养阴清络法对类风湿关节炎骨质破坏的干预作用及机制研究
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摘要
1背景与目的
骨质破坏是类风湿关节炎(Rheumatoid arthritis, RA)的重要病理改变,至今没有特别有效的治疗药物,中医药治疗具有一定的优势。“阴虚络热”是关于RA的重要病机理论,养阴清络治法和清络通痹方(Qingluo-Tongbi formula, QLT)是针对阴虚络热证制定的有效治法和方药。本课题旨在研究养阴清络治法和清络通痹方对RA骨质破坏的干预作用与机制。
2内容与方法
首先通过理论研究探讨RA骨质破坏的发病机制和中医病机,为实验研究工作假说的提出奠定基础；继而按工作假说制定技术路线,设计实验。查阅南京中医药大学图书馆藏书,并在中国知网(CNKI)检索中文文献,在美国斯坦福大学图书馆网站Highwire Press和Pubmed以及馆际互借系统检索研究英文文献；侍诊导师和名老中医,研读其医案,发掘其经验与思想,进行理论研究。
在实验研究中,清络通痹方设大、中、小三个剂量组,对照组选雷公藤多苷(TⅡ)为对照药物,加上模型组和正常对照组有6组。具体实验包括：建立Ⅱ型胶原诱导关节炎(CIA)大鼠模型,光学显微镜观察药物对关节组织病理的影响；采用小鼠胸腺细胞增殖法和ELISA法分别检测药物对CIA大鼠腹腔巨噬细胞(MΦ)分泌IL-1和TNF-α的影响；临床选择处于活动期并符合阴虚络热证的RA患者,抽取外周静脉血,加入含药血清培养,流式细胞术检测T淋巴细胞RANKL的表达;临床获取行关节置换术RA患者的关节滑膜,传代培养成纤维样滑膜细胞(FLS),加入含药血清培养,MTT法检测含药血清对FLS增殖的影响,RT-PCR检测RANKL mRNA的表达；SD大鼠四肢长骨骨髓腔分离骨髓细胞,采用M-CSF+RANKL诱生破骨细胞样细胞(OLC), TRAP染色鉴定,加入含药血清培养,MTT法检测含药血清对OLC活性的影响,TRAP试剂盒检测含药血清对OLC TRAP活力的影响,光学显微镜观察含药血清对OLC在牙质表面形成吸收点窝能力的影响。
3结果
理论研究综述了RA骨质破坏的治疗研究进展,明确IL-1、TNF-α等炎症因子以及RANKL/RANK系统和破骨细胞在RA骨质破坏中的关键作用。论述阴虚络热系RA属热痹者骨质破坏的重要病机形式,治法宜取养阴清络,选方宜用清络通痹方。
实验研究建立了CIA大鼠模型,分组给药后,正常对照组未出现明显的关节滑膜炎症及骨质破坏等病理现象,而模型组大鼠关节滑膜及邻近软组织发生了明显的炎症反应和关节软骨局部变性坏死,TⅡ和QLT三个剂量组关节病变显著减轻。模型组大鼠腹腔MΦ的IL-1和TNF-α分泌水平明显高于正常对照组,TⅡ和QLT给药均可以抑制CIA大鼠腹腔MΦ的IL-1和TNF-α分泌水平。活动期RA患者外周血加入PHA,体外培养72小时,T淋巴细胞的RANKL表达率为14.933±7.00%,添加各组含药血清后的表达率依次为TⅡ组6.17±3.30%、QLT小剂量组11.62±4.28%、QLT中剂量组8.79±4.08%、QLT大剂量组6.47±3.16%。加入大剂量QLT和TⅡ的动物含药血清培养FLS 72小时后,FLS增殖受到了明显的抑制,RT-PCR实验显示其RANKL mRNA电泳条带比正常对照组显著减弱。SD大鼠骨髓细胞加入M-CSF和RANKL诱导后,经显微镜观察和TRAP染色鉴定符合OLC特征,TⅡ和QLT大、中、小三个剂量组含药血清均可抑制其增殖,TⅡ和QLT中剂量与大剂量组含药血清可降低OLC的TRAP活力,减少OLC所致骨吸收陷窝面积。
4结论
养阴清络治法及清络通痹方可以抑制RA炎症反应,下调IL-1、TNF-α和RANKL等细胞因子的表达水平,降低破骨细胞活性与异常增殖,阻止骨质破坏。抑制RANKL过度表达,阻止RANKL与RANK的结合,降低破骨细胞的活性与异常增殖可能是养阴清络治法及清络通痹方干预RA骨质破坏的重要机制。
1 Background and objective
Bone destruction is an important pathological process of rheumatoid arthritis (RA) that no special therapeutic drugs to treat with and treatment of traditional Chinese medicine (TCM) demonstrates favorable as well as potential effects to it. Yin-deficiency-and-Luo-heat is a leading theory to explain the pathogenesy with TCM and Nourish-Yin-and-Clear-Luo treatment rule as well as Qingluo-Tongbi formula (QLT) is effective to the symptoms related. The object of this study is to explore the effects and mechanism of treatment to bone destruction induced by RA with nourish-Yin-and-clear-Luo rule as well as QLT.
2 Items and methods
Look up to the books reserved by the library of Nanjing University of Chinese Medicine and retrieve the digital documents reserved by CNKI through Internet as for Chinese culture; meanwhile, as for English culture, digital documents reserved by Highwire Press of Stanford University and Pubmed are retrieved through Internet, furthermore, some documents are gotten from China Academic Library & Information System. In order to study TCM theory further, following the Supervisor and famous TCM doctors in clinical practices are performed.
Three dose levels including small, medium and large of QLT are set up and ripterygium wilfordii polyglycosidium (TⅡ) is used as the positive control, in addition to model group and normal control, there are 6 groups involved in the experiments. II-type collagen induced arthritis (CIA) rats model are applied and tissue slides of their joints are observed under microscope to detect the effects of drugs on histological changes. Effects of drugs on TNF-αlevel secreted by peritoneal macrophage (MΦ) of rat models are tested by ELISA and IL-1 level by hymocyte proliferation method as well as MTT. Patients who are in the active stage of RA and have Yin-deficincy-and-Luo-heat symptoms are selected and their peripherial bloods are extracted as well as treated with serum containing drugs, then expressions of RANKL are tested with flow cytometry as per direction. Joint synovial membrane tissues are obtained from the patients who subjected to joint replace practices and fiber-forming synovial cells (FLS) are separated and cultured, then serum containing drugs to treat them and examine the FLS proliferation with MTT and expression of RANKL mRNA with RT-PCR respectively. Myelomonocytes from limb bones of SD rats are separated and osteoclast-like cells (OLC) are produced through stimulation with M-CSF as well as RANKL. OLCs are identified with TRAP staining, scrum containing drugs are added to treat with, then activity of OLCs is examined by MTT and TRAP reagent kit, moreover, ability of cells to make point pits on bone are examined to detect the effects of drugs.
3 Results
Advances in treatment research of bone destruction induced by RA were reviewed and key roles of inflammatory factors including IL-1, TNF-αand RANKL/RANK system as well as osteclasts playing in bone destruction had been surveyed. The importance of pathogenesis of Yin-deficiency-and-Luo-heat to RA patients who could be diagnosed as heat-type had been described, meanwhile, the viewpoints that the treatment rule should be applied as nourish-Yin-and-clear-Luo as well as QLT is an effective formula to this symptoms had been discussed.
The joint synovium of rats in normal control group had no symptoms related to inflammation or evidence of bone destruction observed, however obvious inflammatory symptoms were observed in the joints, and articular cartilage erosion as well as focal necrosis was observed in the model group. The inflammatory symptoms of rats treated with TⅡor QLT were inhibited obviously. Comparing with the normal control group, IL-1 secreted by pMΦof model group was higher significantly, and TⅡas well as QLT suppressed the secretion. T lymphocytes within peripherial blood extracted from patients in active stage of RA after stimulation of PHA and being cultured, the RANKL expression of the normal control was 14.933±7.00%, under the treatment with serum containing drugs, expressions of RANKL of each groups were TⅡ:6.41±2.56%, QLT small dose:11.62±4.28%, medium dose: 8.79±4.08%, large dose:6.47±3.16%, respectively. Meanwhile, serum containing drugs demonstrated function to inhibit RANKL expression of synovium fiber-forming cells similarly. Myelomonocytes obtained from rat limb bone cavities after being induced by M-CSF as well as RANKL were found to grow as OLC. And serum containing drugs including TⅡor QLT were able to put down the activity and the energy of OLC to make point pits in the surface of bones.
4 Conclusion
Nourish-Yin-and-Clear-Luo treatment rule as well as QLT demonstrates effects to inhibit the inflammatory reaction of RA, to suppress the expression of cell factors related to bone destruction such as IL-1, TNF-αand RANKL, to depress the activity of osteoclasts and block the development of bone destruction induced by RA. The mechanism that the treatment rule as well as QLT to cure the bone destruction induced by RA may be defined as the inhibition to deregulation of RANKL expression, blockade to the combination between RANKL and RANK and depression to the activity as well as proliferation of osteoclats.
骨质破坏是类风湿关节炎(Rheumatoid arthritis, RA)的重要病理改变,至今没有特别有效的治疗药物,中医药治疗具有一定的优势。“阴虚络热”是关于RA的重要病机理论,养阴清络治法和清络通痹方(Qingluo-Tongbi formula, QLT)是针对阴虚络热证制定的有效治法和方药。本课题旨在研究养阴清络治法和清络通痹方对RA骨质破坏的干预作用与机制。
2内容与方法
首先通过理论研究探讨RA骨质破坏的发病机制和中医病机,为实验研究工作假说的提出奠定基础；继而按工作假说制定技术路线,设计实验。查阅南京中医药大学图书馆藏书,并在中国知网(CNKI)检索中文文献,在美国斯坦福大学图书馆网站Highwire Press和Pubmed以及馆际互借系统检索研究英文文献；侍诊导师和名老中医,研读其医案,发掘其经验与思想,进行理论研究。
在实验研究中,清络通痹方设大、中、小三个剂量组,对照组选雷公藤多苷(TⅡ)为对照药物,加上模型组和正常对照组有6组。具体实验包括：建立Ⅱ型胶原诱导关节炎(CIA)大鼠模型,光学显微镜观察药物对关节组织病理的影响；采用小鼠胸腺细胞增殖法和ELISA法分别检测药物对CIA大鼠腹腔巨噬细胞(MΦ)分泌IL-1和TNF-α的影响；临床选择处于活动期并符合阴虚络热证的RA患者,抽取外周静脉血,加入含药血清培养,流式细胞术检测T淋巴细胞RANKL的表达;临床获取行关节置换术RA患者的关节滑膜,传代培养成纤维样滑膜细胞(FLS),加入含药血清培养,MTT法检测含药血清对FLS增殖的影响,RT-PCR检测RANKL mRNA的表达；SD大鼠四肢长骨骨髓腔分离骨髓细胞,采用M-CSF+RANKL诱生破骨细胞样细胞(OLC), TRAP染色鉴定,加入含药血清培养,MTT法检测含药血清对OLC活性的影响,TRAP试剂盒检测含药血清对OLC TRAP活力的影响,光学显微镜观察含药血清对OLC在牙质表面形成吸收点窝能力的影响。
3结果
理论研究综述了RA骨质破坏的治疗研究进展,明确IL-1、TNF-α等炎症因子以及RANKL/RANK系统和破骨细胞在RA骨质破坏中的关键作用。论述阴虚络热系RA属热痹者骨质破坏的重要病机形式,治法宜取养阴清络,选方宜用清络通痹方。
实验研究建立了CIA大鼠模型,分组给药后,正常对照组未出现明显的关节滑膜炎症及骨质破坏等病理现象,而模型组大鼠关节滑膜及邻近软组织发生了明显的炎症反应和关节软骨局部变性坏死,TⅡ和QLT三个剂量组关节病变显著减轻。模型组大鼠腹腔MΦ的IL-1和TNF-α分泌水平明显高于正常对照组,TⅡ和QLT给药均可以抑制CIA大鼠腹腔MΦ的IL-1和TNF-α分泌水平。活动期RA患者外周血加入PHA,体外培养72小时,T淋巴细胞的RANKL表达率为14.933±7.00%,添加各组含药血清后的表达率依次为TⅡ组6.17±3.30%、QLT小剂量组11.62±4.28%、QLT中剂量组8.79±4.08%、QLT大剂量组6.47±3.16%。加入大剂量QLT和TⅡ的动物含药血清培养FLS 72小时后,FLS增殖受到了明显的抑制,RT-PCR实验显示其RANKL mRNA电泳条带比正常对照组显著减弱。SD大鼠骨髓细胞加入M-CSF和RANKL诱导后,经显微镜观察和TRAP染色鉴定符合OLC特征,TⅡ和QLT大、中、小三个剂量组含药血清均可抑制其增殖,TⅡ和QLT中剂量与大剂量组含药血清可降低OLC的TRAP活力,减少OLC所致骨吸收陷窝面积。
4结论
养阴清络治法及清络通痹方可以抑制RA炎症反应,下调IL-1、TNF-α和RANKL等细胞因子的表达水平,降低破骨细胞活性与异常增殖,阻止骨质破坏。抑制RANKL过度表达,阻止RANKL与RANK的结合,降低破骨细胞的活性与异常增殖可能是养阴清络治法及清络通痹方干预RA骨质破坏的重要机制。
1 Background and objective
Bone destruction is an important pathological process of rheumatoid arthritis (RA) that no special therapeutic drugs to treat with and treatment of traditional Chinese medicine (TCM) demonstrates favorable as well as potential effects to it. Yin-deficiency-and-Luo-heat is a leading theory to explain the pathogenesy with TCM and Nourish-Yin-and-Clear-Luo treatment rule as well as Qingluo-Tongbi formula (QLT) is effective to the symptoms related. The object of this study is to explore the effects and mechanism of treatment to bone destruction induced by RA with nourish-Yin-and-clear-Luo rule as well as QLT.
2 Items and methods
Look up to the books reserved by the library of Nanjing University of Chinese Medicine and retrieve the digital documents reserved by CNKI through Internet as for Chinese culture; meanwhile, as for English culture, digital documents reserved by Highwire Press of Stanford University and Pubmed are retrieved through Internet, furthermore, some documents are gotten from China Academic Library & Information System. In order to study TCM theory further, following the Supervisor and famous TCM doctors in clinical practices are performed.
Three dose levels including small, medium and large of QLT are set up and ripterygium wilfordii polyglycosidium (TⅡ) is used as the positive control, in addition to model group and normal control, there are 6 groups involved in the experiments. II-type collagen induced arthritis (CIA) rats model are applied and tissue slides of their joints are observed under microscope to detect the effects of drugs on histological changes. Effects of drugs on TNF-αlevel secreted by peritoneal macrophage (MΦ) of rat models are tested by ELISA and IL-1 level by hymocyte proliferation method as well as MTT. Patients who are in the active stage of RA and have Yin-deficincy-and-Luo-heat symptoms are selected and their peripherial bloods are extracted as well as treated with serum containing drugs, then expressions of RANKL are tested with flow cytometry as per direction. Joint synovial membrane tissues are obtained from the patients who subjected to joint replace practices and fiber-forming synovial cells (FLS) are separated and cultured, then serum containing drugs to treat them and examine the FLS proliferation with MTT and expression of RANKL mRNA with RT-PCR respectively. Myelomonocytes from limb bones of SD rats are separated and osteoclast-like cells (OLC) are produced through stimulation with M-CSF as well as RANKL. OLCs are identified with TRAP staining, scrum containing drugs are added to treat with, then activity of OLCs is examined by MTT and TRAP reagent kit, moreover, ability of cells to make point pits on bone are examined to detect the effects of drugs.
3 Results
Advances in treatment research of bone destruction induced by RA were reviewed and key roles of inflammatory factors including IL-1, TNF-αand RANKL/RANK system as well as osteclasts playing in bone destruction had been surveyed. The importance of pathogenesis of Yin-deficiency-and-Luo-heat to RA patients who could be diagnosed as heat-type had been described, meanwhile, the viewpoints that the treatment rule should be applied as nourish-Yin-and-clear-Luo as well as QLT is an effective formula to this symptoms had been discussed.
The joint synovium of rats in normal control group had no symptoms related to inflammation or evidence of bone destruction observed, however obvious inflammatory symptoms were observed in the joints, and articular cartilage erosion as well as focal necrosis was observed in the model group. The inflammatory symptoms of rats treated with TⅡor QLT were inhibited obviously. Comparing with the normal control group, IL-1 secreted by pMΦof model group was higher significantly, and TⅡas well as QLT suppressed the secretion. T lymphocytes within peripherial blood extracted from patients in active stage of RA after stimulation of PHA and being cultured, the RANKL expression of the normal control was 14.933±7.00%, under the treatment with serum containing drugs, expressions of RANKL of each groups were TⅡ:6.41±2.56%, QLT small dose:11.62±4.28%, medium dose: 8.79±4.08%, large dose:6.47±3.16%, respectively. Meanwhile, serum containing drugs demonstrated function to inhibit RANKL expression of synovium fiber-forming cells similarly. Myelomonocytes obtained from rat limb bone cavities after being induced by M-CSF as well as RANKL were found to grow as OLC. And serum containing drugs including TⅡor QLT were able to put down the activity and the energy of OLC to make point pits in the surface of bones.
4 Conclusion
Nourish-Yin-and-Clear-Luo treatment rule as well as QLT demonstrates effects to inhibit the inflammatory reaction of RA, to suppress the expression of cell factors related to bone destruction such as IL-1, TNF-αand RANKL, to depress the activity of osteoclasts and block the development of bone destruction induced by RA. The mechanism that the treatment rule as well as QLT to cure the bone destruction induced by RA may be defined as the inhibition to deregulation of RANKL expression, blockade to the combination between RANKL and RANK and depression to the activity as well as proliferation of osteoclats.
引文
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