艾灸对膝骨性关节炎的防治作用及其机理的实验研究
|
摘要
目的
艾灸作为中医的外治法之一,具有操作简便,无痛苦、疗效明显的优点,在临床上治疗膝关节骨性关节炎(osteoarthritis,OA)有较好的疗效,是极具特色的中医治未病疗法之一。但是艾灸治疗膝0A的作用机理仍不十分明确,尤其是对0A的预防作用研究尚未见报道。
因此,本课题在现代科学的方法论指导下,利用现代医学先进的实验技术方法,采用膝关节改良伸直位固定法建立兔膝0A模型,运用艾灸对正在进行造模的兔施以温和灸治,在造模8周后,对软骨标本行组织形态学观察,检测关节液中白细胞介素-1β(IL-1β)和肿瘤坏死因子·-α(TNF-α)的含量,测定软骨细胞凋亡率,观察软骨细胞Bc1-2、Bax和P53蛋白表达,检测关节软骨中Bc 1-2和Fas的mRNA表达,从组织、细胞、分子等不同层面,探讨艾灸对兔膝0A的防治作用和机理,为临床艾灸防治0A提供实验依据。
方法
40只日本大耳白兔,随机分成4组，每组10只：艾灸组(A组)、几丁糖组(B组)、模型组(C组)和正常组(D组)。A、B、C组均用改良伸直位固定法建立膝0A模型,A、B组在造模后立即进行干预,‘A组选取关元、足三里、血海、内外膝眼、阳陵泉等腧穴,用艾条温和灸治，每天1次,每次每穴10min；B组用医用几丁糖(20mg/ml)予以膝关节注射,0.2ml/次,每周1次；C组不做治疗,D组正常饲养，不做任何处理。造模8周后,各组分别从影像学、肉眼、光镜下、透射电镜(TEM)下观察兔膝关节组织形态学情况,并用Mankin评分比较各组膝关节软骨的组织形态学改变；用酶联免疫吸附测定法(ELISA)检测各组关节液中IL-1β和TNF-α的含量；TdT介导的脱氧三磷酸尿苷缺口末端标记法(TUNEL)检测各组软骨细胞凋亡指数(AI)；免疫组织化学法(I HC)观察Bc 1-2、Bax、P53蛋白表达情况；荧光实时定量PCR法(Real-Time PCR)检测各组关节软骨中Bc1-2和Fas的mRNA表达情况。
结果
1.X片观察：A、B组关节间隙正常,未见骨赘生成,C组可见膝关节间隙狭窄,局部有骨赘形成；大体肉眼观察：A、B组关节软骨表面光滑,无软骨缺损,C组关节囊明显增厚,关节软骨呈灰黄色,局部出现溃疡；光镜观察：A组软骨表面光滑,深层细胞排列规律,番红0染色轻度减弱,潮线完整,C组软骨产生裂隙,深达辐射区,深层细胞数目异常,番红0染色中、重度减弱,潮线模糊；Mankin评分：A、B组评分均明显较C组低(P<0.01),A组评分稍低于B组(P>0.05)；电镜观察：A组软骨细胞超微结构接近D组,C组软骨细胞轮廓不清楚,胞膜坏死崩解,胞浆内细胞器消失,细胞裂解为致密颗粒样物质,细胞固缩、变形,甚至出现核分裂,染色质浓聚。
2.A、B组IL-1β和TNF-α含量均明显低于C组(P<0.01)；A组IL-1β含量和TNF-α含量比B组稍低(P>0.05)。
3.A、B组凋亡阳性细胞较少,散在分布于关节软骨浅表区,C组凋亡阳性细胞较多,出现在关节软骨中深层。A、B组凋亡指数明显低于C组(P<0.01)；A组凋亡指数较B组低(P<0.05)。
4.Bc 1-2表达阳性细胞率：A、B组高于C组(P<0.05),A组稍高于B组(P>0.05)；Bax表达阳性细胞率：A、B组明显低于C组(P<0.05),A组低于B组(P<0.05)；Bc1-2/Bax：A组高于B、C、D组(P<0.05)。
P53表达阳性细胞率：A、B组明显低于C组(P<0.01),A组比B组稍低(P>0.05)。
5.Bcl-2 mRNA的相对表达量：A、B、C组分别为D组的1.38±0.96倍、1.27±1.15倍、1.08±0.89倍,A、B组和C组Bc卜2的mRNA表达差别均有非常显著意义(P<0.01),A组和B组差别无显著意义(P>0.05)；Fas mRNA的相对表达量,A、B、C组分别为D组的0.27±0.07倍、0.31±1.13倍、2.32±1.35倍,A、B组和C组Fa s的mRNA表达差别均有非常显著意义(P<0.01),A组和B组差别无显著意义(P>0.05)。
结论
1.用改良伸直位固定法造模8周,可成功建立兔膝0A模型。
2.艾灸关元、血海、内外膝眼、足三里和阳陵泉等腧穴,能防治兔膝0A。
3.艾灸可降低关节液中IL-1β和TNF-α含量,上调Bcl-2 mRNA表达,下调Fas mRNA表达,促进Bc 1-2蛋白表达,抑制Bax和P53蛋白表达,防止软骨基质降解和抑制软骨细胞过度凋亡,从而达到防治兔膝0A的效果。
4.几丁糖可保护关节软骨防治兔膝0A。
Objective
As one of. the effective external treatment in Traditional Chinese Medcine(TCM), Moxibust ion (Mox) has advantages of the simple operation, painlessness and significantly curative effect, there was evidence that Mox shows definite clinical effectiveness in the treatment of osteoarthritis (OA)of the knee, so it is one of the distinctive Traditional Chinese Medicine therapy of preventive treatment of disease.However, the mechanisms of the therapeutic effect of Mox on knee OA are not very well understood, and there are few reports about the protective effect of Mox.
Guided the methodology of the modern system scientific and advanced experimental techniques of modern medicine made use of, the model of rabbit's knee OA was established with modified with immobilized in extension position, ongoing modeling of the rabbits were imposed mild Mox for 8 weeks, the articular cartilage of knee was harvested for observed in histology and morphology, Interleukin-1β(IL-1β), Tumour necrosis factor-α(TNF-α), apoptosis rate of chondrocyte, expression of Bcl-2, Bax, p53 protein and Bcl-2, Fas messenger RNA (mRNA), therapeutic and protective effect of Mox on OA of rabbits and its mechanisms were observed in different levels of tissues, cells and molecules, in order to provide evidences of Mox on OA of the knee in clinic.
Methods
40 healthy Japanese White Rabbits were randmonly divided into 4 groups,10 for each group:group A, group B, group C, group D. The left hind limb of animals in group A, B, C were immobilized with plaster cast in extension position, animals in group A were treated with Mox applied on Guanyuan(CV 4), Zusanli (ST 36), Xuehai (SP 10),Neixiyan(EX-LE4),Dubi(ST 35) and Yanglingquan(GB 34) (each acupoint for 10 min once a day), animals in group B were treated with chitosan(20mg/ml,0.2ml per inject, once a week) and in group C with nothing,animals in group D were used for normal control. After 8 weeks, morphological and histological changes of each group were evaluated through X-ray photographic, naked eye, optical microscope, transmission electron microscopic(TEM) and Mankin's core by examination the change of cartilage in histology and morphology, the concentrations of IL-1βand TNF-αin joint synovial fluid were detected by ELISA, the apoptosis was detected by the terminal deoxnucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, the expressions of Bcl-2,Bax,p53 protein and Bcl-2,Fas mRNA of chondrocytes were detected by Immunohistochemical (IHC) and Real-Time PCR.
Results
1. X-ray:femorotibial joint space width of group A and B was normal, and no osteophytes were found, femorotibial joint space width of group C became obvious narrowed with osteophytes. Observation under naked eyes:the articular surface of group A and B was smooth and intact,but the joints of group C exhibited from oedema to cartilage ulceration and joint capsule fibrosis. Observation under the light microscope:in the group A, the articular surface was smooth and glossy with intact cells,the tidemark was integrity intact, the articular of group C became rough surface with clefts to radial zone, cloned cells and the tidemark crossed by blood vessels. Mankin score:the scores in group A and B were lower than in group C respectively(P<0.01), the scores in group A were not significantly different from in group B(P>0.05). Observation under TEM:the ultrastructure of chondrocytes in group A was similar to in group D,the membranes and nuclear membranes of chondrocytes in group A were intact with some microvilli on the surface of chondrocytes. membranes of chondrocytes in group C were incomplete with several fractures and the cells appeared to leak contents, vacuoles were also seen under the nuclear membrane with bare nuclei, changes were observed with irregular nuclei, prominent vacuoles were observed in early apoptotic cells, obliterated the cytoplasm and its organelle.
2. The concentrations of IL-1βand TNF-αin joint synovial fluid were, determined using ELISA. The concentrations of IL-1βand TNF-a in group A and group B were lower than in group C respectively (P<0.01), the concentrations of IL-1βand TNF-αin group A were not significantly different from in group B (P>0.05).
3. To localize the apoptotic cell death within the cartilage, we stained formalin-fixed, paraffin-embedded cartilage sections by using TUNEL assay, TUNEL staining labels fragmented DNA that was localized in the nucleus.A few of scattered TUNEL-positive cells in group A and group B was detected in the superficial zone of the articular cartilage,lots of TUNEL-positive cells in group C was detected from the superficial zone to the deep zone.
We quantified apoptotic cell death rate using Apoptosis index (AI). AI for chondrocytes in group A and group B was lower than in group C respectively (P<0.01), AI for chondrocytes in group A was not significantly different from in group B (P>0.05).
4. IHC analysis showed the expression of Bcl-2, Bax, p53 protein in articular cartilage.The rate of Bcl-2-positive cells in group A and group B was higher than in group C respectively(P<0.05), the rate of Bcl-2-positive cells in group A was not significantly different from in group B(P>0.05). The rate of Bax-positive cells in group A and group B was lower than in group C respectively (P<0.05), the rate of Bax-positive cells in group A was significantly different from in group B(P<0.05). Bcl-2-positive cells/Bax-positive cells in group A was higher than in group B, C, D (P<0.05).
The rate of P53-positive cells in group A and group B was lower than in group C respectively (P<0.01), the rate of P53-positive cells in group A was not significantly different from in group B (P>0.05).
5. The levels of Bcl-2,Fas mRNA were quantified using by Real-Time PCR. The levels of Bcl-2 mRNA in group A, B, C were 1.38±0.96 fold、1.27±1.15 fold、1.08±0.89 fold, compared with in group D respectively. The levels of Bcl-2 mRNA in group A, B were significantly different from in group C respectively (P<0.01), the levels of Bcl-2 mRNA in group A was not significantly different from in group B respectively (P>0.05).
The levels of Fas mRNA in group A, B, C were 0.27±0.07 fold、0.31±1.13 fold、2.32±1.35 fold, compared with in group D respectively. the levels of Fas mRNA in group A, Bwere significantly different from in group C respectively (P<0.01), the levels of Fas mRNA in group A was not significantly different from in group B respectively (P>0.05).
Conclusions
1. The model of rabbit's knee OA can be successful established with modified with immobilized in extension position for 8 weeks.
2.Mox on Guanyuan (CV 4), Zusanli (ST 36), Xuehai (SP 10),Neixiyan (EX-LE4),Dubi(ST 35)and Yanglingquan(GB 34) show some effectiveness in the treatment of OA of the rabbit'knee.
3.Mox can decrease the joint synovial fluid contents of IL-1βand TNF-α, up-regulate the mRNA and protein expression of Bcl-2 as well as down-regulate the protein expression of Bax,P53 and the mRNA expression of Fas,thereby to inhibit the apoptosis of cartilage cells and delay the degeneration of articular cartilage changes.
4.Chitosan can inhibit the apoptosis of cartilage cells and delay the degeneration of articular cartilage changes.
艾灸作为中医的外治法之一,具有操作简便,无痛苦、疗效明显的优点,在临床上治疗膝关节骨性关节炎(osteoarthritis,OA)有较好的疗效,是极具特色的中医治未病疗法之一。但是艾灸治疗膝0A的作用机理仍不十分明确,尤其是对0A的预防作用研究尚未见报道。
因此,本课题在现代科学的方法论指导下,利用现代医学先进的实验技术方法,采用膝关节改良伸直位固定法建立兔膝0A模型,运用艾灸对正在进行造模的兔施以温和灸治,在造模8周后,对软骨标本行组织形态学观察,检测关节液中白细胞介素-1β(IL-1β)和肿瘤坏死因子·-α(TNF-α)的含量,测定软骨细胞凋亡率,观察软骨细胞Bc1-2、Bax和P53蛋白表达,检测关节软骨中Bc 1-2和Fas的mRNA表达,从组织、细胞、分子等不同层面,探讨艾灸对兔膝0A的防治作用和机理,为临床艾灸防治0A提供实验依据。
方法
40只日本大耳白兔,随机分成4组，每组10只：艾灸组(A组)、几丁糖组(B组)、模型组(C组)和正常组(D组)。A、B、C组均用改良伸直位固定法建立膝0A模型,A、B组在造模后立即进行干预,‘A组选取关元、足三里、血海、内外膝眼、阳陵泉等腧穴,用艾条温和灸治，每天1次,每次每穴10min；B组用医用几丁糖(20mg/ml)予以膝关节注射,0.2ml/次,每周1次；C组不做治疗,D组正常饲养，不做任何处理。造模8周后,各组分别从影像学、肉眼、光镜下、透射电镜(TEM)下观察兔膝关节组织形态学情况,并用Mankin评分比较各组膝关节软骨的组织形态学改变；用酶联免疫吸附测定法(ELISA)检测各组关节液中IL-1β和TNF-α的含量；TdT介导的脱氧三磷酸尿苷缺口末端标记法(TUNEL)检测各组软骨细胞凋亡指数(AI)；免疫组织化学法(I HC)观察Bc 1-2、Bax、P53蛋白表达情况；荧光实时定量PCR法(Real-Time PCR)检测各组关节软骨中Bc1-2和Fas的mRNA表达情况。
结果
1.X片观察：A、B组关节间隙正常,未见骨赘生成,C组可见膝关节间隙狭窄,局部有骨赘形成；大体肉眼观察：A、B组关节软骨表面光滑,无软骨缺损,C组关节囊明显增厚,关节软骨呈灰黄色,局部出现溃疡；光镜观察：A组软骨表面光滑,深层细胞排列规律,番红0染色轻度减弱,潮线完整,C组软骨产生裂隙,深达辐射区,深层细胞数目异常,番红0染色中、重度减弱,潮线模糊；Mankin评分：A、B组评分均明显较C组低(P<0.01),A组评分稍低于B组(P>0.05)；电镜观察：A组软骨细胞超微结构接近D组,C组软骨细胞轮廓不清楚,胞膜坏死崩解,胞浆内细胞器消失,细胞裂解为致密颗粒样物质,细胞固缩、变形,甚至出现核分裂,染色质浓聚。
2.A、B组IL-1β和TNF-α含量均明显低于C组(P<0.01)；A组IL-1β含量和TNF-α含量比B组稍低(P>0.05)。
3.A、B组凋亡阳性细胞较少,散在分布于关节软骨浅表区,C组凋亡阳性细胞较多,出现在关节软骨中深层。A、B组凋亡指数明显低于C组(P<0.01)；A组凋亡指数较B组低(P<0.05)。
4.Bc 1-2表达阳性细胞率：A、B组高于C组(P<0.05),A组稍高于B组(P>0.05)；Bax表达阳性细胞率：A、B组明显低于C组(P<0.05),A组低于B组(P<0.05)；Bc1-2/Bax：A组高于B、C、D组(P<0.05)。
P53表达阳性细胞率：A、B组明显低于C组(P<0.01),A组比B组稍低(P>0.05)。
5.Bcl-2 mRNA的相对表达量：A、B、C组分别为D组的1.38±0.96倍、1.27±1.15倍、1.08±0.89倍,A、B组和C组Bc卜2的mRNA表达差别均有非常显著意义(P<0.01),A组和B组差别无显著意义(P>0.05)；Fas mRNA的相对表达量,A、B、C组分别为D组的0.27±0.07倍、0.31±1.13倍、2.32±1.35倍,A、B组和C组Fa s的mRNA表达差别均有非常显著意义(P<0.01),A组和B组差别无显著意义(P>0.05)。
结论
1.用改良伸直位固定法造模8周,可成功建立兔膝0A模型。
2.艾灸关元、血海、内外膝眼、足三里和阳陵泉等腧穴,能防治兔膝0A。
3.艾灸可降低关节液中IL-1β和TNF-α含量,上调Bcl-2 mRNA表达,下调Fas mRNA表达,促进Bc 1-2蛋白表达,抑制Bax和P53蛋白表达,防止软骨基质降解和抑制软骨细胞过度凋亡,从而达到防治兔膝0A的效果。
4.几丁糖可保护关节软骨防治兔膝0A。
Objective
As one of. the effective external treatment in Traditional Chinese Medcine(TCM), Moxibust ion (Mox) has advantages of the simple operation, painlessness and significantly curative effect, there was evidence that Mox shows definite clinical effectiveness in the treatment of osteoarthritis (OA)of the knee, so it is one of the distinctive Traditional Chinese Medicine therapy of preventive treatment of disease.However, the mechanisms of the therapeutic effect of Mox on knee OA are not very well understood, and there are few reports about the protective effect of Mox.
Guided the methodology of the modern system scientific and advanced experimental techniques of modern medicine made use of, the model of rabbit's knee OA was established with modified with immobilized in extension position, ongoing modeling of the rabbits were imposed mild Mox for 8 weeks, the articular cartilage of knee was harvested for observed in histology and morphology, Interleukin-1β(IL-1β), Tumour necrosis factor-α(TNF-α), apoptosis rate of chondrocyte, expression of Bcl-2, Bax, p53 protein and Bcl-2, Fas messenger RNA (mRNA), therapeutic and protective effect of Mox on OA of rabbits and its mechanisms were observed in different levels of tissues, cells and molecules, in order to provide evidences of Mox on OA of the knee in clinic.
Methods
40 healthy Japanese White Rabbits were randmonly divided into 4 groups,10 for each group:group A, group B, group C, group D. The left hind limb of animals in group A, B, C were immobilized with plaster cast in extension position, animals in group A were treated with Mox applied on Guanyuan(CV 4), Zusanli (ST 36), Xuehai (SP 10),Neixiyan(EX-LE4),Dubi(ST 35) and Yanglingquan(GB 34) (each acupoint for 10 min once a day), animals in group B were treated with chitosan(20mg/ml,0.2ml per inject, once a week) and in group C with nothing,animals in group D were used for normal control. After 8 weeks, morphological and histological changes of each group were evaluated through X-ray photographic, naked eye, optical microscope, transmission electron microscopic(TEM) and Mankin's core by examination the change of cartilage in histology and morphology, the concentrations of IL-1βand TNF-αin joint synovial fluid were detected by ELISA, the apoptosis was detected by the terminal deoxnucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, the expressions of Bcl-2,Bax,p53 protein and Bcl-2,Fas mRNA of chondrocytes were detected by Immunohistochemical (IHC) and Real-Time PCR.
Results
1. X-ray:femorotibial joint space width of group A and B was normal, and no osteophytes were found, femorotibial joint space width of group C became obvious narrowed with osteophytes. Observation under naked eyes:the articular surface of group A and B was smooth and intact,but the joints of group C exhibited from oedema to cartilage ulceration and joint capsule fibrosis. Observation under the light microscope:in the group A, the articular surface was smooth and glossy with intact cells,the tidemark was integrity intact, the articular of group C became rough surface with clefts to radial zone, cloned cells and the tidemark crossed by blood vessels. Mankin score:the scores in group A and B were lower than in group C respectively(P<0.01), the scores in group A were not significantly different from in group B(P>0.05). Observation under TEM:the ultrastructure of chondrocytes in group A was similar to in group D,the membranes and nuclear membranes of chondrocytes in group A were intact with some microvilli on the surface of chondrocytes. membranes of chondrocytes in group C were incomplete with several fractures and the cells appeared to leak contents, vacuoles were also seen under the nuclear membrane with bare nuclei, changes were observed with irregular nuclei, prominent vacuoles were observed in early apoptotic cells, obliterated the cytoplasm and its organelle.
2. The concentrations of IL-1βand TNF-αin joint synovial fluid were, determined using ELISA. The concentrations of IL-1βand TNF-a in group A and group B were lower than in group C respectively (P<0.01), the concentrations of IL-1βand TNF-αin group A were not significantly different from in group B (P>0.05).
3. To localize the apoptotic cell death within the cartilage, we stained formalin-fixed, paraffin-embedded cartilage sections by using TUNEL assay, TUNEL staining labels fragmented DNA that was localized in the nucleus.A few of scattered TUNEL-positive cells in group A and group B was detected in the superficial zone of the articular cartilage,lots of TUNEL-positive cells in group C was detected from the superficial zone to the deep zone.
We quantified apoptotic cell death rate using Apoptosis index (AI). AI for chondrocytes in group A and group B was lower than in group C respectively (P<0.01), AI for chondrocytes in group A was not significantly different from in group B (P>0.05).
4. IHC analysis showed the expression of Bcl-2, Bax, p53 protein in articular cartilage.The rate of Bcl-2-positive cells in group A and group B was higher than in group C respectively(P<0.05), the rate of Bcl-2-positive cells in group A was not significantly different from in group B(P>0.05). The rate of Bax-positive cells in group A and group B was lower than in group C respectively (P<0.05), the rate of Bax-positive cells in group A was significantly different from in group B(P<0.05). Bcl-2-positive cells/Bax-positive cells in group A was higher than in group B, C, D (P<0.05).
The rate of P53-positive cells in group A and group B was lower than in group C respectively (P<0.01), the rate of P53-positive cells in group A was not significantly different from in group B (P>0.05).
5. The levels of Bcl-2,Fas mRNA were quantified using by Real-Time PCR. The levels of Bcl-2 mRNA in group A, B, C were 1.38±0.96 fold、1.27±1.15 fold、1.08±0.89 fold, compared with in group D respectively. The levels of Bcl-2 mRNA in group A, B were significantly different from in group C respectively (P<0.01), the levels of Bcl-2 mRNA in group A was not significantly different from in group B respectively (P>0.05).
The levels of Fas mRNA in group A, B, C were 0.27±0.07 fold、0.31±1.13 fold、2.32±1.35 fold, compared with in group D respectively. the levels of Fas mRNA in group A, Bwere significantly different from in group C respectively (P<0.01), the levels of Fas mRNA in group A was not significantly different from in group B respectively (P>0.05).
Conclusions
1. The model of rabbit's knee OA can be successful established with modified with immobilized in extension position for 8 weeks.
2.Mox on Guanyuan (CV 4), Zusanli (ST 36), Xuehai (SP 10),Neixiyan (EX-LE4),Dubi(ST 35)and Yanglingquan(GB 34) show some effectiveness in the treatment of OA of the rabbit'knee.
3.Mox can decrease the joint synovial fluid contents of IL-1βand TNF-α, up-regulate the mRNA and protein expression of Bcl-2 as well as down-regulate the protein expression of Bax,P53 and the mRNA expression of Fas,thereby to inhibit the apoptosis of cartilage cells and delay the degeneration of articular cartilage changes.
4.Chitosan can inhibit the apoptosis of cartilage cells and delay the degeneration of articular cartilage changes.
引文
[1]Shi F, Gu K, Lu W, et al. Study on the prevalence of arthritis and relevant factors in Shanghai[J]. Zhonghua Liu Xing Bing Xue Za Zhi,2003;24 (12):1136-1140.
[2]Kang X, Fransen M, Zhang Y, et al. The high prevalence of knee osteoarthritis in a rural Chinese population:the Wuchuan osteoarthritis study[J]. Arthritis Rheum,2009;61(5):641-647.
[3]Liu J, Chi I, Chen G, et al. Prevalence and correlates of functional disability in Chinese older adults [J]. Geriatr Gerontol Int,2009;9(3):253-261.
[4]Bitton R. The economic burden of osteoarthritis[J]. Am J Manag Care,2009;15(8 Suppl):S230-235.
[5]Ea HK, Monceau V, Camors E, et al. Annex in V overexpression increased joint chondrocyte apoptosis induced by basic calcium phosphate crystals[J]. Ann Rheum Dis,2008;67(11):1617-1625.
[6]Kawaguchi H. Endochondral ossification signals in cartilage degradation during osteoarthritis progression in experimental mouse models [J].Mol Cells,2008;25(1):1-6.
[7]Heran F, Herand A, Harmand MF.Apoptosis in normal and osteo-arthric human articular cartilage[J].Ann Rheum Dis,2000,59 (12):959.
[8]Gilron I, Milne B,Hong M.Cyclooxygenase-2 inhibitors in postoperative pain management:current evidence and future directions [J]. Anesthesiology,2003;99 (5):1198-1208.
[9]Manek NJ. Medical management of osteoarthritis[J]. Mayo Clin Proc,2001;76(5):533-539.
[10]Felson DT, Lawrence RC, Hochberg MC, et al. Osteoarthritis:new insights. Part2:treatment approaches [J]. Ann Intern Med,2000; 133(9):726-737.
[11]玄勇,鲁艳莉,李晶等.膝关节骨性关节炎的运动疗法[J].中国康复医学杂志,2003；18(9)：523-525.
[12]Schurman DJ, Smith RL. Osteoarthritis:current treatment and future prospects for surgical, medical, and biologic intervention[J].Clin Orthop Relat Res,2004;(427 Suppl): S183-189.
[13]Yanai T, Ishii T, Chang F, et al. Repair of large full-thickness articular cartilage defects in the rabbit:the effects of joint distraction and autologous bone-marrow-derived mesenchymal cell transplantation[J]. J Bone Joint Surg Br,2005; 87 (5): 721-729.
[14]Christensen R, Astrup A, Bliddal H. Weight loss:the treatment of choice for knee osteoarthritis?A randomized trial [J]. Osteo-arthritis Cartilage,2005; 13(1):20-27.
[15]张周良,李斌等.艾灸对血液流变性影响的研究[J].中国血液流变学杂志,2004；14(4).
[16]童惠云,李秀彬.隔物温和灸治疗膝骨性关节炎临床研究[J].针灸临床杂志,2006；(12)：234.
[17]Li ZD, Cao LH, Wang SC. Effect of moxibustion in treating knee joint osteoarthritis and its relation with contents of hyaluronic acid in serum and synovial fluid [J]. Zhongguo Zhong Xi Yi Jie He Za Zhi,2009;29(10):883-885.
[18]王松,沈霖,肖琳.艾灸疗法影响兔膝骨性关节炎软骨细胞凋亡的效应[J].中国临床康复,2006；10(39)：55-58.
[19]Videman T.Experimental osteoarthritis in the rabbit: comparison of different periods of repeated immobilization[J]. Acta Orthop Scand,1982,53(3):339-347.
[20]林汉生,夏苏建.利用SPSS进行随机化实验设计分组[J].中国卫生统计,2005,22(6)：397-398.
[21]李忠仁.实验针灸学[M].北京：中国中医药药出版社,2003：314.
[22]胡元亮.实用动物针灸手册[M].北京：中国农业出版社,2003：288.
[23]宁旭,尹培荣,尚显文.TGF-β1与IGF-I对体外培养兔软骨细胞增殖的影响[J].贵阳医学院学报,2005；30(1)：26-32.
[24]Batiste DL, Kirkley A, Laverty S, et al. Ex vivo characterization of articular cartilage and bone lesions in a rabbit ACL transection model of osteoarthritis using MRI and micro-CT[J].Osteoarthritis Cartilage,2004;12(12):986-996.
[25]欧云生,安洪,鼠骨关节炎动物模型建立的现状[J].中国比较医学杂志,2004；14(1)：41-44.
[26]Guzman RE, Evans MG, Bove S, et al. Mono-iodoacetate-induced histologic changes in subchondral bone and articular cartilage of rat femorotibial joints:an animal model of osteoarthritis [J]. Toxicol Pathol.2003; 31 (6):619-624.
[27]Mahr S,Menard J, Krenn V, et al. Sexual dimorphism in the osteoarthritis of STR/ort mice may be linked to articular cytokines[J].Ann Rheum Dis,2003;62(12):1234-1237.
[28]杨峰,史宗道.用木瓜蛋白酶建立兔颞颌关节骨关节炎模型的研究[J]华西口腔医学杂志,2002；20(5)：330-332.
[29]石辉,何斌,史晨辉,等.用尿激酶型纤溶酶原激活物建立兔骨关节炎模型的研究[J].石河子大学学报(自然科学版),2006，24(1)：66-69.
[30]汪青春,沈培芝,王海彬.骨关节炎动物模型的建立及选择[J].中医正骨,1998,10(3)：39-40.
[31]江捍平,王大平.骨关节炎动物模型[J].中国现代医学杂志,2004,14(6)：153-156.
[32]朱彤,刘勇章,胡小鹏,等.家兔膝关节骨关节炎动物模型的建立[J].医学临床研究,2006,23(8)：1188-1190.
[33]胡阿威,张磊,张功礼,等.改良Hulth法骨关节炎动物模型的建立[J].临床论坛,2003,3(9)：5-6.
[34]白希壮,任继尧.选择性臀肌切断诱发骨关节炎实验模型[J].中华骨科杂志,1994,14(2)：118-120.
[35]邱贵兴,王桂生.兔膝关节制动引起关节软骨退变的实验研究[J].中华骨科杂志,1987；7：175-177.
[36]纪斌平,卫小春,包尚恕,等.制动影响关节软骨愈合的实验研究[J].中国矫形外科杂志,1998；6：438-439.
[37]Welch RD. Bone changes associated with intraossous hypertension in the caprine tibia [J]. J Bone & Joint Surg (AM),1993; 75 (1):53.
[38]孙刚,王永惕.骨内静脉瘀滞、骨内高压在骨性关节炎发病中的作用初探[J].中华骨科杂志，1991；11(5)：374.
[39]谢林,郭振球.膝关节退行性骨关节病与血瘀证[J].湖南中医学院学报,1996；16(3)：75.
[40]Yang L, Carlson SG, McBurney D, et al. Multiple signals induce endoplasmic reticulum stress in both primary and immortalized chondrocytes resulting in loss of differentiation, impaired cell growth, and apoptosis [J]. J Biol Chem,2005;280 (35): 31156-31165.
[41]Carames B, Lopez-Armada MJ, Cillero-Pastor B, et al. Differential effects of tumor necrosis factor-alpha and interleukin-lbeta on cell death in human articular chondrocytes [J]. Osteoarthritis Cartilage,2008;16(6):715-722.
[42]Iannone F, Lapadula G. The pathophysiology of osteoarthritis [J]. Aging Clin Exp Res,2003;15 (5):364-372.
[43]Schwab W, Schulze-Tanzil G, Mobasheri A, et al. Interleukin-lbeta induced expression of the urokinase-type plasminogen activator receptor and its co-localization with MMPs in human articular chondrocytes [J]. Histol Histopathol,2004;19(1):105-12.
[44]Kobayashi M, Squires GR, Mousa A, et al.Role of interleukin-1 and tumor necrosis factor alpha in matrix degradation of human osteoarthritic cartilage[J]. Arthritis Rheum,2005;52 (1): 128-135.
[45]黄剑,卓廉士,彭支莲,等.电针对家兔膝骨关节炎模型关节液中IL-1β、IL-6和TNF-α影响[J].中国中医骨伤科杂志,2007；15(3)：17-21.
[46]Goldring MB. The role of cytokines as inflammatory mediators in osteoarthritis:lessons from animal models [J]. Connect Tissue Res,1999;40(1):1-11.
[47]Fernandes JC, Martel-Pelletier J, Pelletier JP..The role of cytokines in osteoarthritis pathophysiology[J]. Biorheology, 2002;39(1-2):237-246.
[48]Wood DD, Ihrie EJ,Dinarello CA, et al. Isolation of an interleukin-1-like factor from human joint effusions [J]. Arthritis Rheum,1983;26(8):975-983.
[49]Kay JD, Gouze E, Oligino TJ, et al. Intra-articular gene delivery and expression of interleukin-1Ra mediated by self-complementary adeno-associated virus [J].J Gene Med.2009; 11(7):605-614.
[50]管剑龙,施桂英.基质金属蛋白酶与骨关节炎[J].中华风湿病学杂志,2000；4(1)：54-55.
[51]Manacu CA, Martel-Pelletier J, Roy-Beaudry M, et al. Endothelin-1 in osteoarthritic chondrocytes triggers nitric oxide production and upregulates collagenase production[J]. Arthritis Res Ther,2005; 2:324-332.
[52]Rowan AD, Hui W, Cawston TE, et al. Adenoviral gene transfer of interleukin-1 in combination with oncostatin M induces significant joint damage in a murine model. Am J Pathol, 2003;162(6):1975-1984.
[53]Hui W, Rowan AD, Richards CD, Cawston TE. Oncostatin M in combination with tumor necrosis factor alpha induces cartilage damage and matrix metalloproteinase expression in vitro and in vivo. Arthritis Rheum,2003;48(12):3404-3418.
[54]田丰玮,宋军,杨金蓉.艾叶油乳膏剂对兔膝骨性关节炎关节冲洗液中细胞因子含量的影响[J].中医正骨,2005；17(12)：51.
[55]李晓愁,张露芬,郭顺根,等.逆灸对随后佐剂性关节炎大鼠早期及继发期炎性细胞因子和局部足肿胀的影响[J].中国临床康复,2005；9(15)：123-125.
[56]王磊,李学武,张莉.艾灸疗法作用机理国内外研究进展[J].中国针灸,2001；21(9)：567-570.
[57]闵大六，王保太,孟刚,等.乳腺癌和癌前病变中细胞凋亡及其与bcl-2、PCNA表达的关系[J].临床与实验病理学杂志,1999；15(2)：99.
[58]Hashimoto S, Setareh M, Ochs RL,et al. Fas/Fas ligand expression and induction of opoptosis in chondrocytes [J]. Arthritis Rheum,1997;40(8)1749-1755.
[59]Takacs-Buia L,Iordachel C, Efimov N, et al, Pathogenesis of osteoarthritis:chondrocyte replicative senescence or apoptosis[J].Cytometry B Clin Cytom,2008;74(6):356-362.
[60]Nakagawa T, Yasuda T, Hoshikawa H, et al.LOX-1 expressed in cultured rat chondrocytes mediates oxidized LDL-induced cell death-possible role of dephosphorylation of Akt [J].Biochem Biophys Rescommun,2002; 299(1):91-97.
[61]Kim HA, Lee YJ,Seong SC, et al.Apoptotic chondrocyte death in human osteoarthritis [J]. Rheumatol,2000;27(2):455-462.
[62]Gorczyca W, Gong J P,Darzynkiewicz Z.Detection of DNA strand breaks in individual apoptotic cells by the in situ terminal deoxynucleotidyl transferase-and nick translation assay[J]. Cancer Res,1993; 53:1945.
[63]姜卓力,张宝祥,张长春,张福明.膝关节骨性关节炎的现状及进展[J].内蒙古医学杂志,2007；39(3)：327-329.
[64]Pelletier JP, Jovanovic DV, Lascau-Coman V, et al. Selective inhibition of inducible nitric oxide synthase reduces progression of experimental osteoarthritis in vivo:possible link with the reduction in chondrocyte apoptosis and caspase 3 level[J]. Arthritis Rheum,2000;43(6):1290-1299.
[65]Lee SW, Lee HJ, Chung WT,et al.TRAIL induces apoptosis of chondrocytes and influences the pathogenesis of experimentally induced rat osteoarthritis[J].Arthritis Rheum,2004;50(2): 534-542.
[66]Larsen CJ.The BCL2 gene, prototype of a gene family that controls programmed cell death (apoptosis) [J]. Ann Genet,1994; 37(3):121-134.
[67]Erlacher L, Maier R, Ullrich R, et al. Differential expression of the protooncogene bcl-2 in normal and osteoarthritic human articular cartilage[J].J Rheumatol,1995;22(5):926-931.
[68]吴立成,田得祥,于长隆.癌基因与正常及骨关节炎中软骨细胞凋亡关系的研究[J].中国运动医学杂志,1998；17：98-99.
[69]Hashimoto S, Nishiyama T, Hayashi S, et al.Role of p53 in human chondrocyte apoptosis in response to shear strain[J]. Arthritis Rheum,2009;60(8):2340-2349.
[70]Ookawa K, Tsuchida S,Adachi J,et al. Differentiation induced by RB expression and apoptosis induced by p53 expression in an osteosarcoma cell line [J]. Oncogene,1997;14(12):1389-1396.
[71]Okazaki R,Sakai A,Ootsuyama A, et al. Apoptosis and p53 expression in chondrocytes relate to degeneration in articular cartilage of immobilized knee joints [J].J Rheumatol,2003; 30 (3):559-566.
[72]Kim SJ,Hwang SG, Shin DY,et al.p38 kinase regulates nitric oxide-induced apoptosis of articular chondrocytes by accumulating p53 via NFkappa B-dependent transcription and stabilization by serine 15 phosphorylation[J]. J Biol Chem,2002; 277(36):33501-33508.
[73]苏培强,叶伟,李春海,等.IL-1β对体外培养的兔软骨终板细胞生物学行为的影响[J].中国临床解剖学杂志,2007；25(5)：536-539.
[74]Winer J, Jung CK, Shackel I, et al. Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro[J].Anal Biochem,1999; 270 (1):41-49.
[75]Higuchi R, Dollinger G, Walsh PS, et al. Simultaneous amplification and detection of specific DNA sequences [J]. Biotechnology,1992;10(4):413-417.
[76]Kuhn K, Hashimoto S, Lotz M. Cell density modulates apoptosis in human articular chondrocytes [J].J Cell Physiol,1999;180(3): 439-447.
[77]肖晟,李康华,吕红斌,等.川芎嗪对家兔软骨细胞Bc1-2蛋白表达及 凋亡的影响[J].湖南医科大学学报,2003；28(3)：224-226.
[78]Shane Anderson A,Loeser RF. Why is osteoarthritis an age-related disease[J]? Best Pract Res Clin Rheumatol,2010; 24(1):15-26.
[79]Hochberg MC. Epidemiology of osteoarthritis:current concepts and new Insights [J].J Rheumatol Suppl,1991;27:4-6.
[80]Zhang Y,Xu L,Nevitt MC, et al. Comparison of the prevalence of knee osteoarthritis between the elderly Chinese population in Beijing and whites in the United States:The Beijing osteoarthritis study [J]. Arthritis Rheum,2001; 44:2065-2071.
[81]Jordan JM, Helmick CG,Renner JB,et al. Prevalence of knee symptoms and radiographic and symptomatic knee osteoarthritis in African Americans and Caucasians:the Johnston County Osteoarthritis Project [J].J Rheumatol,2007;34:172-180.
[82]Grotle M, Hagen KB, Natvig B, et al. Prevalence and burden of osteoarthritis:results from a population survey in Norway [J].J Rheumatol,2008;35:677-684.
[83]Dillon CF, Rasch EK, Gu Q, et al. Prevalence of knee osteoarthritis in the United States:arthritis data from the Third National Health and Nutrition Examination Survey 1991-1994[J].J Rheumatol,2006;33:2271-2279.
[84]March LM, Bagga H. Epidemiology of osteoarthritis in Australia [J]. Med J Australia,2004;180:S6-10.
[85]O'Connor MI. Sex differences in osteoarthritis of the hip and knee[J].J Am Acad Orthop Surg,2007;15:522-525.
[86]Sarikanth VK, Fryer JL, Zhai G, et al.A meta-analysis of the sex differences prevalence, incidence and severity of osteoarthritis[J]. Osteoarthritis Cartilage,2005;13:769-781.
[87]Felson DT,Zhang Y,Hannan MT,et al. Risk factors for incident radiographic knee osteoarthritis in the elderly:the Framingham Study [J]. Arthritis Rheum,1997;40:728-733.
[88]Arnoldi CC, Linderholm H,Mu.ssbichler H. Venous engorgement and intraosseoushypertension in osteoarthritis of the hip[J].J Bone Joint Surg Br,1972;54(3):409-421.
[89]张德辉,薛刚,黄昌林.应用玻璃酸钠对关节镜术后膝骨关节炎功能恢复的影响[J].中国临床康复,2002；6(12)：1730-1731.
[90]Hughes FJ, Buttery LD, Hukkanen MV,et al. Cytokine-induced prostaglandin E2 synthesis and cyclooxygenase-2 activity are regulated both by a nitric oxide-dependent and-independent mechanism in rat osteoblasts in vitro [J]. J Biol Chem,1999;274 (3):1776-1782.
[91]吕红斌,徐大启,胡建中,等.兔骨关节炎软骨细胞中caspase-3表达及其细胞凋亡的研究[J].临床医学研究,2007；24(9)：1441-1443.
[92]Goldring MB, Birkhead J,Sandell LJ,et al.Interleukin 1 suppresses expression of cartilage-specific types Ⅱ and Ⅸ collagens and increases types Ⅰ and Ⅲ collagens in human chondrocytes[J]. J Clin Invest,1988;82:2026-2037.
[93]郑培銮.艾灸关元穴治休克验案[J].新中医,1990；18(2)：33.
[94]唐省三.针必取三里,灸必加关元[J].山东中医杂志,2002；21(4)：245-246.
[95]唐照亮,宋小鸽,章复清,等.艾灸对关节炎大鼠抗炎消肿作用及细胞因子、自由基影响[J].安徽中医学院学报,2001；20(5)：34.
[96]肖达,陈汉平,赵粹英,等.灸对老年人衰老见证和T细胞亚群的影响[J].辽宁中医杂志,1996；23(12)：563.
[97]夏树林,张贤,谢焕松,等.艾灸治疗对兔KOA软骨损伤及TNF-α、TGF-β1和IGF-1表达调节作用的实验研究[J].江苏中医药,2009；41(6)： 69-71.
[98]洪文学,蔡建,景军.艾灸的热辐射光谱特性研究[J].应用光学,2004；25(4)：1.
[99]李维礼.实用理疗学[M],北京：人民卫生出版社,1993,2：93-129.
[100]费伦,胡颖,郭祖荣,等.传统灸法的现代技术创新[J].上海针灸杂志,2004；23(11)：46.
[101]沈雪勇,费伦,吴耀持,等.特定波段红外灸对放化疗肿瘤患者升白细胞作用观察[J].上海针灸杂志,2005；24(4)：1.
[102]潘浩,胡庆丰,李雄峰,等.补肾壮筋汤对兔早期实验性骨关节炎软骨细胞凋亡及PCNA表达的影响[J].中国中医骨伤科杂志,2004；12(4)：16-20.
[103]肖经难,谢丹,祁开泽.六味地黄丸对兔骨关节炎软骨细胞凋亡的影响[J].湖南中医学院学报,2003；23(5)：11-13.
[104]陈波,郑曙光,马四补.艾灸治疗对兔KOA软骨损伤及MMP-1和TIMP-1表达调节作用的实验研究[J].陕西中医,2009；30(4)：502-504.
[105]丁菊英,艾灸对老年人红细胞免疫和自由基的影响[J].上海针灸杂志,1995；14(1)4-5.
[106]邱洁芬,胡遵荣.试述艾叶的药理作用及临床应用[J].实用中医药杂志,2003；19(8)：446-447.
[107]黄剑,卓廉士,王永渝,等.电针对膝骨关节炎家兔关节液中自由基的影响[J].针刺研究,2008；33(2)：116-119.
[108]谢莉莉,刘光谱.艾灸的治疗作用和机理研究进展[J].针灸临床杂志,2000；16(5)：55.
[109]陈爱民,侯春林,陈庆全,等.几丁糖与透明质酸钠治疗肘关节粘连的对比研究[J].中国矫形外科杂志,2002；10(13)：1289-1290.
[110]程飚,陈峥嵘,董健.关节镜下清理与几丁糖注射治疗老年性骨关节炎55例观察[J].中国矫形外科杂志,2006；14(17)：1345-1346.
[111]王志林,刘世清,陶海鹰,等.关节腔注射几丁糖对兔关节软骨退变的影响[J].中国康复理论与实践,2005；11(11)：919-921.
[112]Sadowski T,Steinmeyer J. Effects of polysulfated glycosaminoglycan and triamcinolone acetonid on the production of proteinases and their inhibitors by IL-lalpha treated articular chondrocytes[J]. Biochem Pharmacol,2002;64 (2):217-227.
[113]刘世清,王海斌,邱波.高脱乙酰度羧甲基壳聚糖对实验性兔膝骨关节炎软骨退行性变的影响[J].中国临床康复,2004；8(26)：5567-5569.
[114]章鸣,高根德.羧甲基几丁糖对兔佐剂性关节炎滑膜细胞体外培养影响实验研究.浙江临床医学,2002；4(6)：405-406.
[115]Lu JX, Prudhommeaux F,Meunier A,et al. Effects of chitosan on rat knee cartilages [J]. Biomaterials,1999;20(20):1937-1944.
[116]吴海山,侯春林,钱齐荣，等.关节内注射壳多糖预防创伤性关节软骨退变的实验研究[J].解放军医学杂志,1995；20(4)：254-256.
[117]熊国胜,陈安民,刘月明,等.软骨细胞在几丁糖和透明质酸钠聚合凝胶中培养的实验研究[J].实用骨科杂志,2005；11(1)：37-40.
[118]Sechriest VF,Miao YJ, Niyibizi C, et al. GAG-augmented polysaccharide hydrogel:a novel biocompatible and biodegradable material to support chondrogenesis [J]. J Biomed Mater Res,2000;49(4):534-541.
[119]Mori T, Okumura M,Matsuura M, et al. Effects of chitin and its derivatives on the proliferation and cytokine production of fibroblasts in vitro[J]. Biomaterials,1997;18(13):947-951.
[120]唐亚东.医用几丁糖治疗膝关节骨性关节炎[J].中国社区医师,2002；18(13)：33.
[1]Liu J, Chi I, Chen G, et al. Prevalence and correlates of functional disability in Chinese older adults[J]. Geriatr Gerontol Int,2009;9(3):253-261.
[2]Bitton R.The economic burden of osteoarthritis[J].Am J Manag Care,2009;15(8 Suppl):S230-235.
[3]Herrero-Beaumont G, Roman-Blas JA,Castaneda S, et al. Primary osteoarthritis no longer primary:three subsets with distinct etiological, clinical,and therapeutic characteristics [J]. Semin Arthritis Rheum,2009;39(2):71-80.
[4]Chen Q.Mouse models and new therapeutic targets for OA[J].J Musculoskelet Neuronal Interact,2008;8(4):311-312.
[5]Lawrence RC, Felson DT, Helmick CG,et al.Estimates of the prevalence of arthritis and other rheumatic conditions in the United States [J].Arthritis Rheum,2008;58(1):26-35.
[6]Grushko G, Schneiderman R,Maroudas A. Some biochemical and biophysical parameters for the study of the pathogenesis of osteoarthritis:a comparison between the processes of ageing and degeneration in human hip cartilage [J]. Connect Tissue Res,1989; 19(2-4):149-176.
[7]Aigner T, Soder S, Gebhard PM, et al. Mechanisms of disease:role of chondrocytes in the pathogenesis of osteoarthritis-structure, chaos and senescence[J]. Nat Clin Pract Rheumatol, 2007;3(7): 391-399.
[8]Shane Anderson A, Loeser RF. Why is osteoarthritis an age-related disease[J]? Best Pract Res Clin Rheumatol,2010;24(1):15-26.
[9]Felson DT. Obesity and osteoarthritis of the knee[J].Bull Rheum Dis,1992; 41 (2):6-7.
[10]Toda Y, Toda T, Takemura Set al. Change in body fat, but not body weight or metabolic correlates of obesity, is related to symptomatic relief of obese patients with knee osteoarthritis after a weight control program [J]. J Rheumatol,1998;25 (11): 2181-2186.
[11]Christensen R, Astrup A, Bliddal H. Weight loss:the treatment of choice for knee osteoarthritis?A randomized trial [J]. Osteoarthritis and Cartilage,2005;13(1):20-27.
[12]van Baar ME,Assendelft WJJ,Dekker J, et al.Effectiveness.of exercise therapy in patients with osteoarthritis of the hip or knee-A systematic review of randomized clinical trials [J]. Arthritis and Rheumatism,1999;42(7):1361-1369.
[13]Paans N, van den Akker-Scheek I, van der Meer K, et al. The effects of exercise and weight loss in overweight patients with hip osteoarthritis:design of a prospective cohort study[J]. BMC Musculoskelet Disord,2009;10:24.
[14]Felson DT, Zhang Y, Anthony JM, et al. Weight loss reduces the risk for symptomatic knee osteoarthritis in women. The Framingham Study [J]. Ann Intern Med,1992;116(7):535-539.
[15]Niu J, Zhang YQ, Torner J, et al. Is obesity a risk factor for progressive radiographic kneeosteoarthritis[J]?Arthritis Rheum,2009;61(3):329-35.
[16]Gabay O, Hall DJ, erenbaum F, et al. Osteoarthritis and obesity: experimental models [J]. Joint Bone Spine,2008;75(6):675-9.
[17]World Health Organisation. The burden of musculoskeletal conditions at the start of the new millenium Report of a WHO Scientific Group WHO Technical Report Series No 919. Geneva, WHO; 2003.
[18]Andersen RE, Crespo CJ, Ling SM, et al. Prevalence of significant knee pain among older Americans:results from the Third National Health and Nutrition Examination Survey[J].J Am Geriatr Soc,1999;47(12):1435-1438.
[19]Thomas E, Peat G, Harris L, et al. The prevalence of pain and pain interference in a general population of older adults:cross-sectional findings from the North Staffordshire Osteoarthritis Project(NorStOP) [J].Pain,2004;110(1-2):361-368.
[20]Anderson JJ,Felson DT. Factors associated with osteoarthritis of the knee in the first national Health and Nutrition Examination Survey (HANES I). Evidence for an association with overweight, race, and physical demands of work[J]. Am J Epidemiol,1988;128(1):179-89.
[21]Jordan JM, Linder GF, Renner JB, et al. The impact of arthritis in rural populations [J].Arthritis Care Res,1995;8(4):242-250.
[22]Jordan JM, Renner JB, Luta G, et al. Hip osteoarthritis is not rare in African-Americans and is different than in Caucasians[J]. Arthritis Rheum,1997;40 (Suppl):S236.
[23]Clark AG, Jordan JM,Vilim VV,et al. Serum cartilage oligomeric matrix protein reflects osteoarthritis presence and severity: the Johnston County Osteoarthritis Project [J]. Arthritis Rheum,1999;42:2356-2364.
[24]Spector TD,Cicuttini F,Baker J,et al.Genetic influences on osteoarthritis in women:a twin study [J]. BMJ,1996;312(7063): 940-943.
[25]Chapman K,Mustafa Z, Irven C, et al. Osteoarthritis-susceptibility locus on chromosome llq, detected by linkage [J].Am J Hum Genet,1999;65(1):167-174.
[26]MacGregor AJ, Li Q, Spector TD, et al.The genetic influence on radiographic osteoarthritis is site specific at the hand, hip and knee [J].Rheumatology (Oxford),2009;48(3):277-280.
[27]Sharma L, Lou C, Felson DT, et al. Laxity in healthy and osteoarthritic knees [J]. Arthritis Rheum,1999;42(5):861-870.
[28]Sharma L. Proprioceptive impairment in osteoarthritis [J]. Rheum Dis Clin North Am,1999;25(2):299-314.
[29]Petrella RJ, Lattanzio PJ, Nelson MG. Effect of age and activity on knee joint proprioception[J]. Am J Phys Med Rehabil,1997; 76(3):235-241.
[30]Sharma L, Pai YC,Holtkamp K, et al. Is knee joint proprioception worse in the arthritic knee versus the unaffected knee in unilateral knee osteoarthritis[J]?Arthritis Rheum,1997;40(8): 1518-1525.
[31]Felson DT, Chaisson CE, Hill CL, et al.The association of bone marrow lesions with pain in knee osteoarthritis[J]. Ann Intern Med,2001;134(7):541-549.
[32]Dequeker J,Mokassa L, Aerssens J. Bone density and osteo-arthritis [J].J Rheumatol,1995;43(Suppl):98-100.
[33]Lajeunesse D,Massicotte F, Pelletier J-P, et al.Subchondral bone sclerosis in osteoarthritis:not just an innocent bystander[J].Mod Rheumatol,2003; 13(1):7-14.
[34]Brandi ML, Collin-Osdoby P.Vascular biology and the skeleton [J].J Bone Miner Res,2006;21(2):183-192.
[35]Felson DT, McLaughlin S, Goggins J, et al.Bone marrow edema and its relation toprogression of knee osteoarthritis[J]. Ann Intern Med,2003;139 (5Pt1):330-336.
[36]Hunter DJ, Zhang Y, Niu J, et al. Increase in bone marrow lesions associated with cartilage loss:a longitudinal magnetic resonance imaging study of knee osteoar-thritis [J]. Arthritis Rheum,2006;54(5):1529-1535.
[37]Garnero P, Peterfy C, Zaim S, et al. Bone marrow abnormalities on magnetic resonance imaging are associated with type Ⅱ collagen degradation in knee osteoarthritis:a three-month longitudinal study [J]. Arthritis Rheum,2005; 52.(9):2822-2829.
[38]Zhai G, Blizzard L, Srikanth V,et al. Correlates of knee pain in older adults:Tasmanian Older Adult Cohort Study[J]. Arthritis Rheum,2006;55(2):264-271.
[39]Carrino JA, Blum J,Parellada JA, et al. MRI of bone marrow edema-like signal in the pathogenesis of subchondral cysts [J]. Osteoarthritis Cartilage,2006;14(10):1081-1085.
[40]Arnoldi CC, Linderholm H, Mussbichler H. Venous engorgement and intraosseoushypertension in osteoarthritis of the hip [J].J Bone Joint Surg Br,1972;54(3):409-421.
[41]Wang L, Fritton SP, Weinbaum S, et al.On bone adaptation due to venous stasis [J].J Biomech,2003;36(10):1439-1451.
[42]Arnoldi CC.The relationship between intraosseous and intraarticular pressure. In:Arlet J,Ficat RP,Hungerford DS, eds. Bone circulation[J]. Baltimore:Williams and Wilkins,1984; 213-215.
[43]Lucht U, Djurhuus JC, S(?)rensen S, et al. The relationship between increasing intraarticular pressures and intraosseous pressures in the juxtaarticular bones. An experimental investigation in dogs[J]. Acta OrthopScand,1981;52(5):491-495.
[44]Wood DD, Ihrie EJ, Dinarello CA, et al. Isolation of an interleukin-1-like factor from human joint effusions[J]. Arthritis Rheum,1983;26(8):975-983.
[45]Kay JD, Gouze E, Oligino TJ, et al. Intra-articular gene delivery and expression of interleukin-1Ra mediated by self-complementary adeno-associated virus [J].J Gene Med.2009;11 (7):605-614.
[46]Goldring MB, Birkhead J,Sandell LJ, et al. Interleukin 1 suppresses expression of cartilage-specific types II and IX collagens and increases types I and III collagens in human chondrocytes[J]. J Clin Invest,1988; 82:2026-2037.
[47]Manacu CA,Martel-Pelletier J, Roy-Beaudry M, et al. Endothelin-1 in osteoarthritic chondrocytes triggers nitric oxide production and upregulates collagenase production[J]. Arthritis Res Ther,2005;2:324-332.
[48]管剑龙,施桂英.基质金属蛋白酶与骨关节炎[J].中华风湿病学杂志,2000；4(1)：54-55.
[49]Kobayashi M, Squires GR, Mousa A, et al. Role of interleukin-1 and tumor necrosis factor alpha in matrix degradation of human osteoarthritic cartilage[J]. Arthritis Rheum,2005;52(1):128-135.
[50]Rowan AD, Hui W, Cawston TE, et al. Adenoviral gene transfer of interleukin-1 in combination with oncostatin M induces significant joint damage in a murine model. Am J Pathol, 2003;162(6):1975-1984.
[51]Hui W, Rowan AD, Richards CD, Cawston TE. Oncostatin M in combination with tumor necrosis factor alpha induces cartilage damage and matrix metalloproteinase expression in vitro and in vivo. Arthritis Rheum,2003;48(12):3404-3418.
[52]Iwanaga H, Matsumoto T, Enomoto H, et al. Enhanced expression of insulin-like growth factor-binding proteins in human osteoarthritic cartilage detected by immunohistochemistry and in situ hybridization[J]. Osteoarthritis Cartilage,2005;13 (5): 439-448.
[53]Sgaglione NA,Miniaci. A, Gillogly SD, et al. Update on advanced surgical techniques in the treatment of traumatic focal articular cartilage lesions in the knee [J]. Arthroscopy,2002; 18 (2Suppl1):9-32.
[54]Grimaud E, Heymann D, Redini F. Recent advances in TGF-beta effects on chondrocyte metabolism. Potential therapeutic roles of TGF-beta in cartilage disorders [J]. Cytokine Growth Factor Rev,2002;13(3):241-257.
[55]Sellers RS, Zhang R, Glasson SS, et al. Repair of articular cartilage defects one year after treatment with recombinant human bone morphogenetic protein-2 (rhBMP-2) [J]. J Bone Joint Surg Am,2000; 82(2):151-160.
[56]Sanyal A, Oursler MJ, Clemens VR,et al. Temporal expression patterns of BMP receptors and collagen Ⅱ(B)during periosteal chondrogenesis [J].J Orthop Res,2002;20(1):58-65.
[57]Hashimoto S, Setareh M, Ochs RL, et al. Fas/Fas ligand expression and induction of opoptosis in chondrocytes [J]. Arthritis Rheum,1997;40(8)1749-1755.
[58]Tak a cs-Buia L, Iordachel C,Efimov N, et al. Pathogenesis of osteoarthritis:chondrocyte replicative senescence or apoptosis[J].Cytometry B Clin Cytom,2008;74(6):356-362.
[59]Heran F,Herand A,Harmand MF. Apoptosis in normal and osteo-arthric human articular cartilage[J]. Ann Rheum Dis,2000,59 (12):959.
[60]Nakagawa T, Yasuda T, Hoshikawa H, et al.LOX-1 expressed in cultured rat chondrocytes mediates oxidized LDL-induced cell death-possible role of dephosphorylation of Akt [J]. Biochem Biophys Rescommun,2002;299(1):91-97.
[61]Kim HA, Lee YJ, Seong SC,et al.Apoptotic chondrocyte death in human osteoarthritis [J]. Rheumatol,2000;27(2):455-462.
[62]Ea HK, Monceau V, Camors E,et al. Annexin V overexpression increased joint chondrocyte apoptosis induced by basic calcium phosphate crystals[J].Ann Rheum Dis,2008;67(11):1617-1625.
[63]Kawaguchi H.Endochondral ossification signals in cartilage degradation during osteoarthritis progression in experimental mouse models [J].Mol Cells,2008;25(1):1-6.
[64]Yang L,Carlson SG,McBurney D, et al.Multiple signals induce endoplasmic reticulum stress in both primary and immortalized chondrocytes resulting in loss of differentiation, impaired cell growth, and apoptosis [J].J Biol Chem,2005;280(35):31156-31165.
[65]Hughes FJ, Buttery LD,Hukkanen MV, et al. Cytokine-induced prostaglandin E2 synthesis and cyclooxygenase-2 activity are regulated both by a nitric oxide-dependent and-independent mechanism in rat osteoblasts in vitro [J].J Biol Chem,1999;274 (3):1776-1782.
[66]Okamoto K, Kobayashi T, Kobata T, et al. Fas-associated death domain protein is a Fas-mediated apoptosis modulator in synoviocytes [J]. Rheumatology (Oxford),2000;39(5):471-480.
[67]Wu GJ, Chen TG, Chang HC,et al. Nitric oxide from bothexogenous and endogenous sources activates mitochondria-dependent events and induces insults to human chondrocytes [J].J Cell Biochem,2007;101(6):1520-1531.
[68]Maneiro E, Lopez-Armada MJ,de Andres MC, et al. Effect of nitric oxide on mitochondrial respiratory activity of human articular chondrocytes [J].Ann Rheum Dis,2005;64(3):388-395.
[69]Del Carlo M Jr,Loeser RF.Nitric oxide-mediated chondrocyte cell death requires the generation of additional reactive oxygen species [J]. Arthritis Rheum,2002;46 (2):394-403.
[70]Lee SW, Lee HJ, Chung WT, et al.TRAIL induces apoptosis of chondrocytes and influences the pathogenesis of experimentally induced rat osteoarthritis[J]. Arthritis Rheum,2004;50 (2): 534-542.
[71]Okazaki R, Sakai A, Ootsuyama A, et al. Apoptosis and p53 expression in chondrocytes relate to degeneration in articular cartilage of immobilized knee joints [J].J Rheumatol,2003; 30 (3):559-566.
[72]Larsen CJ.The BCL2 gene, prototype of a gene family that controls programmed cell death (apoptosis) [J]. Ann Genet,1994; 37(3):121-134.
[73]吕红斌,徐大启,胡建中,等.兔骨关节炎软骨细胞中caspase-3表达及其细胞凋亡的研究[J].临床医学研究,2007；24(9)：1441-1443.
[74]Pelletier JP, Jovanovic DV, Lascau-Coman V, et al. Selective inhibition of inducible nitric oxide synthase reduces progression of experimental osteoarthritis in vivo:possible link with the reduction in chondrocyte apoptosis and caspase 3 level [J]. Arthritis Rheum,2000;43(6):1290-1299.
[75]Hashimoto S,Ochs RL,Komiya S, et al. Linkage of chondrocyte apoptosis and cartilage degradation in human osteoarthritis [J]. Arthritis Rheum,1998;41(9):1632-1638.
[76]Batiste DL, Kirkley A, Laverty S, et al. Ex vivo characterization of articular cartilage and bone lesions in a rabbit ACL transection model of osteoarthritis using MRI and micro-CT[J]. Osteoarthritis Cartilage,2004;12(12):986-996.
[77]欧云生,安洪,鼠骨关节炎动物模型建立的现状[J].中国比较医学杂志,2004；14(1)：41-44.
[78]Guzman RE, Evans MG, Bove S, et al.Mono-iodoacetate-induced histologic changes in subchondral bone and articular cartilage of rat femorotibial joints:an animal model of osteoarthritis [J]. Toxicol Pathol.2003;31(6):619-624.
[79]Mahr S,Menard J,Krenn V, et al.Sexual dimorphism in the osteoarthritis of STR/ort mice may be linked to articular cytokines [J].Ann Rheum Dis,2003;62(12):1234-1237.
[80]杨峰,史宗道.用木瓜蛋白酶建立兔颞颌关节骨关节炎模型的研究[J]华西口腔医学杂志,2002；20(5)：330-332.
[81]石辉,何斌,史晨辉,等.用尿激酶型纤溶酶原激活物建立兔骨关节炎模型的研究[J].石河子大学学报(自然科学版),2006,24(1)：66-69.
[82]汪青春,沈培芝,王海彬.骨关节炎动物模型的建立及选择[J].中医正骨,1998,10(3)：39-40.
[83]江捍平，王大平.骨关节炎动物模型[J].中国现代医学杂志,2004,14(6)：153-156.
[84]朱彤,刘勇章,胡小鹏,等.家兔膝关节骨关节炎动物模型的建立[J].医学临床研究,2006,23(8)：1188-1190.
[85]胡阿威,张磊,张功礼,等.改良Hulth法骨关节炎动物模型的建立[J].临床论坛,2003,3(9)：5-6.
[86]白希壮,任继尧.选择性臀肌切断诱发骨关节炎实验模型[J].中华骨科杂志,1994,14(2)：118-120.
[87]Videman T.Experimental osteoarthritis in the rabbit: comparison of different periods of repeated immobilization [J]. Acta Orthop Scand,1982,53(3):339-347.
[88]邱贵兴,王桂生.兔膝关节制动引起关节软骨退变的实验研究[J].中华骨科杂志,1987；7：175-177.
[89]Fransen M,McConnell S. Land-based exercise for osteoarthritis of the knee:a metaanalysis of randomized controlled trials [J]. J Rheumatol,2009;36(6):1109-1117.
[90]Messier SP,Loeser RF,Mitchell MN, et al.Exercise and weight loss in obese older adults with knee osteoarthritis:a preliminary study [J].J Am Geriatr Soc,2000; 48 (9):1062-1072.
[91]Deyle GD, Henderson NE, Matekel RL, et al. Effectiveness of manual physical therapy and exercise in osteoarthritis of the knee. A randomized, controlled trial[J]. Ann Intern Med,2000;132 (3): 173-181.
[92]Iwamoto J,Takeda T,Sato Y.Effect of muscle strengthening exercises on the muscle strength in patients with osteoarthritis of the knee [J]. Knee,2007;14(3):224-230.
[93]Mazzuca SA, Brandt KD, Katz BP, et al. Effects of self-care education on the health status of inner-city patients with osteoarthritis of the knee[J]. Arthritis Rheum,1997;40(8): 1466-1474.
[94]Tohyama H, Yasuda K, Kaneda K. Treatment of osteoarthritis of the knee with heel wedges [J]. Int Orthop,1991;15(1):31-33.
[95]Kirkley A, Webster-Bogaert S, Litchf ield R, et al.The effect of bracing on varus gonarthrosis[J].J Bone Joint Surg Am,1999; 81 (4):539-348.
[96]Takahashi KA, Tonomura H,Arai Y, et al. Hyperthermia for the treatment of articular cartilage with osteoarthritis [J].Int J Hyperthermia,2009;25(8):661-667.
[97]Naito K, Watari T,Muta T, et al. Low-intensity pulsed ultrasound (LIPUS) increases the articular cartilage type Ⅱ collagen in a rat osteoarthritis model [J].J Orthop Res,2010; 28 (3):361- 369.
[98]Silva LE,Valim V,Pessanha AP,et al.Hydrotherapy versus conventional land-based exercise for the management of patients with osteoarthritis of the knee:a randomized clinical trial [J].Phys Ther,2008;88(1):12-21.
[99]Gremeaux V,Renault J,Pardon L,et al.Low-frequency electric muscle stimulation combined with physical therapy after total hip arthroplasty for hip osteoarthritis in elderly patients:a randomized controlled trial[J]. Arch Phys Med Rehabil,2008; 89(12):2265-2273.
[100]Lin YS,Huang MH,Chai C. Effects of helium-neon laser on the mucopolysaccharide induction in experimental osteoarthritic cartilage[J]. Osteoarthritis Cartilage,2006;14(4):377-383.
[101]Lu TW, Wei IP, Liu YH, et al. Immediate effects of acupuncture on gait patterns in patients with knee osteoarthritis[J].Chin Med J (Engl),2010; 123(2):165-172.
[102]唐照亮,宋小鸽,章复清,等.艾灸对关节炎大鼠抗炎消肿作用及细胞因子、自由基影响[J].安徽中医学院学报,2001；20(5)：34.
[103]李晓愁,张露芬,郭顺根,等.逆灸对随后佐剂性关节炎大鼠早期及继发期炎性细胞因子和局部足肿胀的影响[J].中国临床康复,2005；9(15)：123-125.
[104]王磊,李学武,张莉.艾灸疗法作用机理国内外研究进展[J].中国针灸,2001；21(9)：567-570.
[105]肖达,陈汉平,赵粹英,等.灸对老年人衰老见证和T细胞亚群的影响[J].辽宁中医杂志,1996；23(12)：563.
[106]田丰玮,宋军,杨金蓉.艾叶油乳膏剂对兔膝骨性关节炎关节冲洗液中细胞因子含量的影响[J].中医正骨,2005；17(12)：51.
[107]夏树林,张贤,谢焕松,等.艾灸治疗对兔KOA软骨损伤及TNF-α、 TGF-β1和IGF-1表达调节作用的实验研究[J].江苏中医药,2009；41(6)：69-71.
[108]Altman R,Barkin RL. Topical therapy for osteoarthritis:clinical and pharmacologic perspectives[J]. Postgrad Med,2009; 121(2):139-147.
[109]Puenpatom RA,Victor T. Increased prevalence of metabolic syndrome inindividuals with osteoarthritis:an analysis of NHANES III data [J]. Postgrad Med,2009;121(6):9-20.
[110]Geba Gregory P, Weaver Arthur L, Polis Adam B, et al. Efficacy of rofecoxib, celecoxib, and acetaminophen in osteoarthritis of the knee:a randomized trial [J].JAMA,2002;287(1):64-71.
[111]Haf lah NH, Jaarin K,Abdullah S, et al. Palm vitamin E and glucosamine sulphate in the treatment of osteoarthritis of the knee [J]. Saudi Med J,2009; 30(11):1432-1438.
[112]Naito K, Watari T, Furuhata A, et al. Evaluation of the effect of glucosamine on an experimental rat osteoarthritis model [J]. Life Sci,2010. [Epub ahead of print]
[113]Shimizu M, Higuchi H, Takagishi K, et al. Clinical and biochemical characteristics after intra-articular injection for the treatment of osteoarthritis of the knee:prospective randomized study of sodium hyaluronate and corticosteroid [J].J Orthop Sci,2010; 15 (1):51-56.
[114]Zhou JL, Liu SQ, Qiu B, et al.The protective effect of sodium hyaluronate on the cartilage of rabbit osteoarthritis by inhibiting peroxisome proliferator-activated receptor-gamma messenger RNA expression [J]. Yonsei Med J,2009;50(6):832-827.
[115]刘世清,王海斌,邱波.高脱乙酰度羧甲基壳聚糖对实验性兔膝骨关节炎软骨退行性变的影响[J].中国临床康复,2004；8(26)：5567- 5569.
[116]Lu JX,Prudhommeaux F, Meunier A,et al.Effects of chitosan on rat knee cartilages [J]. Biomaterials,1999; 20(20):1937-1944.
[117]吴海山,侯春林,钱齐荣,等.关节内注射壳多糖预防创伤性关节软骨退变的实验研究[J].解放军医学杂志,1995；20(4)：254-256.
[118]王志林,刘世清,陶海鹰,等.关节腔注射几丁糖对兔关节软骨退变的影响[J].中国康复理论与实践,2005；11(11)：919-921.
[119]章鸣,高根德.羧甲基几丁糖对兔佐剂性关节炎滑膜细胞体外培养影响实验研究.浙江临床医学,2002；4(6)：405-406.
[120]熊国胜,陈安民,刘月明,等.软骨细胞在几丁糖和透明质酸钠聚合凝胶中培养的实验研究[J].实用骨科杂志,2005；11(1)：37-40.
[121]Sechriest VF,Miao YJ, Niyibizi C, et al. GAG-augmented polysaccharide hydrogel:a novel biocompatible and biodegradable material to support chondrogenesis [J].J Biomed Mater Res,2000; 49 (4):534-541.
[122]Mori T, Okumura M,Matsuura M,et al. Effects of chitin and its derivatives on the proliferation and cytokine production of fibroblasts in vitro[J]. Biomaterials,1997; 18 (13):947-951.
[123]唐亚东.医用几丁糖治疗膝关节骨性关节炎[J].中国社区医师,2002；18(13)：33.
[124]Akizuki S,Yasukawa Y,Takizawa T.Does arthroscopic abrasion arthroplasty promote cartilage regeneration in osteoarthritic knees with eburnation? A prospective study of high tibial osteotomy with abrasion arthroplasty versus high tibial osteotomy alone [J]. Arthroscopy,1997;13(1):9-17.
[125]Miller BS,Steadman JR,Briggs KK,et al.Patient satisfaction and outcome after microfracture of the degenerative knee[J].J Knee Surg,2004;17(1):13-17.
[126]Henderson I,Lavigne P, Valenzuela H, et al. Autologous chondrocyte implantation:superior biologic properties of hyaline cartilage repairs [J]. Clin Orthop Relat Res,2007; 455: 253-261.
[127]Gillogly SD,Myers TH, Reinold MM. Treatment of full-thickness chondral defects in the knee with autologous chondrocyte implantation[J].J Orthop Sports Phys Ther,2006; 36(10):751-764.
[128]Alberti C. Tissue engineering technologies:just a quick note about transplantation of bioengineered donor trachea and augmentation cystoplasty by de novo engineered bladder tissue[J].G Chir,2009; 30(11-12):514-519.
[129]Evans CH, Gouze E, Gouze JN, et al.Gene therapeutic approaches-transfer in vivo[J].Adv Drug Deliv Rev,2006; 58 (2):243-258.
[130]Santangelo KS, Baker SA, Nuovo G, et al. Detectable reporter gene expression following transduction of adenovirus and adeno-associated virus serotype 2 vectors within full-thickness osteoarthritic and unaffected canine cartilage in vitro and unaffected guinea pig cartilage in vivo[J].J Orthop Res,2010; 28 (2):149-155.
[2]Kang X, Fransen M, Zhang Y, et al. The high prevalence of knee osteoarthritis in a rural Chinese population:the Wuchuan osteoarthritis study[J]. Arthritis Rheum,2009;61(5):641-647.
[3]Liu J, Chi I, Chen G, et al. Prevalence and correlates of functional disability in Chinese older adults [J]. Geriatr Gerontol Int,2009;9(3):253-261.
[4]Bitton R. The economic burden of osteoarthritis[J]. Am J Manag Care,2009;15(8 Suppl):S230-235.
[5]Ea HK, Monceau V, Camors E, et al. Annex in V overexpression increased joint chondrocyte apoptosis induced by basic calcium phosphate crystals[J]. Ann Rheum Dis,2008;67(11):1617-1625.
[6]Kawaguchi H. Endochondral ossification signals in cartilage degradation during osteoarthritis progression in experimental mouse models [J].Mol Cells,2008;25(1):1-6.
[7]Heran F, Herand A, Harmand MF.Apoptosis in normal and osteo-arthric human articular cartilage[J].Ann Rheum Dis,2000,59 (12):959.
[8]Gilron I, Milne B,Hong M.Cyclooxygenase-2 inhibitors in postoperative pain management:current evidence and future directions [J]. Anesthesiology,2003;99 (5):1198-1208.
[9]Manek NJ. Medical management of osteoarthritis[J]. Mayo Clin Proc,2001;76(5):533-539.
[10]Felson DT, Lawrence RC, Hochberg MC, et al. Osteoarthritis:new insights. Part2:treatment approaches [J]. Ann Intern Med,2000; 133(9):726-737.
[11]玄勇,鲁艳莉,李晶等.膝关节骨性关节炎的运动疗法[J].中国康复医学杂志,2003；18(9)：523-525.
[12]Schurman DJ, Smith RL. Osteoarthritis:current treatment and future prospects for surgical, medical, and biologic intervention[J].Clin Orthop Relat Res,2004;(427 Suppl): S183-189.
[13]Yanai T, Ishii T, Chang F, et al. Repair of large full-thickness articular cartilage defects in the rabbit:the effects of joint distraction and autologous bone-marrow-derived mesenchymal cell transplantation[J]. J Bone Joint Surg Br,2005; 87 (5): 721-729.
[14]Christensen R, Astrup A, Bliddal H. Weight loss:the treatment of choice for knee osteoarthritis?A randomized trial [J]. Osteo-arthritis Cartilage,2005; 13(1):20-27.
[15]张周良,李斌等.艾灸对血液流变性影响的研究[J].中国血液流变学杂志,2004；14(4).
[16]童惠云,李秀彬.隔物温和灸治疗膝骨性关节炎临床研究[J].针灸临床杂志,2006；(12)：234.
[17]Li ZD, Cao LH, Wang SC. Effect of moxibustion in treating knee joint osteoarthritis and its relation with contents of hyaluronic acid in serum and synovial fluid [J]. Zhongguo Zhong Xi Yi Jie He Za Zhi,2009;29(10):883-885.
[18]王松,沈霖,肖琳.艾灸疗法影响兔膝骨性关节炎软骨细胞凋亡的效应[J].中国临床康复,2006；10(39)：55-58.
[19]Videman T.Experimental osteoarthritis in the rabbit: comparison of different periods of repeated immobilization[J]. Acta Orthop Scand,1982,53(3):339-347.
[20]林汉生,夏苏建.利用SPSS进行随机化实验设计分组[J].中国卫生统计,2005,22(6)：397-398.
[21]李忠仁.实验针灸学[M].北京：中国中医药药出版社,2003：314.
[22]胡元亮.实用动物针灸手册[M].北京：中国农业出版社,2003：288.
[23]宁旭,尹培荣,尚显文.TGF-β1与IGF-I对体外培养兔软骨细胞增殖的影响[J].贵阳医学院学报,2005；30(1)：26-32.
[24]Batiste DL, Kirkley A, Laverty S, et al. Ex vivo characterization of articular cartilage and bone lesions in a rabbit ACL transection model of osteoarthritis using MRI and micro-CT[J].Osteoarthritis Cartilage,2004;12(12):986-996.
[25]欧云生,安洪,鼠骨关节炎动物模型建立的现状[J].中国比较医学杂志,2004；14(1)：41-44.
[26]Guzman RE, Evans MG, Bove S, et al. Mono-iodoacetate-induced histologic changes in subchondral bone and articular cartilage of rat femorotibial joints:an animal model of osteoarthritis [J]. Toxicol Pathol.2003; 31 (6):619-624.
[27]Mahr S,Menard J, Krenn V, et al. Sexual dimorphism in the osteoarthritis of STR/ort mice may be linked to articular cytokines[J].Ann Rheum Dis,2003;62(12):1234-1237.
[28]杨峰,史宗道.用木瓜蛋白酶建立兔颞颌关节骨关节炎模型的研究[J]华西口腔医学杂志,2002；20(5)：330-332.
[29]石辉,何斌,史晨辉,等.用尿激酶型纤溶酶原激活物建立兔骨关节炎模型的研究[J].石河子大学学报(自然科学版),2006，24(1)：66-69.
[30]汪青春,沈培芝,王海彬.骨关节炎动物模型的建立及选择[J].中医正骨,1998,10(3)：39-40.
[31]江捍平,王大平.骨关节炎动物模型[J].中国现代医学杂志,2004,14(6)：153-156.
[32]朱彤,刘勇章,胡小鹏,等.家兔膝关节骨关节炎动物模型的建立[J].医学临床研究,2006,23(8)：1188-1190.
[33]胡阿威,张磊,张功礼,等.改良Hulth法骨关节炎动物模型的建立[J].临床论坛,2003,3(9)：5-6.
[34]白希壮,任继尧.选择性臀肌切断诱发骨关节炎实验模型[J].中华骨科杂志,1994,14(2)：118-120.
[35]邱贵兴,王桂生.兔膝关节制动引起关节软骨退变的实验研究[J].中华骨科杂志,1987；7：175-177.
[36]纪斌平,卫小春,包尚恕,等.制动影响关节软骨愈合的实验研究[J].中国矫形外科杂志,1998；6：438-439.
[37]Welch RD. Bone changes associated with intraossous hypertension in the caprine tibia [J]. J Bone & Joint Surg (AM),1993; 75 (1):53.
[38]孙刚,王永惕.骨内静脉瘀滞、骨内高压在骨性关节炎发病中的作用初探[J].中华骨科杂志，1991；11(5)：374.
[39]谢林,郭振球.膝关节退行性骨关节病与血瘀证[J].湖南中医学院学报,1996；16(3)：75.
[40]Yang L, Carlson SG, McBurney D, et al. Multiple signals induce endoplasmic reticulum stress in both primary and immortalized chondrocytes resulting in loss of differentiation, impaired cell growth, and apoptosis [J]. J Biol Chem,2005;280 (35): 31156-31165.
[41]Carames B, Lopez-Armada MJ, Cillero-Pastor B, et al. Differential effects of tumor necrosis factor-alpha and interleukin-lbeta on cell death in human articular chondrocytes [J]. Osteoarthritis Cartilage,2008;16(6):715-722.
[42]Iannone F, Lapadula G. The pathophysiology of osteoarthritis [J]. Aging Clin Exp Res,2003;15 (5):364-372.
[43]Schwab W, Schulze-Tanzil G, Mobasheri A, et al. Interleukin-lbeta induced expression of the urokinase-type plasminogen activator receptor and its co-localization with MMPs in human articular chondrocytes [J]. Histol Histopathol,2004;19(1):105-12.
[44]Kobayashi M, Squires GR, Mousa A, et al.Role of interleukin-1 and tumor necrosis factor alpha in matrix degradation of human osteoarthritic cartilage[J]. Arthritis Rheum,2005;52 (1): 128-135.
[45]黄剑,卓廉士,彭支莲,等.电针对家兔膝骨关节炎模型关节液中IL-1β、IL-6和TNF-α影响[J].中国中医骨伤科杂志,2007；15(3)：17-21.
[46]Goldring MB. The role of cytokines as inflammatory mediators in osteoarthritis:lessons from animal models [J]. Connect Tissue Res,1999;40(1):1-11.
[47]Fernandes JC, Martel-Pelletier J, Pelletier JP..The role of cytokines in osteoarthritis pathophysiology[J]. Biorheology, 2002;39(1-2):237-246.
[48]Wood DD, Ihrie EJ,Dinarello CA, et al. Isolation of an interleukin-1-like factor from human joint effusions [J]. Arthritis Rheum,1983;26(8):975-983.
[49]Kay JD, Gouze E, Oligino TJ, et al. Intra-articular gene delivery and expression of interleukin-1Ra mediated by self-complementary adeno-associated virus [J].J Gene Med.2009; 11(7):605-614.
[50]管剑龙,施桂英.基质金属蛋白酶与骨关节炎[J].中华风湿病学杂志,2000；4(1)：54-55.
[51]Manacu CA, Martel-Pelletier J, Roy-Beaudry M, et al. Endothelin-1 in osteoarthritic chondrocytes triggers nitric oxide production and upregulates collagenase production[J]. Arthritis Res Ther,2005; 2:324-332.
[52]Rowan AD, Hui W, Cawston TE, et al. Adenoviral gene transfer of interleukin-1 in combination with oncostatin M induces significant joint damage in a murine model. Am J Pathol, 2003;162(6):1975-1984.
[53]Hui W, Rowan AD, Richards CD, Cawston TE. Oncostatin M in combination with tumor necrosis factor alpha induces cartilage damage and matrix metalloproteinase expression in vitro and in vivo. Arthritis Rheum,2003;48(12):3404-3418.
[54]田丰玮,宋军,杨金蓉.艾叶油乳膏剂对兔膝骨性关节炎关节冲洗液中细胞因子含量的影响[J].中医正骨,2005；17(12)：51.
[55]李晓愁,张露芬,郭顺根,等.逆灸对随后佐剂性关节炎大鼠早期及继发期炎性细胞因子和局部足肿胀的影响[J].中国临床康复,2005；9(15)：123-125.
[56]王磊,李学武,张莉.艾灸疗法作用机理国内外研究进展[J].中国针灸,2001；21(9)：567-570.
[57]闵大六，王保太,孟刚,等.乳腺癌和癌前病变中细胞凋亡及其与bcl-2、PCNA表达的关系[J].临床与实验病理学杂志,1999；15(2)：99.
[58]Hashimoto S, Setareh M, Ochs RL,et al. Fas/Fas ligand expression and induction of opoptosis in chondrocytes [J]. Arthritis Rheum,1997;40(8)1749-1755.
[59]Takacs-Buia L,Iordachel C, Efimov N, et al, Pathogenesis of osteoarthritis:chondrocyte replicative senescence or apoptosis[J].Cytometry B Clin Cytom,2008;74(6):356-362.
[60]Nakagawa T, Yasuda T, Hoshikawa H, et al.LOX-1 expressed in cultured rat chondrocytes mediates oxidized LDL-induced cell death-possible role of dephosphorylation of Akt [J].Biochem Biophys Rescommun,2002; 299(1):91-97.
[61]Kim HA, Lee YJ,Seong SC, et al.Apoptotic chondrocyte death in human osteoarthritis [J]. Rheumatol,2000;27(2):455-462.
[62]Gorczyca W, Gong J P,Darzynkiewicz Z.Detection of DNA strand breaks in individual apoptotic cells by the in situ terminal deoxynucleotidyl transferase-and nick translation assay[J]. Cancer Res,1993; 53:1945.
[63]姜卓力,张宝祥,张长春,张福明.膝关节骨性关节炎的现状及进展[J].内蒙古医学杂志,2007；39(3)：327-329.
[64]Pelletier JP, Jovanovic DV, Lascau-Coman V, et al. Selective inhibition of inducible nitric oxide synthase reduces progression of experimental osteoarthritis in vivo:possible link with the reduction in chondrocyte apoptosis and caspase 3 level[J]. Arthritis Rheum,2000;43(6):1290-1299.
[65]Lee SW, Lee HJ, Chung WT,et al.TRAIL induces apoptosis of chondrocytes and influences the pathogenesis of experimentally induced rat osteoarthritis[J].Arthritis Rheum,2004;50(2): 534-542.
[66]Larsen CJ.The BCL2 gene, prototype of a gene family that controls programmed cell death (apoptosis) [J]. Ann Genet,1994; 37(3):121-134.
[67]Erlacher L, Maier R, Ullrich R, et al. Differential expression of the protooncogene bcl-2 in normal and osteoarthritic human articular cartilage[J].J Rheumatol,1995;22(5):926-931.
[68]吴立成,田得祥,于长隆.癌基因与正常及骨关节炎中软骨细胞凋亡关系的研究[J].中国运动医学杂志,1998；17：98-99.
[69]Hashimoto S, Nishiyama T, Hayashi S, et al.Role of p53 in human chondrocyte apoptosis in response to shear strain[J]. Arthritis Rheum,2009;60(8):2340-2349.
[70]Ookawa K, Tsuchida S,Adachi J,et al. Differentiation induced by RB expression and apoptosis induced by p53 expression in an osteosarcoma cell line [J]. Oncogene,1997;14(12):1389-1396.
[71]Okazaki R,Sakai A,Ootsuyama A, et al. Apoptosis and p53 expression in chondrocytes relate to degeneration in articular cartilage of immobilized knee joints [J].J Rheumatol,2003; 30 (3):559-566.
[72]Kim SJ,Hwang SG, Shin DY,et al.p38 kinase regulates nitric oxide-induced apoptosis of articular chondrocytes by accumulating p53 via NFkappa B-dependent transcription and stabilization by serine 15 phosphorylation[J]. J Biol Chem,2002; 277(36):33501-33508.
[73]苏培强,叶伟,李春海,等.IL-1β对体外培养的兔软骨终板细胞生物学行为的影响[J].中国临床解剖学杂志,2007；25(5)：536-539.
[74]Winer J, Jung CK, Shackel I, et al. Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro[J].Anal Biochem,1999; 270 (1):41-49.
[75]Higuchi R, Dollinger G, Walsh PS, et al. Simultaneous amplification and detection of specific DNA sequences [J]. Biotechnology,1992;10(4):413-417.
[76]Kuhn K, Hashimoto S, Lotz M. Cell density modulates apoptosis in human articular chondrocytes [J].J Cell Physiol,1999;180(3): 439-447.
[77]肖晟,李康华,吕红斌,等.川芎嗪对家兔软骨细胞Bc1-2蛋白表达及 凋亡的影响[J].湖南医科大学学报,2003；28(3)：224-226.
[78]Shane Anderson A,Loeser RF. Why is osteoarthritis an age-related disease[J]? Best Pract Res Clin Rheumatol,2010; 24(1):15-26.
[79]Hochberg MC. Epidemiology of osteoarthritis:current concepts and new Insights [J].J Rheumatol Suppl,1991;27:4-6.
[80]Zhang Y,Xu L,Nevitt MC, et al. Comparison of the prevalence of knee osteoarthritis between the elderly Chinese population in Beijing and whites in the United States:The Beijing osteoarthritis study [J]. Arthritis Rheum,2001; 44:2065-2071.
[81]Jordan JM, Helmick CG,Renner JB,et al. Prevalence of knee symptoms and radiographic and symptomatic knee osteoarthritis in African Americans and Caucasians:the Johnston County Osteoarthritis Project [J].J Rheumatol,2007;34:172-180.
[82]Grotle M, Hagen KB, Natvig B, et al. Prevalence and burden of osteoarthritis:results from a population survey in Norway [J].J Rheumatol,2008;35:677-684.
[83]Dillon CF, Rasch EK, Gu Q, et al. Prevalence of knee osteoarthritis in the United States:arthritis data from the Third National Health and Nutrition Examination Survey 1991-1994[J].J Rheumatol,2006;33:2271-2279.
[84]March LM, Bagga H. Epidemiology of osteoarthritis in Australia [J]. Med J Australia,2004;180:S6-10.
[85]O'Connor MI. Sex differences in osteoarthritis of the hip and knee[J].J Am Acad Orthop Surg,2007;15:522-525.
[86]Sarikanth VK, Fryer JL, Zhai G, et al.A meta-analysis of the sex differences prevalence, incidence and severity of osteoarthritis[J]. Osteoarthritis Cartilage,2005;13:769-781.
[87]Felson DT,Zhang Y,Hannan MT,et al. Risk factors for incident radiographic knee osteoarthritis in the elderly:the Framingham Study [J]. Arthritis Rheum,1997;40:728-733.
[88]Arnoldi CC, Linderholm H,Mu.ssbichler H. Venous engorgement and intraosseoushypertension in osteoarthritis of the hip[J].J Bone Joint Surg Br,1972;54(3):409-421.
[89]张德辉,薛刚,黄昌林.应用玻璃酸钠对关节镜术后膝骨关节炎功能恢复的影响[J].中国临床康复,2002；6(12)：1730-1731.
[90]Hughes FJ, Buttery LD, Hukkanen MV,et al. Cytokine-induced prostaglandin E2 synthesis and cyclooxygenase-2 activity are regulated both by a nitric oxide-dependent and-independent mechanism in rat osteoblasts in vitro [J]. J Biol Chem,1999;274 (3):1776-1782.
[91]吕红斌,徐大启,胡建中,等.兔骨关节炎软骨细胞中caspase-3表达及其细胞凋亡的研究[J].临床医学研究,2007；24(9)：1441-1443.
[92]Goldring MB, Birkhead J,Sandell LJ,et al.Interleukin 1 suppresses expression of cartilage-specific types Ⅱ and Ⅸ collagens and increases types Ⅰ and Ⅲ collagens in human chondrocytes[J]. J Clin Invest,1988;82:2026-2037.
[93]郑培銮.艾灸关元穴治休克验案[J].新中医,1990；18(2)：33.
[94]唐省三.针必取三里,灸必加关元[J].山东中医杂志,2002；21(4)：245-246.
[95]唐照亮,宋小鸽,章复清,等.艾灸对关节炎大鼠抗炎消肿作用及细胞因子、自由基影响[J].安徽中医学院学报,2001；20(5)：34.
[96]肖达,陈汉平,赵粹英,等.灸对老年人衰老见证和T细胞亚群的影响[J].辽宁中医杂志,1996；23(12)：563.
[97]夏树林,张贤,谢焕松,等.艾灸治疗对兔KOA软骨损伤及TNF-α、TGF-β1和IGF-1表达调节作用的实验研究[J].江苏中医药,2009；41(6)： 69-71.
[98]洪文学,蔡建,景军.艾灸的热辐射光谱特性研究[J].应用光学,2004；25(4)：1.
[99]李维礼.实用理疗学[M],北京：人民卫生出版社,1993,2：93-129.
[100]费伦,胡颖,郭祖荣,等.传统灸法的现代技术创新[J].上海针灸杂志,2004；23(11)：46.
[101]沈雪勇,费伦,吴耀持,等.特定波段红外灸对放化疗肿瘤患者升白细胞作用观察[J].上海针灸杂志,2005；24(4)：1.
[102]潘浩,胡庆丰,李雄峰,等.补肾壮筋汤对兔早期实验性骨关节炎软骨细胞凋亡及PCNA表达的影响[J].中国中医骨伤科杂志,2004；12(4)：16-20.
[103]肖经难,谢丹,祁开泽.六味地黄丸对兔骨关节炎软骨细胞凋亡的影响[J].湖南中医学院学报,2003；23(5)：11-13.
[104]陈波,郑曙光,马四补.艾灸治疗对兔KOA软骨损伤及MMP-1和TIMP-1表达调节作用的实验研究[J].陕西中医,2009；30(4)：502-504.
[105]丁菊英,艾灸对老年人红细胞免疫和自由基的影响[J].上海针灸杂志,1995；14(1)4-5.
[106]邱洁芬,胡遵荣.试述艾叶的药理作用及临床应用[J].实用中医药杂志,2003；19(8)：446-447.
[107]黄剑,卓廉士,王永渝,等.电针对膝骨关节炎家兔关节液中自由基的影响[J].针刺研究,2008；33(2)：116-119.
[108]谢莉莉,刘光谱.艾灸的治疗作用和机理研究进展[J].针灸临床杂志,2000；16(5)：55.
[109]陈爱民,侯春林,陈庆全,等.几丁糖与透明质酸钠治疗肘关节粘连的对比研究[J].中国矫形外科杂志,2002；10(13)：1289-1290.
[110]程飚,陈峥嵘,董健.关节镜下清理与几丁糖注射治疗老年性骨关节炎55例观察[J].中国矫形外科杂志,2006；14(17)：1345-1346.
[111]王志林,刘世清,陶海鹰,等.关节腔注射几丁糖对兔关节软骨退变的影响[J].中国康复理论与实践,2005；11(11)：919-921.
[112]Sadowski T,Steinmeyer J. Effects of polysulfated glycosaminoglycan and triamcinolone acetonid on the production of proteinases and their inhibitors by IL-lalpha treated articular chondrocytes[J]. Biochem Pharmacol,2002;64 (2):217-227.
[113]刘世清,王海斌,邱波.高脱乙酰度羧甲基壳聚糖对实验性兔膝骨关节炎软骨退行性变的影响[J].中国临床康复,2004；8(26)：5567-5569.
[114]章鸣,高根德.羧甲基几丁糖对兔佐剂性关节炎滑膜细胞体外培养影响实验研究.浙江临床医学,2002；4(6)：405-406.
[115]Lu JX, Prudhommeaux F,Meunier A,et al. Effects of chitosan on rat knee cartilages [J]. Biomaterials,1999;20(20):1937-1944.
[116]吴海山,侯春林,钱齐荣，等.关节内注射壳多糖预防创伤性关节软骨退变的实验研究[J].解放军医学杂志,1995；20(4)：254-256.
[117]熊国胜,陈安民,刘月明,等.软骨细胞在几丁糖和透明质酸钠聚合凝胶中培养的实验研究[J].实用骨科杂志,2005；11(1)：37-40.
[118]Sechriest VF,Miao YJ, Niyibizi C, et al. GAG-augmented polysaccharide hydrogel:a novel biocompatible and biodegradable material to support chondrogenesis [J]. J Biomed Mater Res,2000;49(4):534-541.
[119]Mori T, Okumura M,Matsuura M, et al. Effects of chitin and its derivatives on the proliferation and cytokine production of fibroblasts in vitro[J]. Biomaterials,1997;18(13):947-951.
[120]唐亚东.医用几丁糖治疗膝关节骨性关节炎[J].中国社区医师,2002；18(13)：33.
[1]Liu J, Chi I, Chen G, et al. Prevalence and correlates of functional disability in Chinese older adults[J]. Geriatr Gerontol Int,2009;9(3):253-261.
[2]Bitton R.The economic burden of osteoarthritis[J].Am J Manag Care,2009;15(8 Suppl):S230-235.
[3]Herrero-Beaumont G, Roman-Blas JA,Castaneda S, et al. Primary osteoarthritis no longer primary:three subsets with distinct etiological, clinical,and therapeutic characteristics [J]. Semin Arthritis Rheum,2009;39(2):71-80.
[4]Chen Q.Mouse models and new therapeutic targets for OA[J].J Musculoskelet Neuronal Interact,2008;8(4):311-312.
[5]Lawrence RC, Felson DT, Helmick CG,et al.Estimates of the prevalence of arthritis and other rheumatic conditions in the United States [J].Arthritis Rheum,2008;58(1):26-35.
[6]Grushko G, Schneiderman R,Maroudas A. Some biochemical and biophysical parameters for the study of the pathogenesis of osteoarthritis:a comparison between the processes of ageing and degeneration in human hip cartilage [J]. Connect Tissue Res,1989; 19(2-4):149-176.
[7]Aigner T, Soder S, Gebhard PM, et al. Mechanisms of disease:role of chondrocytes in the pathogenesis of osteoarthritis-structure, chaos and senescence[J]. Nat Clin Pract Rheumatol, 2007;3(7): 391-399.
[8]Shane Anderson A, Loeser RF. Why is osteoarthritis an age-related disease[J]? Best Pract Res Clin Rheumatol,2010;24(1):15-26.
[9]Felson DT. Obesity and osteoarthritis of the knee[J].Bull Rheum Dis,1992; 41 (2):6-7.
[10]Toda Y, Toda T, Takemura Set al. Change in body fat, but not body weight or metabolic correlates of obesity, is related to symptomatic relief of obese patients with knee osteoarthritis after a weight control program [J]. J Rheumatol,1998;25 (11): 2181-2186.
[11]Christensen R, Astrup A, Bliddal H. Weight loss:the treatment of choice for knee osteoarthritis?A randomized trial [J]. Osteoarthritis and Cartilage,2005;13(1):20-27.
[12]van Baar ME,Assendelft WJJ,Dekker J, et al.Effectiveness.of exercise therapy in patients with osteoarthritis of the hip or knee-A systematic review of randomized clinical trials [J]. Arthritis and Rheumatism,1999;42(7):1361-1369.
[13]Paans N, van den Akker-Scheek I, van der Meer K, et al. The effects of exercise and weight loss in overweight patients with hip osteoarthritis:design of a prospective cohort study[J]. BMC Musculoskelet Disord,2009;10:24.
[14]Felson DT, Zhang Y, Anthony JM, et al. Weight loss reduces the risk for symptomatic knee osteoarthritis in women. The Framingham Study [J]. Ann Intern Med,1992;116(7):535-539.
[15]Niu J, Zhang YQ, Torner J, et al. Is obesity a risk factor for progressive radiographic kneeosteoarthritis[J]?Arthritis Rheum,2009;61(3):329-35.
[16]Gabay O, Hall DJ, erenbaum F, et al. Osteoarthritis and obesity: experimental models [J]. Joint Bone Spine,2008;75(6):675-9.
[17]World Health Organisation. The burden of musculoskeletal conditions at the start of the new millenium Report of a WHO Scientific Group WHO Technical Report Series No 919. Geneva, WHO; 2003.
[18]Andersen RE, Crespo CJ, Ling SM, et al. Prevalence of significant knee pain among older Americans:results from the Third National Health and Nutrition Examination Survey[J].J Am Geriatr Soc,1999;47(12):1435-1438.
[19]Thomas E, Peat G, Harris L, et al. The prevalence of pain and pain interference in a general population of older adults:cross-sectional findings from the North Staffordshire Osteoarthritis Project(NorStOP) [J].Pain,2004;110(1-2):361-368.
[20]Anderson JJ,Felson DT. Factors associated with osteoarthritis of the knee in the first national Health and Nutrition Examination Survey (HANES I). Evidence for an association with overweight, race, and physical demands of work[J]. Am J Epidemiol,1988;128(1):179-89.
[21]Jordan JM, Linder GF, Renner JB, et al. The impact of arthritis in rural populations [J].Arthritis Care Res,1995;8(4):242-250.
[22]Jordan JM, Renner JB, Luta G, et al. Hip osteoarthritis is not rare in African-Americans and is different than in Caucasians[J]. Arthritis Rheum,1997;40 (Suppl):S236.
[23]Clark AG, Jordan JM,Vilim VV,et al. Serum cartilage oligomeric matrix protein reflects osteoarthritis presence and severity: the Johnston County Osteoarthritis Project [J]. Arthritis Rheum,1999;42:2356-2364.
[24]Spector TD,Cicuttini F,Baker J,et al.Genetic influences on osteoarthritis in women:a twin study [J]. BMJ,1996;312(7063): 940-943.
[25]Chapman K,Mustafa Z, Irven C, et al. Osteoarthritis-susceptibility locus on chromosome llq, detected by linkage [J].Am J Hum Genet,1999;65(1):167-174.
[26]MacGregor AJ, Li Q, Spector TD, et al.The genetic influence on radiographic osteoarthritis is site specific at the hand, hip and knee [J].Rheumatology (Oxford),2009;48(3):277-280.
[27]Sharma L, Lou C, Felson DT, et al. Laxity in healthy and osteoarthritic knees [J]. Arthritis Rheum,1999;42(5):861-870.
[28]Sharma L. Proprioceptive impairment in osteoarthritis [J]. Rheum Dis Clin North Am,1999;25(2):299-314.
[29]Petrella RJ, Lattanzio PJ, Nelson MG. Effect of age and activity on knee joint proprioception[J]. Am J Phys Med Rehabil,1997; 76(3):235-241.
[30]Sharma L, Pai YC,Holtkamp K, et al. Is knee joint proprioception worse in the arthritic knee versus the unaffected knee in unilateral knee osteoarthritis[J]?Arthritis Rheum,1997;40(8): 1518-1525.
[31]Felson DT, Chaisson CE, Hill CL, et al.The association of bone marrow lesions with pain in knee osteoarthritis[J]. Ann Intern Med,2001;134(7):541-549.
[32]Dequeker J,Mokassa L, Aerssens J. Bone density and osteo-arthritis [J].J Rheumatol,1995;43(Suppl):98-100.
[33]Lajeunesse D,Massicotte F, Pelletier J-P, et al.Subchondral bone sclerosis in osteoarthritis:not just an innocent bystander[J].Mod Rheumatol,2003; 13(1):7-14.
[34]Brandi ML, Collin-Osdoby P.Vascular biology and the skeleton [J].J Bone Miner Res,2006;21(2):183-192.
[35]Felson DT, McLaughlin S, Goggins J, et al.Bone marrow edema and its relation toprogression of knee osteoarthritis[J]. Ann Intern Med,2003;139 (5Pt1):330-336.
[36]Hunter DJ, Zhang Y, Niu J, et al. Increase in bone marrow lesions associated with cartilage loss:a longitudinal magnetic resonance imaging study of knee osteoar-thritis [J]. Arthritis Rheum,2006;54(5):1529-1535.
[37]Garnero P, Peterfy C, Zaim S, et al. Bone marrow abnormalities on magnetic resonance imaging are associated with type Ⅱ collagen degradation in knee osteoarthritis:a three-month longitudinal study [J]. Arthritis Rheum,2005; 52.(9):2822-2829.
[38]Zhai G, Blizzard L, Srikanth V,et al. Correlates of knee pain in older adults:Tasmanian Older Adult Cohort Study[J]. Arthritis Rheum,2006;55(2):264-271.
[39]Carrino JA, Blum J,Parellada JA, et al. MRI of bone marrow edema-like signal in the pathogenesis of subchondral cysts [J]. Osteoarthritis Cartilage,2006;14(10):1081-1085.
[40]Arnoldi CC, Linderholm H, Mussbichler H. Venous engorgement and intraosseoushypertension in osteoarthritis of the hip [J].J Bone Joint Surg Br,1972;54(3):409-421.
[41]Wang L, Fritton SP, Weinbaum S, et al.On bone adaptation due to venous stasis [J].J Biomech,2003;36(10):1439-1451.
[42]Arnoldi CC.The relationship between intraosseous and intraarticular pressure. In:Arlet J,Ficat RP,Hungerford DS, eds. Bone circulation[J]. Baltimore:Williams and Wilkins,1984; 213-215.
[43]Lucht U, Djurhuus JC, S(?)rensen S, et al. The relationship between increasing intraarticular pressures and intraosseous pressures in the juxtaarticular bones. An experimental investigation in dogs[J]. Acta OrthopScand,1981;52(5):491-495.
[44]Wood DD, Ihrie EJ, Dinarello CA, et al. Isolation of an interleukin-1-like factor from human joint effusions[J]. Arthritis Rheum,1983;26(8):975-983.
[45]Kay JD, Gouze E, Oligino TJ, et al. Intra-articular gene delivery and expression of interleukin-1Ra mediated by self-complementary adeno-associated virus [J].J Gene Med.2009;11 (7):605-614.
[46]Goldring MB, Birkhead J,Sandell LJ, et al. Interleukin 1 suppresses expression of cartilage-specific types II and IX collagens and increases types I and III collagens in human chondrocytes[J]. J Clin Invest,1988; 82:2026-2037.
[47]Manacu CA,Martel-Pelletier J, Roy-Beaudry M, et al. Endothelin-1 in osteoarthritic chondrocytes triggers nitric oxide production and upregulates collagenase production[J]. Arthritis Res Ther,2005;2:324-332.
[48]管剑龙,施桂英.基质金属蛋白酶与骨关节炎[J].中华风湿病学杂志,2000；4(1)：54-55.
[49]Kobayashi M, Squires GR, Mousa A, et al. Role of interleukin-1 and tumor necrosis factor alpha in matrix degradation of human osteoarthritic cartilage[J]. Arthritis Rheum,2005;52(1):128-135.
[50]Rowan AD, Hui W, Cawston TE, et al. Adenoviral gene transfer of interleukin-1 in combination with oncostatin M induces significant joint damage in a murine model. Am J Pathol, 2003;162(6):1975-1984.
[51]Hui W, Rowan AD, Richards CD, Cawston TE. Oncostatin M in combination with tumor necrosis factor alpha induces cartilage damage and matrix metalloproteinase expression in vitro and in vivo. Arthritis Rheum,2003;48(12):3404-3418.
[52]Iwanaga H, Matsumoto T, Enomoto H, et al. Enhanced expression of insulin-like growth factor-binding proteins in human osteoarthritic cartilage detected by immunohistochemistry and in situ hybridization[J]. Osteoarthritis Cartilage,2005;13 (5): 439-448.
[53]Sgaglione NA,Miniaci. A, Gillogly SD, et al. Update on advanced surgical techniques in the treatment of traumatic focal articular cartilage lesions in the knee [J]. Arthroscopy,2002; 18 (2Suppl1):9-32.
[54]Grimaud E, Heymann D, Redini F. Recent advances in TGF-beta effects on chondrocyte metabolism. Potential therapeutic roles of TGF-beta in cartilage disorders [J]. Cytokine Growth Factor Rev,2002;13(3):241-257.
[55]Sellers RS, Zhang R, Glasson SS, et al. Repair of articular cartilage defects one year after treatment with recombinant human bone morphogenetic protein-2 (rhBMP-2) [J]. J Bone Joint Surg Am,2000; 82(2):151-160.
[56]Sanyal A, Oursler MJ, Clemens VR,et al. Temporal expression patterns of BMP receptors and collagen Ⅱ(B)during periosteal chondrogenesis [J].J Orthop Res,2002;20(1):58-65.
[57]Hashimoto S, Setareh M, Ochs RL, et al. Fas/Fas ligand expression and induction of opoptosis in chondrocytes [J]. Arthritis Rheum,1997;40(8)1749-1755.
[58]Tak a cs-Buia L, Iordachel C,Efimov N, et al. Pathogenesis of osteoarthritis:chondrocyte replicative senescence or apoptosis[J].Cytometry B Clin Cytom,2008;74(6):356-362.
[59]Heran F,Herand A,Harmand MF. Apoptosis in normal and osteo-arthric human articular cartilage[J]. Ann Rheum Dis,2000,59 (12):959.
[60]Nakagawa T, Yasuda T, Hoshikawa H, et al.LOX-1 expressed in cultured rat chondrocytes mediates oxidized LDL-induced cell death-possible role of dephosphorylation of Akt [J]. Biochem Biophys Rescommun,2002;299(1):91-97.
[61]Kim HA, Lee YJ, Seong SC,et al.Apoptotic chondrocyte death in human osteoarthritis [J]. Rheumatol,2000;27(2):455-462.
[62]Ea HK, Monceau V, Camors E,et al. Annexin V overexpression increased joint chondrocyte apoptosis induced by basic calcium phosphate crystals[J].Ann Rheum Dis,2008;67(11):1617-1625.
[63]Kawaguchi H.Endochondral ossification signals in cartilage degradation during osteoarthritis progression in experimental mouse models [J].Mol Cells,2008;25(1):1-6.
[64]Yang L,Carlson SG,McBurney D, et al.Multiple signals induce endoplasmic reticulum stress in both primary and immortalized chondrocytes resulting in loss of differentiation, impaired cell growth, and apoptosis [J].J Biol Chem,2005;280(35):31156-31165.
[65]Hughes FJ, Buttery LD,Hukkanen MV, et al. Cytokine-induced prostaglandin E2 synthesis and cyclooxygenase-2 activity are regulated both by a nitric oxide-dependent and-independent mechanism in rat osteoblasts in vitro [J].J Biol Chem,1999;274 (3):1776-1782.
[66]Okamoto K, Kobayashi T, Kobata T, et al. Fas-associated death domain protein is a Fas-mediated apoptosis modulator in synoviocytes [J]. Rheumatology (Oxford),2000;39(5):471-480.
[67]Wu GJ, Chen TG, Chang HC,et al. Nitric oxide from bothexogenous and endogenous sources activates mitochondria-dependent events and induces insults to human chondrocytes [J].J Cell Biochem,2007;101(6):1520-1531.
[68]Maneiro E, Lopez-Armada MJ,de Andres MC, et al. Effect of nitric oxide on mitochondrial respiratory activity of human articular chondrocytes [J].Ann Rheum Dis,2005;64(3):388-395.
[69]Del Carlo M Jr,Loeser RF.Nitric oxide-mediated chondrocyte cell death requires the generation of additional reactive oxygen species [J]. Arthritis Rheum,2002;46 (2):394-403.
[70]Lee SW, Lee HJ, Chung WT, et al.TRAIL induces apoptosis of chondrocytes and influences the pathogenesis of experimentally induced rat osteoarthritis[J]. Arthritis Rheum,2004;50 (2): 534-542.
[71]Okazaki R, Sakai A, Ootsuyama A, et al. Apoptosis and p53 expression in chondrocytes relate to degeneration in articular cartilage of immobilized knee joints [J].J Rheumatol,2003; 30 (3):559-566.
[72]Larsen CJ.The BCL2 gene, prototype of a gene family that controls programmed cell death (apoptosis) [J]. Ann Genet,1994; 37(3):121-134.
[73]吕红斌,徐大启,胡建中,等.兔骨关节炎软骨细胞中caspase-3表达及其细胞凋亡的研究[J].临床医学研究,2007；24(9)：1441-1443.
[74]Pelletier JP, Jovanovic DV, Lascau-Coman V, et al. Selective inhibition of inducible nitric oxide synthase reduces progression of experimental osteoarthritis in vivo:possible link with the reduction in chondrocyte apoptosis and caspase 3 level [J]. Arthritis Rheum,2000;43(6):1290-1299.
[75]Hashimoto S,Ochs RL,Komiya S, et al. Linkage of chondrocyte apoptosis and cartilage degradation in human osteoarthritis [J]. Arthritis Rheum,1998;41(9):1632-1638.
[76]Batiste DL, Kirkley A, Laverty S, et al. Ex vivo characterization of articular cartilage and bone lesions in a rabbit ACL transection model of osteoarthritis using MRI and micro-CT[J]. Osteoarthritis Cartilage,2004;12(12):986-996.
[77]欧云生,安洪,鼠骨关节炎动物模型建立的现状[J].中国比较医学杂志,2004；14(1)：41-44.
[78]Guzman RE, Evans MG, Bove S, et al.Mono-iodoacetate-induced histologic changes in subchondral bone and articular cartilage of rat femorotibial joints:an animal model of osteoarthritis [J]. Toxicol Pathol.2003;31(6):619-624.
[79]Mahr S,Menard J,Krenn V, et al.Sexual dimorphism in the osteoarthritis of STR/ort mice may be linked to articular cytokines [J].Ann Rheum Dis,2003;62(12):1234-1237.
[80]杨峰,史宗道.用木瓜蛋白酶建立兔颞颌关节骨关节炎模型的研究[J]华西口腔医学杂志,2002；20(5)：330-332.
[81]石辉,何斌,史晨辉,等.用尿激酶型纤溶酶原激活物建立兔骨关节炎模型的研究[J].石河子大学学报(自然科学版),2006,24(1)：66-69.
[82]汪青春,沈培芝,王海彬.骨关节炎动物模型的建立及选择[J].中医正骨,1998,10(3)：39-40.
[83]江捍平，王大平.骨关节炎动物模型[J].中国现代医学杂志,2004,14(6)：153-156.
[84]朱彤,刘勇章,胡小鹏,等.家兔膝关节骨关节炎动物模型的建立[J].医学临床研究,2006,23(8)：1188-1190.
[85]胡阿威,张磊,张功礼,等.改良Hulth法骨关节炎动物模型的建立[J].临床论坛,2003,3(9)：5-6.
[86]白希壮,任继尧.选择性臀肌切断诱发骨关节炎实验模型[J].中华骨科杂志,1994,14(2)：118-120.
[87]Videman T.Experimental osteoarthritis in the rabbit: comparison of different periods of repeated immobilization [J]. Acta Orthop Scand,1982,53(3):339-347.
[88]邱贵兴,王桂生.兔膝关节制动引起关节软骨退变的实验研究[J].中华骨科杂志,1987；7：175-177.
[89]Fransen M,McConnell S. Land-based exercise for osteoarthritis of the knee:a metaanalysis of randomized controlled trials [J]. J Rheumatol,2009;36(6):1109-1117.
[90]Messier SP,Loeser RF,Mitchell MN, et al.Exercise and weight loss in obese older adults with knee osteoarthritis:a preliminary study [J].J Am Geriatr Soc,2000; 48 (9):1062-1072.
[91]Deyle GD, Henderson NE, Matekel RL, et al. Effectiveness of manual physical therapy and exercise in osteoarthritis of the knee. A randomized, controlled trial[J]. Ann Intern Med,2000;132 (3): 173-181.
[92]Iwamoto J,Takeda T,Sato Y.Effect of muscle strengthening exercises on the muscle strength in patients with osteoarthritis of the knee [J]. Knee,2007;14(3):224-230.
[93]Mazzuca SA, Brandt KD, Katz BP, et al. Effects of self-care education on the health status of inner-city patients with osteoarthritis of the knee[J]. Arthritis Rheum,1997;40(8): 1466-1474.
[94]Tohyama H, Yasuda K, Kaneda K. Treatment of osteoarthritis of the knee with heel wedges [J]. Int Orthop,1991;15(1):31-33.
[95]Kirkley A, Webster-Bogaert S, Litchf ield R, et al.The effect of bracing on varus gonarthrosis[J].J Bone Joint Surg Am,1999; 81 (4):539-348.
[96]Takahashi KA, Tonomura H,Arai Y, et al. Hyperthermia for the treatment of articular cartilage with osteoarthritis [J].Int J Hyperthermia,2009;25(8):661-667.
[97]Naito K, Watari T,Muta T, et al. Low-intensity pulsed ultrasound (LIPUS) increases the articular cartilage type Ⅱ collagen in a rat osteoarthritis model [J].J Orthop Res,2010; 28 (3):361- 369.
[98]Silva LE,Valim V,Pessanha AP,et al.Hydrotherapy versus conventional land-based exercise for the management of patients with osteoarthritis of the knee:a randomized clinical trial [J].Phys Ther,2008;88(1):12-21.
[99]Gremeaux V,Renault J,Pardon L,et al.Low-frequency electric muscle stimulation combined with physical therapy after total hip arthroplasty for hip osteoarthritis in elderly patients:a randomized controlled trial[J]. Arch Phys Med Rehabil,2008; 89(12):2265-2273.
[100]Lin YS,Huang MH,Chai C. Effects of helium-neon laser on the mucopolysaccharide induction in experimental osteoarthritic cartilage[J]. Osteoarthritis Cartilage,2006;14(4):377-383.
[101]Lu TW, Wei IP, Liu YH, et al. Immediate effects of acupuncture on gait patterns in patients with knee osteoarthritis[J].Chin Med J (Engl),2010; 123(2):165-172.
[102]唐照亮,宋小鸽,章复清,等.艾灸对关节炎大鼠抗炎消肿作用及细胞因子、自由基影响[J].安徽中医学院学报,2001；20(5)：34.
[103]李晓愁,张露芬,郭顺根,等.逆灸对随后佐剂性关节炎大鼠早期及继发期炎性细胞因子和局部足肿胀的影响[J].中国临床康复,2005；9(15)：123-125.
[104]王磊,李学武,张莉.艾灸疗法作用机理国内外研究进展[J].中国针灸,2001；21(9)：567-570.
[105]肖达,陈汉平,赵粹英,等.灸对老年人衰老见证和T细胞亚群的影响[J].辽宁中医杂志,1996；23(12)：563.
[106]田丰玮,宋军,杨金蓉.艾叶油乳膏剂对兔膝骨性关节炎关节冲洗液中细胞因子含量的影响[J].中医正骨,2005；17(12)：51.
[107]夏树林,张贤,谢焕松,等.艾灸治疗对兔KOA软骨损伤及TNF-α、 TGF-β1和IGF-1表达调节作用的实验研究[J].江苏中医药,2009；41(6)：69-71.
[108]Altman R,Barkin RL. Topical therapy for osteoarthritis:clinical and pharmacologic perspectives[J]. Postgrad Med,2009; 121(2):139-147.
[109]Puenpatom RA,Victor T. Increased prevalence of metabolic syndrome inindividuals with osteoarthritis:an analysis of NHANES III data [J]. Postgrad Med,2009;121(6):9-20.
[110]Geba Gregory P, Weaver Arthur L, Polis Adam B, et al. Efficacy of rofecoxib, celecoxib, and acetaminophen in osteoarthritis of the knee:a randomized trial [J].JAMA,2002;287(1):64-71.
[111]Haf lah NH, Jaarin K,Abdullah S, et al. Palm vitamin E and glucosamine sulphate in the treatment of osteoarthritis of the knee [J]. Saudi Med J,2009; 30(11):1432-1438.
[112]Naito K, Watari T, Furuhata A, et al. Evaluation of the effect of glucosamine on an experimental rat osteoarthritis model [J]. Life Sci,2010. [Epub ahead of print]
[113]Shimizu M, Higuchi H, Takagishi K, et al. Clinical and biochemical characteristics after intra-articular injection for the treatment of osteoarthritis of the knee:prospective randomized study of sodium hyaluronate and corticosteroid [J].J Orthop Sci,2010; 15 (1):51-56.
[114]Zhou JL, Liu SQ, Qiu B, et al.The protective effect of sodium hyaluronate on the cartilage of rabbit osteoarthritis by inhibiting peroxisome proliferator-activated receptor-gamma messenger RNA expression [J]. Yonsei Med J,2009;50(6):832-827.
[115]刘世清,王海斌,邱波.高脱乙酰度羧甲基壳聚糖对实验性兔膝骨关节炎软骨退行性变的影响[J].中国临床康复,2004；8(26)：5567- 5569.
[116]Lu JX,Prudhommeaux F, Meunier A,et al.Effects of chitosan on rat knee cartilages [J]. Biomaterials,1999; 20(20):1937-1944.
[117]吴海山,侯春林,钱齐荣,等.关节内注射壳多糖预防创伤性关节软骨退变的实验研究[J].解放军医学杂志,1995；20(4)：254-256.
[118]王志林,刘世清,陶海鹰,等.关节腔注射几丁糖对兔关节软骨退变的影响[J].中国康复理论与实践,2005；11(11)：919-921.
[119]章鸣,高根德.羧甲基几丁糖对兔佐剂性关节炎滑膜细胞体外培养影响实验研究.浙江临床医学,2002；4(6)：405-406.
[120]熊国胜,陈安民,刘月明,等.软骨细胞在几丁糖和透明质酸钠聚合凝胶中培养的实验研究[J].实用骨科杂志,2005；11(1)：37-40.
[121]Sechriest VF,Miao YJ, Niyibizi C, et al. GAG-augmented polysaccharide hydrogel:a novel biocompatible and biodegradable material to support chondrogenesis [J].J Biomed Mater Res,2000; 49 (4):534-541.
[122]Mori T, Okumura M,Matsuura M,et al. Effects of chitin and its derivatives on the proliferation and cytokine production of fibroblasts in vitro[J]. Biomaterials,1997; 18 (13):947-951.
[123]唐亚东.医用几丁糖治疗膝关节骨性关节炎[J].中国社区医师,2002；18(13)：33.
[124]Akizuki S,Yasukawa Y,Takizawa T.Does arthroscopic abrasion arthroplasty promote cartilage regeneration in osteoarthritic knees with eburnation? A prospective study of high tibial osteotomy with abrasion arthroplasty versus high tibial osteotomy alone [J]. Arthroscopy,1997;13(1):9-17.
[125]Miller BS,Steadman JR,Briggs KK,et al.Patient satisfaction and outcome after microfracture of the degenerative knee[J].J Knee Surg,2004;17(1):13-17.
[126]Henderson I,Lavigne P, Valenzuela H, et al. Autologous chondrocyte implantation:superior biologic properties of hyaline cartilage repairs [J]. Clin Orthop Relat Res,2007; 455: 253-261.
[127]Gillogly SD,Myers TH, Reinold MM. Treatment of full-thickness chondral defects in the knee with autologous chondrocyte implantation[J].J Orthop Sports Phys Ther,2006; 36(10):751-764.
[128]Alberti C. Tissue engineering technologies:just a quick note about transplantation of bioengineered donor trachea and augmentation cystoplasty by de novo engineered bladder tissue[J].G Chir,2009; 30(11-12):514-519.
[129]Evans CH, Gouze E, Gouze JN, et al.Gene therapeutic approaches-transfer in vivo[J].Adv Drug Deliv Rev,2006; 58 (2):243-258.
[130]Santangelo KS, Baker SA, Nuovo G, et al. Detectable reporter gene expression following transduction of adenovirus and adeno-associated virus serotype 2 vectors within full-thickness osteoarthritic and unaffected canine cartilage in vitro and unaffected guinea pig cartilage in vivo[J].J Orthop Res,2010; 28 (2):149-155.