前期实验发现,压力上调成骨细胞表达PGE2,进而上调RANKL、M-CSF的表达和下调骨保护蛋白(osteoprotegerin, OPG)的表达,从而诱导OC分化。
IL-17是一种重要的促炎性细胞因子,1993年首次由活化的T细胞(TH17)克隆而来,直到近年来人们才对其有了一定的认识。IL-17结构独特,与其他已知的蛋白和白介素的结构没有相似性,在人类和鼠类的基因组包括至少6个成员(A-F)和5个受体成员(RA-RE).而功能方面,IL-17具有强大的促炎症作用和骨吸收的作用。近年来的研究发现,IL-17可促进IL-1,TNF-a的合成,诱导IL-6和IL-8在成纤维细胞内的表达。可增强OB内TNF-α、PGF2a诱导IL-6的合成作用,IL-17可上调多种细胞内RANKL的表达而促进OC的分化。作为最新发现的骨吸收炎性因子,IL-17在多种涉及骨丢失疾病中的重要作用不断被发现和深入研究,如牙周炎,风湿性关节炎,骨关节炎等。因此,我们设想IL-17参与正畸过程中的牙槽骨的吸收,通过OB促进OC的分化和功能。但是机械力作用下IL-17在OB内的表达情况,目前国内外尚无报道,而IL-17通过什么机制参与OC的分化过程,目前尚不清楚。
因此,本研究通过检测压力作用下IL-17及其受体在OB内的表达；研究IL-17A调控OC分化相关因子在OB内的表达及其作用机制；检测IL-17调节OB诱导OC分化的作用,探讨IL-17在体外介导OB诱导OC的作用,为进一步阐明正畸牙移动和牙槽骨改建的分子生物学机制提供理论和实践依据。
实验方法
1.检测压力作用下,IL-17及其受体在OB内的表达情况.
以来自新生小鼠颅骨的细胞系-MC3T3-E1细胞作为OB,用含10%FBS的a-MEM培养。按2.0 x 104 cells/cm2的密度将细胞接种于96孔板,用含50 mM磷酸甘油和50μg/ml抗坏血酸的培养液培养7-10天,茜素红染色观察矿化结节。按相同密度将细胞接种于100 mm培养皿,待细胞融合80%,换用含1%FBS的a-MEM培养液培养12h后,开始施加压力。按实验室以往研究,采用细胞均匀加力装置施加0、1.0、2.0或3.0g/cm2(0、98、196或294Pa)的压力,加力时间分别为1h、3h、6h、9h、12h或24h。活细胞计数试剂盒检测压力对细胞生长的影响,选择对细胞生长影响小的1.0和2.0g/cm2作为实验组。加力结束后,采用实时定量RT-PCR检测IL-17家族、IL-17受体家族、IL-lα、IL-6mRNA表达情况,采用细胞免疫荧光技术和ELISA方法检测加力9h后IL-17A蛋白表达情况。
按相同密度将细胞接种于100 mm培养皿,待细胞融合80%,换用含1%FBS的a-MEM培养液培养12h后,加入0或10 ng/ml的IL-17A继续培养6h、24h或72h,实时定量RT-PCR检测IL-17受体mRNA表达情况。
2.检测IL-17A调控OC分化相关因子在OB内表达的作用及机制。
按2.0×104 cells/cm2的密度将MC3T3-E1细胞接种于100 mm培养皿,待细胞融合80%,换用含1%FBS的a-MEM培养液培养12h。分别进行以下实验。
(1)加入0、0.1、1或10ng/ml的IL-17A继续培养6h、12h、24h、48h或72h。实时定量RT-PCR检测RANKL、OPG、M-CSF、IL-lα、IL-6、TNF-α、COX-1和COX-2mRNA表达情况,ELISA方法检测PGE2、RANKL、OPG、M-CSF、IL-lα、IL-6和TNF-a蛋白表达情况。
(2)加入0或1.5 ng/ml的PGE2继续培养24h。实时定量RT-PCR检测RANKL、OPG、M-CSF、IL-lα、IL-6和TNF-a mRNA表达情况。
(3)加入0或10 ng/ml的IL-17A和／或10μ,M塞来昔布(COX-2抑制剂)继续培养24h或72h。ELISA方法检测PGE2、RANKL、OPG、M-CSF、IL-la、IL-6和TNF-α蛋白表达情况。3.检测IL-17A间接诱导破骨样细胞(osteoclast-like cells,OCL)分化的作用和机制。
按2.0 x 104 cells/cm2的密度将MC3T3-E1细胞接种于100 mm培养皿,待细胞融合80%,加入0或10 ng／ml的IL-17A的含1%FBS的a-MEM继续培养72h。再换用含1%FBS的a-MEM培养12h,收集细胞培养上清。按照30%的比例与含10%FBS的a-MEM混合,加入50 ng/ml的RANKL,作为条件培养液。以鼠源性单核-巨噬细胞系RAW264.7作为破骨细胞前体,用含10%FBS的a-MEM培养,2天换液一次。按1.25 x 104 cells/cm2的密度将RAW264.7细胞接种于96孔板,孵育24h后,换用条件培养液培养3,5,7或10天,抗酒石酸酸性磷酸酶(TRAP)染色鉴定和计数OCL。按1.25×104 cells/cm2的密度将RAW264.7细胞接种于6孔板,孵育24h后,换用条件培养液培养3,5,7或10天,实时定量RT-PCR和Western-blot方法分别检测组织蛋白酶K、基质金属蛋白酶(MMP)-9和碳酸酐酶(CA) II mRNA和蛋白表达情况。
按2.0 x 104 cells/cm2的密度将MC3T3-E1细胞接种于100 mm的培养皿,待细胞融合80%,加入的IL-17A (0或10 ng/ml)和／或10μM塞来昔布的含1%FBS的a-MEM继续培养72h。再换用含1%FBS的a-MEM培养12h,收集细胞培养上清。按照30%的比例与含10%FBS的a-MEM混合,加入50 ng/ml的RANKL,作为条件培养液。按1.25 x 104 cells/cm2的密度将RAW264.7细胞接种于96孔板或6孔板,孵育24h后,换用条件培养液培养7天,TRAP染色鉴定和计数OCL,实时定量RT-PCR方法检测组织蛋白酶K、MMP-9和CAIImRNA表达情况。
实验结果
1.压力作用下,IL-17及其受体在OB内的表达情况。
1.1压力作用下,IL-17家族mRNA在OB内的表达情况
在一个加力周期内,对照组和实验组的IL-17(A-F) mRNA的表达逐渐升高,6h达到最高,9h后表达逐渐降低,IL-17A mRNA的表达水平在IL-17家族中最高。与对照组相比,IL-17A.IL-17D和IL-17E mRNA的表达在1.0和2.0g/cm2的压力加载后的3h,6h,9h,12h和24h均显著增强(P<0.05或P<0.01)；IL-17B.IL-17C和IL-17F mRNA的表达在1.0或2.0 g/cm2的压力加载后的6h,9h,12h和24h均显著增强(P<0.05或P<0.01)。在细胞加力后的初期和中期(3h,6h,9h),IL-17A-F mRNA的表达随着压力的增加而增强,但在细胞加力后的后期(12h,24h),IL-17A-F mRNA在1.0 g/cm2力值加载条件下比2.0g/cm2加载条件下的表达更多。
1.2压力作用下,IL-17受体家族mRNA在OB内的表达情况
在一个加力周期内,对照组和实验组的IL-17RA、IL-17RC和IL-17RD mRNA的表达逐渐升高,9h达到最高,12h后表达逐渐降低,IL-17RB和IL-17RE mRNA的表达逐渐升高,6h达到最高,9h后表达逐渐降低。IL-17RC mRNA的表达水平在IL-17受体家族中最高。与对照组相比,IL-17RA和IL-17RE mRNA的表达在1.0和2.0g/cm2的压力加载后的6h,9h,12h和24h均显著增强(P<0.05或P
1.3压力作用下,IL-17A蛋白在OB内的表达情况
细胞加力9h后,对照组中未见IL-17A蛋白的表达；细胞加载1.0g/cm2压力的实验组,部分细胞的细胞质内呈现红色荧光,IL-17A蛋白水平为7.125 pg/ml,细胞加载2.0 g/cm2压力的实验组,部分细胞的细胞质内呈现红色荧光,IL-17A蛋白水平为9.019 pg/ml。表明随压力增加,IL-17A蛋白表达增加。
1.4 IL-17A调节IL-17受体家族mRNA在OB内的表达情况
IL-17A作用于成骨细胞后,与对照组相比,IL-17RA、IL-17RB、IL-17RC和IL-17RE mRNA的表达均有显著增加(P<0.05),但IL-17RD的表达没有显著性差异。
1.5压力作用下,IL-la和IL-6mRNA在OB内的表达情况
在一个加力周期内,对照组和实验组的IL-1a和IL-6 mRNA的表达逐渐升高。与对照组相比,IL-1αmRNA的表达在1.0或2.0g/cm2的压力加载后的6h、9h、12h和24h均显著增强(P<0.01); IL-6 mRNA的表达在1.0或2.0 g/cm2的压力加载后的9h、12h和24h均显著增强(P<0.05或P<0.01)。
2.IL-17A调控OC分化相关因子在OB内表达的作用及机制。
2.1 IL-17A调节RANKL、OPG、M-CSFmRNA和蛋白在OB内的表达情况
在IL-17A刺激作用下,与对照组相比,实验组的RANKL和M-CSF mRNA表达显著增加,OPG mRNA表达显著降低：RANKL mRNA表达在24h-72h增加了1.3-1.8倍(P<0.05或P<0.01),M-CSF mRNA表达在72h增加了1.6-1.9倍(P<0.01),OPG mRNA表达在48h-72h降低了0.8-0.9(P<0.05)。
IL-17A刺激成骨细胞72h后,与对照组相比,实验组的RANKL和M-CSF蛋白表达显著增加,OPG蛋白表达显著降低：RANKL蛋白表达增加了1.9-2.4倍(P
2.2 IL-17A调节骨吸收炎性因子mRNA和蛋白在OB内的表达情况
对照组和实验组的IL-1αmRNA表达逐渐降低,直到48h；IL-6 mRNA表达逐渐升高到24h,48h后逐渐降低；TNF-a mRNA表达逐渐升高,直到72h。在IL-17A刺激作用下,与对照组相比,实验组的骨吸收炎性因子mRNA表达显著增加：IL-lαmRNA表达在6h-72h增加了1.3-4.3倍(P<0.05或P<0.01),IL-6mRNA表达在6h-72h增加了1.3-2.5倍(P<0.05或P<0.01),TNF-a mRNA表达在12h-72h增加了1.2-3.5倍(P<0.05或P<0.01)。
IL-17A刺激OB的24h后,与对照组相比,实验组的骨吸收炎性因子蛋白表达显著增加：IL-1a蛋白表达显著增加了1.3-1.5倍(P<0.05或P<0.01),IL-6蛋白表达显著增加了2.1-2.6倍(P<0.01),IL-17A刺激OB的72h后,TNF-a蛋白表达显著增加了1.5倍(P<0.01)。2.3 IL-17A调节COX-1和COX-2 mRNA在OB内的表达情况
对照组和实验组的COX-2 mRNA表达逐渐降低,直到48h。在IL-17A刺激作用下,与对照组相比,实验组COX-2mRNA表达在6h、12h和24h显著增加了1.2-2.4倍(P<0.01)。但COX-1的mRNA表达不受IL-17A的影响。2.4 IL-17A和／或celecoxib调节PGE2在OB内的表达情况
在IL-17A刺激作用下,与对照组相比,实验组的PGE2蛋白表达显著增加,并呈剂量依赖性的特点：在6h,24h和72h分别增加了1.06-2.19倍,1.57-2.05倍和2.75-3.50倍。在IL-17A和celecoxib共同作用的24h, celecoxib阻滞了IL-17A对PGE2的刺激作用,PGE2蛋白含量显著降低,接近于对照组的水平。表明IL-17A是通过上调COX-2的表达而增加PGE2的表达。
2.5 PGE2调节OC分化相关因子mRNA在OB内的表达情况
在PGE2作用下,与对照组相比,实验组的RANKL和M-CSF的nRNA表达显著增加(P<0.01),OPG的mRNA表达显著降低(P<0.05)；实验组的IL-1a和IL-6的mRNA表达显著增加(P<0.01),但TNF-α的]mRNA表达无显著性差异。2.6 celecoxib对IL-17A调节OC分化相关因子蛋白在OB内表达的影响作用
在IL-17A和celecoxib共同作用的72h后,celecoxib阻滞了IL-17A对RANKL、OPG和M-CSF的刺激作用,RANKL和M-CSF蛋白含量显著降低,OPG蛋白表达显著增加,接近于对照组的水平。
在IL-17A和celecoxib共同作用24h后,celecoxib阻滞了IL-17A对IL-1a和IL-6的刺激作用, IL-1a和IL-6蛋白含量显著降低,接近于对照组的水平,IL-17A和celecoxib共同作用72h后,TNF-α的蛋白表达与对照组相比无显著性差异。
3.IL-17A间接诱导oCL分化的作用。
3.1 IL-17A诱导OCL形成的作用
用IL-17A处理或未处理的条件培养液培养RAW264.7细胞的第3天,可见TRAP染色阳性的多核巨细胞(OCL)出现,第5天和第7天,细胞体积变大,数量增加,第10天,OCL逐渐减少。在第5天和第7天,与对照组相比,IL-17A处理的条件培养液诱导的OCL体积较大,数量显著增多,分别增加1.45倍和1.34倍(P<0.01)。3.2 IL-17A调节cathepsin K, MMP-9和CAⅡmRNA在OCL内的表达情况
用IL-17A处理或未处理的条件培养液培养RAW264.7细胞的10天内,cathepsin K, MMP-9 mRNA的表达逐渐增加,CAⅡmRNA的表达没有明显变化,只在第10天轻微增加。与对照组相比,实验组的cathepsin K mRNA的表达在第5天和7天分别增加了1.50和1.40倍(P<0.05或P<0.01),实验组的MMP-9 mRNA的表达在第7天增加了1.31倍(P<0.01)。但实验组的CAⅡmRNA的表达没有明显变化。
3.3 IL-17A调节cathepsin K, MMP-9和CAⅡ蛋白在OCL内的表达情况
用IL-17A处理或未处理的条件培养液培养RAW264.7细胞的第10天,cathepsin K, MMP-9和CAⅡ蛋白表达与其mRNA表达相似。与对照组相比,实验组的cathepsin K的蛋白表达增加了1.35倍(P<0.01),实验组的MMP-9的蛋白表达增加了1.42倍(P<0.01)。而实验组的CAⅡ的蛋白表达没有明显变化。
3.4 celecoxib对IL-17A诱导OCL形成的影响作用
用IL-17A处理或未处理的条件培养液培养RAW264.7细胞的第7天,与对照组相比,IL-17A处理的条件培养液诱导的OCL体积较大,数量显著增多(P<0.01)。用IL-17A和celecoxib处理的条件培养液培养RAW264.7,OCL数量显著下降,接近于对照组的水平。celecoxib阻滞了lL-17A对OCL的间接诱导作用。
3.5 celecoxib对IL-17A调节cathepsin K和MMP-9 mRNA表达的影响作用
用IL-17A和celecoxib处理的条件培养液培养RAW264.7, cathepsin K和MMP-9mRNA显著下降(P<0.05),接近于对照组的水平。表明COX-2抑制剂阻滞了IL-17A对cathepsin K和MMP-9 mRNA表达的上调作用。
结论1.成骨细胞MC3T3-E1可在mRNA水平表达6个IL-17家族成员(IL-17A-F)和5个受体家族成员(IL-17RA-RE),并在蛋白水平表达IL-17A,因此,成骨细胞也可产生IL-17。
2.压力诱导IL-la, IL-6, IL-17及其受体的mRNA和IL-17A蛋白在成骨细胞内的表达增强,而且IL-17A在其家族成员中的表达水平最高。提示IL-17可能参与机械力诱导的牙槽骨吸收过程。
3.IL-17A显著上调RANKL和M-CSF,下调OPG的mRNA和蛋白在成骨细胞内的表达：IL-17A显著上调IL-1α, IL-6和TNF-a的mRNA和蛋白在成骨细胞内的表达,证实IL-17A在体外调控成骨细胞内的破骨细胞分化相关因子的表达。
4.IL-17A通过上调COX-2/PGE2的表达(可被celecoxib沮滞),从而调控破骨细胞分化相关因子在成骨细胞内的表达,揭示了该调控作用的机制。
5.IL-17A促进成骨细胞诱导破骨样细胞的分化,并上调cathepsin K, MMP-91的mRNA和蛋白在破骨样细胞中的表达,证实IL-17在体外促进成骨细胞诱导破骨样细胞的分化和功能。
6.IL-17A通过上调成骨细胞内COX-2/PGE2的表达(可被celecoxib阻滞),调控破骨细胞分化相关因子的表达,从而促进成骨细胞诱导破骨样细胞的分化和功能,揭示了IL-17在体外促进成骨细胞诱导破骨样细胞的分化相关的机制。
7.本研究探讨了IL-17在体外介导成骨细胞诱导破骨样细胞分化的作用,为进一步阐明正畸牙移动和牙槽骨改建的分子生物学机制提供理论和实践依据。
Background and Objective
Alveolar bone resorption is the first step of bone remodeling during orthodontic treatment and mature osteoclast (OC) is the only cell to be responsible for bone resorption. OB mediate pOC diffentiation and activation by multiple factors and ways..Those factors were called bone resorption-relative factors. Mechanical stress induces OB to produce such facorrs. Among them, Receptor activator of NF-kB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) are the two key factors inducing OC differentiation and function. Inflammatory mediators released from periodontal tissue trigger the biological process of alveolar bone resorption. Interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-αare known as born resorption-related-inflammatory cytokines and play important roles to stimulate OC differentiation and activity. Higher levels of prostaglandin E2 (PGE2) were found in the gingival crevicular fluid of teeth undergoing orthodontic movement. PGE2 is able to mediate the inflammatory response and to induce bone resorption through the stimulation of OC differentiation. In addition, the application of compressive force induces bone formation by increasing levels of PGE2 in OB. These reports suggest that PGE2 plays an important role in bone remodeling affecting bone resorption and formation via autocrine action. We recently reported that compressive force induces osteoclast differentiation by increasing M-CSF production and decreasing OPG production via PGE2 in OB.
IL-17 is a kind of inflammatory cytokines.It originally was cloned from activated T cells (Thl7 cells) but is well known until resently. It shares little or no homology with other proteins and interleukins. At least six members of the family and five subtypes of receptors (IL-17Rs) are in the human and mouse genomes. IL-17 induced inflammation and affect osteoclastic resorption indirectly via osteoblasts. Some reports indicate that IL-17 shows a synergistic effect with IL-10 and TNF-a and induces production of IL-6 in fibroblasts. In OB, there were reported that IL-17 enhanced the synthesis of TNF-a-stimulated IL-6 synthesis and prostaglandin F2a-stimulated IL-6. IL-17 stimulates bone resorption by inducing RANKL expression. So we hypothesize that IL-17 involves in and mediates the process of alveolar bone resorption via OB.However, the expression of IL-17 in OB induced by orthodonic force has not been reported.
Therefore, in the present study, we examined the effect of compressive force on the expression of IL-17 and their receptors in OB. We also examined the effect of different concertration of IL-17 on OC differentiation via OB and the indirect effect of IL-17 inducing OC formation, and investigate in vitro the roles of IL-17 inducing OCL formation via OB. This study will contribute to a better understanding of the molecular biology mechanism of orthodontic tooth movement and alveolar bone remodeling.
Methods
1. Measure the expression of mRNA and protein of IL-17s and their receptors in osteoblast during compressive force.
MC3T3-E1 cells from a mouse calvarial cell line were used as osteoblast-like cells. MC3T3-E1 cells were maintained in a-minimal essential medium containing 10% (v/v) heat-inactivated fetal bovine serum at 37℃in a humidified atmosphere of 95% air and 5% CO2. MC3T3-E1 cells were placed into 96-well tissue plates at a density of 2.0 x 104 cells/cm2 and cultured for 7-10 days in a-MEM containing 50 mMβ-glycerophosphate and 50μg/ml ascorbic acid. The presence of mineralized nodules was determined by staining with alizarin red S. For being applied the compressive force, MC3T3-E1 cells were seeded in 100-mm cell culture dishes at a density of 2.0×104 cells/cm2 and incubated until 90% confluent. The cells were then compressed continuously using a uniform compression method similar to those described previously. The cells were subjected to 1.0,2.0 or 3.0 g/cm2 (98,196 or294 Pa, respectively) compressive force for 1,3,6,9,12, or 24 h. The cell growth was measured by Cell Counting Kit after being subjected to the compressive force. Then 1.0 and 2.0g/cm2 compressive force were chosen for experiment. The expression of mRNA of IL-17s, their receptors and IL-la, IL-6 was measured by Real time RT-PCR. IL-17A protein expression after 9h was measured by immunofluorescence and ELISA.
MC3T3-E1 cells were seeded onto 100-mm cell tissue culture dishes at a density of 2 x 104cells/cm2. After overnight incubation, the cells were cultured for 6h,24h or 72 h in a-MEM with 0 or 10ng/ml IL-17A. The expression of mRNA of IL-17Rs was measured by Real time RT-PCR.
2. Measure the effect of IL-17A on PGE2 and cytokines expression in osteoblast.
MC3T3-E1 cells were seeded onto 100-mm cell tissue culture dishes at a density of 2 x 104cells/cm2. Then change the medium with 1% FBS for 12h after 80% confluent.
(1) The cells were cultured for up to 72 h in a-MEM with 0,0.1,1.0, or lOng/ml IL-17A. The expression of mRNA of COX 1, COX2, RANKL, OPG, M-CSF, IL-la, IL-6, TNF-a was measured by Real time RT-PCR. The expression of protein of PGE2, RANKL, OPG, M-CSF, IL-la, IL-6, TNF-a was measured by ELISA.
(2) The cells were cultured for up to 24 h in a-MEM with 0 or 1.5 ng/ml PGE2. The expression of mRNA of RANKL, OPG, M-CSF, IL-la, IL-6 andTNF-a was measured at 24h by RT-PCR.
(3) The cells were cultured for up to 72 h in a-MEM with 0, or 10 ng/ml IL-17A alone or in the presence of 10μM celecoxib. The expression of protein of PGE2, RANKL, OPG, M-CSF, IL-la, IL-6, TNF-a was measured by ELISA.
3. The effct of IL-17A on osteoclast-like cells differentiation via osteoblast.
MC3T3-E1 cells were seeded onto 100-mm culture dishes at a density of 2 x 104 cells cm 2 and left overnight to settle. The cells were then cultured for up to 72 h inα-MEM with 0 or 10 ng mL-1 IL-17A. The cell culture medium was changed to a-MEM without IL-17A, and the cells cultured for a further 24 h. Each sample of culture medium collected was diluted to 30% and supplemented with 50 ng mL-1 of soluble RANKL to be used as conditioned medium. RAW264.7 cells were plated into 96-well microplates at a density of 1.25 x 104 cells cm-2 and left overnight to settle. Conditioned medium plus or minus IL-17A was then added to the cells for up to 10 days. Cells were then fixed and stained on days 3,5,7, and 10 of culture using a TRAP staining kit. RAW264.7 cells were plated into 6-well microplates at a density of 1.25×104 cells cm-2 and cultured for up to 10 days in the conditioned medium. The expression of mRNA and protein of cathepsin K, MMP-9 and CAII was measured by Real time RT-PCR and Western-blot respectively.
MC3T3-E1 cells were seeded onto 100-mm culture dishes at a density of 2×104 cells cm-2 and left overnight to settle. The cells were then cultured for up to 72 h in the presence or absence of 10ng/ml IL-17A and/or 10μM celecoxib. The cell culture medium was changed to a-MEM without IL-17A and celecoxib, and the cells cultured for a further 24 h. Each sample of culture medium collected was diluted to 30% and supplemented with 50 ng mL-1 of soluble RANKL to be used as conditioned medium. RAW264.7 cells were plated into 96-well microplates or 6-well microplates at a density of 1.25×104 cells cm-2 and left overnight to settle. Conditioned medium was then added to the cells for 7 days. Osteoclastogenesis was measured by TRAP staining. The expression of protein of cathepsin K and MMP-9 was measured by Western-blot.
Results
1. The expression of mRNA and protein of IL-17s and their receptors in osteoblast during compressive force.
1.1 The expressions of IL-17s mRNA with compressive force
With or without compressive force, the expressions of IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F mRNA increased gradually until 6 h of culture, and decreased gradually after 9 h. In addition, the expression of IL-17A was the highest among IL-17s with or without compressive force. The expressions of IL-17A, IL-17D, and IL-17E mRNA increased significantly compared to the control at 1.0 and/or 2.0 g/cm2 after 3,6,9,12, and 24 h of culture. The expressions of IL-17B, IL-17C, and IL-17F increased significantly compared to the control at 1.0 and/or 2.0 g/cm2 after 6,9,12, and 24 h of culture. The expressions of IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F at 3,6, and 9 h of culture increased with the strength of the compressive force compared to the control, whereas the expression at 1.0 g/cm2 after 12 and 24 h of culture indicated a higher value than that at 2.0 g/cm2 compressive force at the same time points.
1.2 The expression of lL-17Rs mRNA with compressive force
With or without compressive force, the expressions of IL-17RA, IL-17RC, and IL-17RD mRNA increased gradually until 9 h of culture, and decreased gradually after 12 h. The expressions of IL-17RB and IL-17RE increased gradually until 6 h of culture, and decreased gradually after 9 h. In addition, the expression of IL-17RC mRNA was the highest among IL-17Rs with or without compressive force. The expressions of IL-17RA and IL-17RE increased significantly compared to the control at 1.0 and/or 2.0 g/cm2 over 6-24 h of culture. The expressions of IL-17RC and IL-17RD increased significantly compared to the control at 1.0 and/or 2.0 g/cm2 over 6-12 h of culture. The expression of IL-17RB increased significantly compared to the control at 1.0 and/or 2.0 g/cm2 over 3-9 h of culture. The expressions of IL-17RA, IL-17RB, IL-17RC, IL-17RD and IL-17RE increased with the compressive force strength compared to the control at 3,6 and 9 h of culture, whereas the expressions at 1.0 g/cm2 and 12 and 24 h of culture indicated a higher value than that at 2.0 g/cm2 compressive force at the same time points, excluding IL-17RC at 24 h.
1.3 The expression of lL-17A protein with compressive force
IL-17A protein was not detected after 9h of compressive force stimulation in control group. Red fluorescence was detected in the cytoplasm of part of cells in the compressive force stimulating group.IL-17A protein level is 7.125pg/ml With 1.0 g/cm2 compressive force and 9.019pg/ml with 2.0 g/cm2 compressive force.
1.4 The expression of IL-17 Rs protein with IL-17A stimulation
MC3T3-E1 cells were cultured with or without 10 ng/ml IL-17A for up to 72 h. Compared to the control, the gene expression of IL-17RA, IL-17RB, IL-17RC, and IL-17RE increased significantly in the presence of 10 ng/ml IL-17A after culture for 6, 24, or 72 h, whereas the expression of IL-17RD was not affected.
1.5 The expression of lL-1αand IL-6 mRNA with compressive force
With or without compressive force, the expressions of IL-la and IL-6 mRNA increased gradually. The expressions of IL-la mRNA increased significantly compared to the control at 1.0 and/or 2.0 g/cm2 after 6,9,12, and 24 h of culture(P<0.01). The expressions of IL-6 increased significantly compared to the control at 1.0 and/or 2.0 g/cm2 after 9,12, and 24 h of culture (P<0.05或P<0.01)
2. The effect of IL-17A on PGE2 and cytokines expression in osteoblast.
2.1 Effect of IL-17A on the expression of RANKL, M-CSF and OPG mRNA and protein
Compared to the control, the expression of RANKL and M-CSF increased significantly in the presence of 0.1,1.0, and/or lOng/ml IL-17A after culture for 24 and/or 72 h. On the other hand, the expression of OPG decreased significantly in the presence of 0.1,1.0, and 10ng/ml IL-17A after 72 h. The expression increased by 1.3-1.8-fold on RANKL (P>0.05 or P>0.01), by 1.6-1.9-fold on M-CSF (P>0.01) and decreased by 0.8-0.9 on OPG (P>0.05).
With the addition of IL-17A after 72h, the production of RANKL and M-CSF increased and OPG decreased significantly compared to control levels:the expression increased by 1.9-2.4-fold on RANKL (P>0.05), by 1.2-1.4-fold on M-CSF (P>0.05) and by 0.7-0.8 on OPG (P>0.05).
2.2 Effect of IL-17A on the expression of inflammatory cytokines mRNA and protein
In both the presence and absence of IL-17A, IL-la expression decreased gradually until 48 h of culture, whereas TNF-a expression increased gradually until 72 h of culture. The expression of IL-6 increased gradually until 24 h of culture and decreased after 48 h. With the addition of IL-17A, the production of each cytokine increased significantly compared to control levels at 6,12,24,48 and/or 72 h of culture:the 0xpression increased by 1.3-4.3-fold on IL-la (P<0.05 or P<0.01),1.3-2.5-fold on IL-6(P<0.05 or P<0.01) and 1.2-3.5-fold on TNF-a(P<0.05 or P<0.01).
With the addition of IL-17A after 24h or 72h, the production of IL-1α, IL-6 and TNF-a increased significantly compared to control levels:the expression increased by 1.3-1.5-fold on IL-la (P<0.05 or P<0.01), by 2.1-2.6-fold on IL-6 (P<0.01) and by 1.5-fold on TNF-a (P<0.01).
2.3Effect of IL-17A on the expression of COXs mRNA
In both the presence and absence of IL-17A, COX-2 expression decreased gradually until 48 h of culture. With the addition of IL-17A, COX-2 expression increased significantly compared to control levels at 6,12 and 24 h:the expression increased by 1.2-2.4-fold. In contrast, COX-1 expression was not affected by the addition of IL-17A and was changed depending on the culture days.
2.4 Effect of IL-17A and/or celecoxib on PGE2 production
With the addition of IL-17A, PGE2 production at 6,24, and 72 h of culture increased by 1.06-2.19,1.57-2.05, and 2.75-3.50-fold, respectively, in a dose-dependent manner in the presence of IL-17A. When celecoxib was present in the culture media, the stimulatory effect of IL-17A on PGE2 production was inhibited since the levels of PGE2 production remained similar to those in the untreated controls. These data suggest that the indirect stimulatory effect of IL-17A on PGE2 levels is dependent on COX-2 activity.
2.5 Effect of PGE2 on the production of osteoclast differention-related factors
With the addition of PGE2 after 24h, the production of RANKL and M-CSF increased significantly compared to control levels (P<0.01), whereas the production of OPG decreased significantly compared to control levels (P<0.05).
With the addition of PGE2 after 24h, the production of IL-la and IL-6 increased significantly compared to control levels (P<0.01), but the production of TNF-a was not affected.
2.6 Effect of lL-17A and celecoxib on the expression of osteoclast differention-related factors protein
When celecoxib was present in the culture with IL-17A, it appeared to block the stimulatory effect of IL-17A on the production of RANKL, M-CSF and OPG; the levels of these productions in cells treated with both IL-17A and celecoxib were similar to that in the controls without IL-17A.
When celecoxib was present in the culture with IL-17 A, it appeared to block the stimulatory effect of IL-17A on the production of IL-1 a, IL-6; the levels of these productions in cells treated with both IL-17A and celecoxib were similar to that in the controls without IL-17A. In contrast, TNF-a was not affected by the addition of celecoxib.
3. The indirect effect of IL-17A on osteoblast-like cells differentiation via osteoblast.
3.1 Indirect effects of IL-17A on TRAP staining of osteoclast-like cells
The multinucleated cell numbers increased after 3 days of culture. In both conditioned medium from IL-17A-treated and untreated cells, the number of TRAP-positive multinucleated cells increased gradually until day 7 of culture, and decreased from day 7 to 10. TRAP staining of osteoclast-like cells in the conditioned medium from IL-17-treated cells on days 5 and 7 of culture was stronger than the conditioned medium from untreated control cells. The number of TRAP-positive multinucleated cells increased significantly in the conditioned medium from IL-17A-treated cells compared to that of the controls on days 5 and 7 of culture, increasing by 1.45-and 1.34-fold, respectively.
3.2 Indirect effects of IL-17A on cathepsin K, MMP-9, and CAⅡmRNA expression
In both conditioned medium from IL-17A-treated and untreated MC3T3-E1 cells, the expression of cathepsin K and MMP-9 increased gradually until day 10 of culture, whereas CA II expression remained unchanged until day 7, eventually increasing on day 10. Cathepsin K expression in the conditioned medium from IL-17A-treated cells increased significantly by 1.50-and 1.40-fold, on days 7 and 10 of culture, respectively, compared with that of the conditioned medium from untreated control cells. In addition, MMP-9 expression in the medium from IL-17A-treated cells increased significantly by 1.31-fold compared to untreated cells on day 10 of culture. CA II expression remained unaffected by IL-17A treatment until day 10 of culture.
3.3 Indirect effects of IL-17A on cathepsin K, MMP-9, and CAⅡprotein expression
When the protein levels of cathepsin K and MMP-9 in the conditioned medium from IL-17A-treated cells were quantified, similar to the data observed from the mRNA analysis, their levels increased by 1.35-and 1.42-fold, respectively, compared with the untreated control cells. CAⅡexpression was again unaffected by indirect IL-17A treatment. Thus, the indirect effects of IL-17A on cathepsin K, MMP-9, and CAⅡmRNA expression levels were correlated with their protein levels in conditioned media.
3.4 Indirect effect of IL-17A and/or celecoxib on TRAP staining of osteoclast-like cells
TRAP staining of osteoclast-like cells in the conditioned medium from IL-17-treated MC3T3-E1 cells was significantly stronger than untreated cells. The addition of celecoxib to the IL-17A conditioned media reduced TRAP staining of osteoclast-like cells to levels identical to the untreated cells. In addition, celecoxib blocked the stimulatory indirect effect of IL-17A on the number of TRAP-positive multinucleated cells.
3.5 Indirect effects of IL-17A and/or celecoxib on cathepsin K and MMP-9 mRNA expression
The mRNA levels of both cathepsin K and MMP-9 in the conditioned medium from MC3T3-E1 cells treated with both IL-17A and celecoxib were similar to those in the controls lacking IL-17A. These data suggest that COX-2 inhibition by celecoxib inhibits the ability of IL-17A to stimulate cathepsin K and MMP-9 expression in the conditioned media.
Conclusion
1. MC3T3-E1 cells express six different IL-17 subtypes and five different IL-17R subtypes at the mRNA level and IL-17A at protein level.
2. Compressive force induces the expression of IL-la,IL-6, IL-17s and IL-17Rs in these cells, which suggests that IL-17s may be involved in the alveolar bone resorption during orthodontic tooth movement.
3. IL-17A increased the mRNA and protein expression of RANKL and M-CSF, decreased expression of OPG in dose-dependent way. IL-17A also stimulates the expression of bone resorption-related inflammatory cytokines. It indicates that IL-17A in vitro regulates bone resorption-related cytokines expression in osteoblast.
4. IL-17A stimulates bone resorption-related cytokines expression through an autocrine mechanism involving celecoxib-blocked PGs by increasing COX-2 expression, mainly PGE2, in osteoblasts.
5. IL-17A stimulates not only the differentiation of RAW264.7 cells into osteoclast-like cells but also the expression of cathepsin K and MMP-9 in osteoclast-like cells. It indicates that IL-17A in vitro indirectly stimulates the differentiation and function of osteoclast-like cells via osteoblasts.
6. IL-17A stimulates osteoclast-like cells differentiation through an autocrine mechanism involving celecoxib-blocked PGs by increasing COX-2 expression, mainly PGE2, in osteoblasts.
7. This study will contrubuteto a better understanding of molecule mechanism of bone remodeling during tooth movement.
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1. Takahashi, N., Udagawa, N., Suda, T. A new member of tumor necrosis factor ligand family, ODF/OPGL/TRANCE/RANKL, regulates osteoclast differentiation and function. Biochem. Biophys. Res. Commun 1999; 256:449-455.
2. Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie M.T, Martin J. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocrin Rev 1999; 20:345-357.
3. Teitelbaum SL. Bone resorption by osteoclast. Sceince 2000; 289:1504-1508.
4. Mizuno A, Amizuka N, Irie K, et al. Severeosteoporosis in mice lacking osteoclasogenesis inhibitory factor osteoprotegerin. Biochem Biophys Res Commun 1998; 247:610-5.
5. Simonet W.S, Lacey D.L, Dunstan C.R, Kelley M, Chang M.-S, Luthy R, Nguyen H.Q, Wooden S, Bennett L, et al. Osteoprotegerin:a novel secreted protein involved in the regulation of bone density. Cell 1997; 89:309-9.
6. Boyce BF, Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys 2008; 15:473:139-46.
7. Matsuo K, Irie N. Osteoclast-osteoblast communication. Arch Biochem Biophys 2008; 473:201-9.
8. Lee KJ, Park YC, Yu HS, Choi SH, Yoo YJ. Effects of continuous and interrupted orthodontic force on interleukin-1β and prostaglandin E2 production in gingival crevicular fluid. Am J Orthod Dentofac Orthop 2004; 125:168-177.
9. Tuncer BB, Ozmerlc N, Tuncer C, Teoman I, Cakilci B, Yucel A, et al. Levels of interleukin-8 during tooth movement. Angle Orthod 2004; 75:631-636.
10. Jager A, Zhang D, Kawarizadeh A, Tolba R, Braumann B, Lossdorfer S, et al. Soluble cytokine receptor treatment in experimental orthodontic tooth movement in the rat. Eur J Orthod 2005;27:1-11.
11. Basaran G, Ozer T, Kaya FA, Hamamci O. Interleukins 2,6, and 8 levels in human gingival sulcus during orthodontic treatment. Am J Orthod Dentofac Orthop 2006;130:7.e1-e6.
12. Bletsa A, Berggreen E, Brudvik P. Interleukin-1α and tumor necrosis factor-a expression during the early phases of orthodontic tooth movement in rats. Eur J Oral Sci 2006;114:423-429.
13. Koyama Y, Mitsui N, Suzuki N, Yanagisawa M, Sanuki R, Isokawa K, et al. Effect of compressive force on the expression of inflammatory cytokines and their receptors in osteoblastic Saos-2 cells. Arch Oral Biol 2008; 53:488-496.
14. Li H, Cuartas E, Cui W, Choi Y, Crawford TD, Ke HZ, Kobayashi KS, Flavell RA, Vignery A. IL-1 receptor-associated kinase M is a central regulator of osteoclast differentiation and activation. J Exp Med 2005; 201:1169-1177.
15. Rossa C, Ehmann K, Liu M, Patil C, Kirkwood KL. MKK3/6-p38 MAPK signaling is required for IL-1 beta and TNF-alpha-induced RANKL expression in bone marrow stromal cells. J Interferon Cytokine Res 2006; 26:719-729.
16. Akaogi J, Nozaki T, Satoh M, Yamada H. Role of PGE2 and EP receptors in the pathogenesis of rheumatoid arthritis and as a novel therapeutic strategy. Endocr Metab Immune Disord Drug Targets.2006; 6:383-394.
17. Ishimi Y, Miyaura C, Jin CH, Akatsu T, Abe E, Nakamura Y, et al. IL-6 is produced by osteoblasts and induces bone resorption. J Immunol 1990; 145: 3297-3303.
18. Rozen N, Ish-Shalom S, Rachmiel A, Stein H, Lewinson D. Interleukin-6 modulates trabecular and endochondral bone turnover in the nude mouse by stimulating osteoclast differentiation. Bone 2000; 26:469-74.
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