RANKL/OPG在强直性脊柱炎外周关节骨质破坏病理机制中的作用
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摘要
目的：
本研究拟通过检测RANKL、OPG和CD68蛋白在强直性脊柱炎(AS)外周关节滑膜组织中的表达，并以类风湿关节炎(RA)、骨关节炎(OA)患者和健康对照者的外周关节滑膜组织为对照，了解细胞核因子кB受体活化因子配基(RANKL)、护骨素(OPG)和代表单核/巨噬细胞标记的CD68蛋白表达与AS患者炎性关节病理改变及疾病活动性的相关性，试图从炎性关节局部RANKL/OPG平衡调节这一角度进一步探讨AS关节炎症及骨质破坏的发病机制，为AS病情评判与治疗提供理论基础。
方法：
应用单克隆抗体，通过免疫组织化学方法检测13例AS、16例RA、17例OA及6例健康对照关节滑膜组织中RANKL、OPG、CD68蛋白表达及分布状况；鉴于抗酒石酸酸性磷酸酶(TRAP)是破骨细胞或前体细胞的一种标志酶，本研究还采用酶组织化学法分析各组滑膜组织TRAP染色阳性细胞表达及分布状况，通过计算机辅助图象分析系统和半定量分析方法确定RANKL、OPG、CD68以及TRAP在各滑膜组织中表达量之间的差异，分析各因子表达与炎性指标及关节X线分期之间的相关性。
结果：
(1)OPG蛋白在所有13例AS滑膜组织中均有阳性表达，阳性细胞主要分布于滑膜衬里层、衬里下层区域，滑膜软骨交界区OPG表达明显低于滑膜衬里层和衬里下层；2例健康对照滑膜组织中有
军医进修学院博土学位论文RANKL10pe在牙直性脊柱 周关节骨质玻坏痛理机删中的作用
阳性表达，但明显低于AS患者组。RA及OA患者组未见OPG阳
性表达。
（2）AS患者组滑膜组织RANKL表达水平明显升高，阳性细胞
主要见于滑膜组织衬甩层和滑膜软骨交界区。AS 患者组RANKI。
蛋白与RA患者组无明显差异刀A患者组和健康对照组滑膜织织中
未见阳性表达信号。
（3）AS和 RA滑膜组织中 RANKL表达量与关节 X线分州呈小
十 关（十 关系数 r分别为 0．7 3，0．41，P值分别为 0．0 0 3，0．0 ZI）。
（4）CD68蛋白在各组滑膜组织中滑膜细胞中均有表达，主要
表达于滑膜衬里层，AS及RA 患者组滑膜组织中表达强度显著高
于OA和健康对照组。
（5）TRAP染色结果表明，RANKL丰富表达的 AS和 RA i A·
滑膜组织中，TRAP 染色阳性细胞数量增加，AS 患者组滑腴组织
TRAP 阳性细胞百分数显著低于RA 组。在滑膜－软骨交界区域，
＊＊＊P着色强度明显增加，＊A及正常对照组滑膜中 ＊＊AP阳忖细
胞少见。
（6）RA组RANKL表达与滑膜组织中的TRAP阳性细胞百分
数呈正相关（十关系数r—0．442，P＝0．043）。
结论：
（l）AS患者组滑膜组织中OPG表达水平明显高于健康对照组
（P＜0刀01），而＊A、＊A滑膜组织中未见＊PG表达，说明＊PG的
高水平表达是滑膜组织对炎症反应／关节破坏所特有的表现，OPG
的局部表达是维持AS关节骨代谢稳定的重要因素，这可能是大多
数AS患者外周关节受累预后好于RA的原因之一。
（2）AS患者组滑膜软骨交界区中OPG表达量显著减少可能是
4
军医进修学院博士学位论文RANKL10PG在羹盅性存柱 周关节骨质玻坏病 制中的作用
导致关节骨质破坏的重要原因，提示关节局部应用 O P G治疗有 l。J能
改善受累关节的骨质破坏状况。
（3）AS患者组受累关节滑膜组织中RANKL表达量明显Ifti十木
出现关节破坏的AS患者，其表达量与关节骨质破坏程度密切川关，
说明RANKL在AS患者骨质破坏病理机制中起重要作用，AS思K
滑膜组织中RANKL表达模式与RA相似，提示AS思者骨质破坏的
病理机制可能与RA类似。
（4） 炎性关节滑膜组织CD68阳性细胞及TRAP阳性细胞数＿量
增加为破骨细胞的生成提供了细胞数量基础，这些均是RANKL过
度表达的结果。RANKL 表达与骨质破坏的密切相关提示抑制
RANKL活性就可能有效阻断破骨细胞前体细胞向破骨细胞的转化，
达到对炎性关节疾病的骨质破坏的治疗。
OBJECTIVES
To detect the RANKL, OPG and CD68 protein levels in synovial tissues from ankylosing spondylitis(AS ) patients and compare the expression levels of RANKL, OPG and CD68 protein in AS , rheumatoid arthritis(RA), and osteoarthritis(OA) and normal synovial tissues. RANKL/OPG expressions were correlated with pathological changes of inflammatory joints to explore the role of RANKL / OPG in the pathogenesis of bone destruction in AS. METHODS
Immunohistochemical analysis was performed using monoclonal antibodies to detect RANKL, OPG and CD68 protein expression in 13 AS, 16 RA,17 OA patients and 6 healthy controls. The presence of TRAP positive cells in the synovial tissues of patients with AS and RA was examined by enzyme histochemistry. The labeled synovial tissue sections were quantified by digital image analysis and semiquantitative analysis to compare the expression of RANKL, OPG, CD68 and TRAP positve cells in different patient groups and normal subjects. In addition, RANKL expression and OPG expression were correlated with certain inflammatory indices (including ESR, CRP, blood platelet count) and radiological stage of involved joints respectively. RESULTS
(1) Positive staining of OPG was seen in all 13 AS patients. OPG expression was predominantly seen in the synovial lining layer and subling areas. Positive staining of OPG was also found in the synovial tissues of 2 normal subjects, but the OPG levels were significantly lower. No positive staining of OPG was found in synovial tissues from all patients with RA and OA.
(2) Positive staining of RANKL was seen respectively in all 13 AS patients and 16 patients with RA, and positive expression was distributed predominantly in the synovial lining layer and at synovium-cartilage junctions. There was no significant difference between levels of RANKL expression in tissues from patients with AS and in tissues from RA. No positive staining of RANKL was observed in 6 normal subjects and all OA patients.
(3) Positive correlation was found between RANKL protein expression and X-ray stage of involved joints destruction of patients with AS and RA (r=0.73,0.41, P=0.003,0.021 respectively).
(4) Positive staining of CD68 was seen in synovial tissues from all the patients with AS, RA, OA and normal subjects, and the expression levels of CD68 from patients with AS and RA were higher than those from OA patients and healthy subjects. The CD68 positive cells were abundant mainly in lining layer.
(5) In areas where elevated RANKL expression levels were present, the number of TRAP positive staining cells were found significantly increased in AS and RA synovium. The percentage of TRAP positive cells in synovium from AS patients was significantly lower than that from RA patients. The intensity of TRAP staining at synovium-cartilage junctions was notably increased. TRAP positive cells were rarely observed in synovium from OA patients and normal controls.
(6) There was positive correlation between the number of TRAP positive cells and the RANKL expression (r=0.442, P-0.043) in RA patients. CONCLUSIONS
(1) Higher levels of OPG were expressed in synovial tissues from AS patients than in tissues from normal subjects (P<0.001). No OPG was found in synovial tissues from patients with RA and OA, suggesting that OPG expression may be the consequence
of synoviocytes' reaction to inflammation and that OPG may have a protective effect on bone integrity. This serves a possible explanation for the better prognosis of the peripheral joint involvement in AS patients in comparison with RA patients.
(2) Decrease in OPG levels at synovium-cartilage junctions is likely to be the main cause of bone destruction in AS patients. OPG may well have a therapeutic role in preventing bone destruction in AS.
(3) Higher levels of RANKL were expressed in synovial tissues from AS patients with bone destruction than in tissues from subjects with healthy joints. RANKL protein expression was closely related with the degree of bone destruction, suggesting that it play a role in
本研究拟通过检测RANKL、OPG和CD68蛋白在强直性脊柱炎(AS)外周关节滑膜组织中的表达，并以类风湿关节炎(RA)、骨关节炎(OA)患者和健康对照者的外周关节滑膜组织为对照，了解细胞核因子кB受体活化因子配基(RANKL)、护骨素(OPG)和代表单核/巨噬细胞标记的CD68蛋白表达与AS患者炎性关节病理改变及疾病活动性的相关性，试图从炎性关节局部RANKL/OPG平衡调节这一角度进一步探讨AS关节炎症及骨质破坏的发病机制，为AS病情评判与治疗提供理论基础。
方法：
应用单克隆抗体，通过免疫组织化学方法检测13例AS、16例RA、17例OA及6例健康对照关节滑膜组织中RANKL、OPG、CD68蛋白表达及分布状况；鉴于抗酒石酸酸性磷酸酶(TRAP)是破骨细胞或前体细胞的一种标志酶，本研究还采用酶组织化学法分析各组滑膜组织TRAP染色阳性细胞表达及分布状况，通过计算机辅助图象分析系统和半定量分析方法确定RANKL、OPG、CD68以及TRAP在各滑膜组织中表达量之间的差异，分析各因子表达与炎性指标及关节X线分期之间的相关性。
结果：
(1)OPG蛋白在所有13例AS滑膜组织中均有阳性表达，阳性细胞主要分布于滑膜衬里层、衬里下层区域，滑膜软骨交界区OPG表达明显低于滑膜衬里层和衬里下层；2例健康对照滑膜组织中有
军医进修学院博土学位论文RANKL10pe在牙直性脊柱 周关节骨质玻坏痛理机删中的作用
阳性表达，但明显低于AS患者组。RA及OA患者组未见OPG阳
性表达。
（2）AS患者组滑膜组织RANKL表达水平明显升高，阳性细胞
主要见于滑膜组织衬甩层和滑膜软骨交界区。AS 患者组RANKI。
蛋白与RA患者组无明显差异刀A患者组和健康对照组滑膜织织中
未见阳性表达信号。
（3）AS和 RA滑膜组织中 RANKL表达量与关节 X线分州呈小
十 关（十 关系数 r分别为 0．7 3，0．41，P值分别为 0．0 0 3，0．0 ZI）。
（4）CD68蛋白在各组滑膜组织中滑膜细胞中均有表达，主要
表达于滑膜衬里层，AS及RA 患者组滑膜组织中表达强度显著高
于OA和健康对照组。
（5）TRAP染色结果表明，RANKL丰富表达的 AS和 RA i A·
滑膜组织中，TRAP 染色阳性细胞数量增加，AS 患者组滑腴组织
TRAP 阳性细胞百分数显著低于RA 组。在滑膜－软骨交界区域，
＊＊＊P着色强度明显增加，＊A及正常对照组滑膜中 ＊＊AP阳忖细
胞少见。
（6）RA组RANKL表达与滑膜组织中的TRAP阳性细胞百分
数呈正相关（十关系数r—0．442，P＝0．043）。
结论：
（l）AS患者组滑膜组织中OPG表达水平明显高于健康对照组
（P＜0刀01），而＊A、＊A滑膜组织中未见＊PG表达，说明＊PG的
高水平表达是滑膜组织对炎症反应／关节破坏所特有的表现，OPG
的局部表达是维持AS关节骨代谢稳定的重要因素，这可能是大多
数AS患者外周关节受累预后好于RA的原因之一。
（2）AS患者组滑膜软骨交界区中OPG表达量显著减少可能是
4
军医进修学院博士学位论文RANKL10PG在羹盅性存柱 周关节骨质玻坏病 制中的作用
导致关节骨质破坏的重要原因，提示关节局部应用 O P G治疗有 l。J能
改善受累关节的骨质破坏状况。
（3）AS患者组受累关节滑膜组织中RANKL表达量明显Ifti十木
出现关节破坏的AS患者，其表达量与关节骨质破坏程度密切川关，
说明RANKL在AS患者骨质破坏病理机制中起重要作用，AS思K
滑膜组织中RANKL表达模式与RA相似，提示AS思者骨质破坏的
病理机制可能与RA类似。
（4） 炎性关节滑膜组织CD68阳性细胞及TRAP阳性细胞数＿量
增加为破骨细胞的生成提供了细胞数量基础，这些均是RANKL过
度表达的结果。RANKL 表达与骨质破坏的密切相关提示抑制
RANKL活性就可能有效阻断破骨细胞前体细胞向破骨细胞的转化，
达到对炎性关节疾病的骨质破坏的治疗。
OBJECTIVES
To detect the RANKL, OPG and CD68 protein levels in synovial tissues from ankylosing spondylitis(AS ) patients and compare the expression levels of RANKL, OPG and CD68 protein in AS , rheumatoid arthritis(RA), and osteoarthritis(OA) and normal synovial tissues. RANKL/OPG expressions were correlated with pathological changes of inflammatory joints to explore the role of RANKL / OPG in the pathogenesis of bone destruction in AS. METHODS
Immunohistochemical analysis was performed using monoclonal antibodies to detect RANKL, OPG and CD68 protein expression in 13 AS, 16 RA,17 OA patients and 6 healthy controls. The presence of TRAP positive cells in the synovial tissues of patients with AS and RA was examined by enzyme histochemistry. The labeled synovial tissue sections were quantified by digital image analysis and semiquantitative analysis to compare the expression of RANKL, OPG, CD68 and TRAP positve cells in different patient groups and normal subjects. In addition, RANKL expression and OPG expression were correlated with certain inflammatory indices (including ESR, CRP, blood platelet count) and radiological stage of involved joints respectively. RESULTS
(1) Positive staining of OPG was seen in all 13 AS patients. OPG expression was predominantly seen in the synovial lining layer and subling areas. Positive staining of OPG was also found in the synovial tissues of 2 normal subjects, but the OPG levels were significantly lower. No positive staining of OPG was found in synovial tissues from all patients with RA and OA.
(2) Positive staining of RANKL was seen respectively in all 13 AS patients and 16 patients with RA, and positive expression was distributed predominantly in the synovial lining layer and at synovium-cartilage junctions. There was no significant difference between levels of RANKL expression in tissues from patients with AS and in tissues from RA. No positive staining of RANKL was observed in 6 normal subjects and all OA patients.
(3) Positive correlation was found between RANKL protein expression and X-ray stage of involved joints destruction of patients with AS and RA (r=0.73,0.41, P=0.003,0.021 respectively).
(4) Positive staining of CD68 was seen in synovial tissues from all the patients with AS, RA, OA and normal subjects, and the expression levels of CD68 from patients with AS and RA were higher than those from OA patients and healthy subjects. The CD68 positive cells were abundant mainly in lining layer.
(5) In areas where elevated RANKL expression levels were present, the number of TRAP positive staining cells were found significantly increased in AS and RA synovium. The percentage of TRAP positive cells in synovium from AS patients was significantly lower than that from RA patients. The intensity of TRAP staining at synovium-cartilage junctions was notably increased. TRAP positive cells were rarely observed in synovium from OA patients and normal controls.
(6) There was positive correlation between the number of TRAP positive cells and the RANKL expression (r=0.442, P-0.043) in RA patients. CONCLUSIONS
(1) Higher levels of OPG were expressed in synovial tissues from AS patients than in tissues from normal subjects (P<0.001). No OPG was found in synovial tissues from patients with RA and OA, suggesting that OPG expression may be the consequence
of synoviocytes' reaction to inflammation and that OPG may have a protective effect on bone integrity. This serves a possible explanation for the better prognosis of the peripheral joint involvement in AS patients in comparison with RA patients.
(2) Decrease in OPG levels at synovium-cartilage junctions is likely to be the main cause of bone destruction in AS patients. OPG may well have a therapeutic role in preventing bone destruction in AS.
(3) Higher levels of RANKL were expressed in synovial tissues from AS patients with bone destruction than in tissues from subjects with healthy joints. RANKL protein expression was closely related with the degree of bone destruction, suggesting that it play a role in
引文
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38. Tak PP, Breedveld FC. Analysis of serial synovial biopasies as a screening method for predicting the effects of therapeutic interventions, J Clin Rheumatol 1997; 3: 186-7
39. Youssef PP, Triantafillou S, Parker A, et al. Variability in cytokine and cell adhesion molecule staining in arthroscopic synovial biopsies: quatification using color video image analysis. J Rheumatol 1997, 24:2291-8.
40. Youssef PP, Triantafillou S, Parker A, et al. Efects of pulse
methylprednisolone on cell adhesion molecules in the synovial membrane in rheumatoid arthritis. Arthritis Rheum 1996, 39:1970-9
41. Krnna MC, Versendaal H, Jonker M, et al. Asymoptomatic synovitis precedes clinical manifest arthritis. Arthritis Rheum 1998, 41:1481-8.
42. Tak PP, Smeets TJM, Daha MR, et al. Analysis of the synotial cellular infiltrate in early rheumatoid synovial tissue in relation to disease activity. Arthritis Rheum 1997, 40:217-25.
43. Tak PP, Smeets TJM, Daha MR, et al. Analysis of the synotial cellular infiltrate in early rheumatoid synovial tissue in relation to disease activity. Arthritis Rheum 1997, 40:217-25.
44. Bresnihan B, Cunnane G, Youssef P, et al. Microscopic messurement of synovial memvrane inflammation in rheumatoid arthritis: proposals for the evaluation of tissue samples by quantitative analysis. Br J Rheumatol 1998, 37:636-42.
45. Youssef PP. Smeets TJM, Bresnihan B, et al. Microscopic measurement of inflammation in the rheumatoid arthritis synovial membrane: a comparison of semiquantiative and quantitatice analysis. Br J Rheumatol 1998, 37:1003-7.
46. Yasuda H, Shima N, Nakagawa N, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteo clastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA, 1998, 95:3597-602.
47.Wong BR, Rho J, Arron J, et al. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J Biol Chem 1997, 272:25190-94.
48.Roodman GD. Cell biology of the osteoclast. Exp Hematol 1999, 27:1229-41.
49.Anderson DM, Maraskovsky E, Billingsley WL, et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 1997, 390: 175-79.
50.Kong YY, Feige U, Sarosi I, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999, 402:304-09.
51.Hofbauer LC, Khosla S, Dunstan CR, et al. The role of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res 2000, 15:2-12.
52.Hofbauer LC, Heufelder AE. The role of receptor activator of nuclear factor-B ligand and osteoproteferin in the pathogentsis and treatment of metabolic bone disease. J Clin Endocr Metab 2000, 85:2355-2363.
53.Redlich K, Hayer S, Ricci R, et al. Ostedclasts are essential for TNF-α mediated joint destruction. J Clin Invest 2002, 110:1419-1427.
54.Lacey DL, Timms E, Tan KL, et al. Osteoprotegeriin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998, 96:3540-3545.
55.Kotake S, Sato K, Kim KJ, et al. Interleukin-6 and soluble
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56.Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 1996, 14:397-440.
57.Bendele A, McComb J, Gould T, et al. Animal models of arthritis: relevance to human disease. Toxicol Pathol 1999, 27:134-42.
58.Panayi GS, Lanchbury JS, Kingsley GH. The importance of the T cell in initiating and maintaining the chronic synovitis of rheumatoid arthritis. Arthritis Rheum 1992, 35:729-35.
59.Fazzalari NL, Kuliwaba JS, Arkins GJ, et al. The ratio of messenger RNA levels of receptor activator of nuclear factor kappaB ligand to osteoprolege in correlates with bone remodeling indices in normal human cancellous cone but not in ostearthritis. J Bone Miner Res 2001, 16:1015-27.
60.Kong YY, Feige U, Sarosi L, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999,403:304-9.
61.Harwood NJ, Kartsogiannis V, Quinn JMW, et al. Activated T lymphocytes support osteoclast formation in vitro. Biochem Biophys Res Commun 1999, 265:144-50.
62.Ji H, Pettit A, Ohmura K, et al. Critical roles for interleukin 1 and tumor necrosis factor a in antibody-induced arthritis. J Exp Med 2002, 196:77-85.
63.Redlich K, Hayer S, Maier A, et al. Tumor necrosis factor
alpha-mediated joint destruction is inhibited by targeting osteoclasts with osteoprotegerin. Arthritis Rheum 2002, 46:785-92.
64.Mori H, Kitazawa R, Mizuki S, et al. RANK ligand, RANK, and OPG expression in type Ⅱ collagen-induced arthritis mouse. Histochem Cell Biol 2002, 117:283-92.
65.Takayanagi H, Lizuka H, Nakagawa T, et al. Involvement of receptor activator of nuclear factor κ B ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum 2000, 43:259-269.
66.Shigeyama Y, PaP T, Kunzler P, et al. Expression of osteoclast differentiation factor in rheumatoid arthritis. Arthritis Rheum 2000, 43:2523-30.
67.Katake S, Udagawa N, Harkada M, et al. Activated human T cells directly induce osteoclastogenesis from human monocytes: possible role of T cells in bone destruction in rheumatoid arthritis patients. Arthritis Rheum 2001, 44:1003-12.
68.Itanaga I, Fujikawa Y, Sabakbar A, et al. Rheumatoid arthritis synovial macrophage-osteoclast differentiation is osteoprotegerin ligand-dependent, J Pathol 2000, 192:97-104.
69.Haynes DR, Crotti TN, Loric M, et al. Osteoprotegerin and receptor activator of nuclear factor kappaB ligand regulate osteoclast formation by cells in the human rheumatoid arthiritic joint. Rheumatol (Oxford) 2001, 40:623-30.
70.Suzuki Y, Tsutmi Y, Nakagawa M, et al. Osteoclast-like cells in an in vitro model of bone destruction by rheumatoid synovuim.
Rheumatol (Oxford) 2001, 40:672-82.
71.Koch A, Campagnuolo G, Bolon B, et al. Kinetics of bone protection by recombinant osteoprotogerin therapy in Lewis rats with mycobacteria-induced adjuvant arthritis. Arthritis Rheum 2001, 44:S267.
72.Romas E, Gillespie MT, Martin TJ. Involvement of receptor activator of NfkappaB ligand and tumor necrosis factor-alpha in bone destruction in rheumatoid arthritis. Bone 2002, 30:340-6.
73.Olee T, Kuhn K, Brinson DC, et al. The osteoprotegerin/ receptor activator of nuclear factor kappaB/receptor activator of nuclear factor kappaB ligand system in cartilage. Arthritis Rheum 2001, 44:2768-76.
74.Pettit AR, Ji H, von Stechow D, et al. TRANCE/RANKL knockout mice are protected from bone erosion in the K/BxN serum transfer model of arthritis. Am J Pathol 2001, 159:1689-1699.
75.Kotake S, Udagawa N, Hakoda M, et al. Activated human T cells directly induce osteoclastogenesis from human monocytes: possible role of T cells in bone destruction in rheumatoid arthritis patients. Arthritis Rheum 2001, 44:1003-12.
76.Kontoyiannis D, Kollias G. Fibroblast biology: synovial fibroblasts in rheumatoid arthritis: leading role or chorus line? Arthritis Res 2000, 2:342-343.
77.Gravallese EM, Manning C, Tsay A, et al. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum 2000, 43:250-258.
78．戴冽，汤美安，尹培达．滑膜巨噬细胞与类风湿关节炎病情活动及关节破坏的相关性．中华风湿病学杂志 1999；2(4)：229-231．
79. Bywaters EGL. Pathological specificity of ankylosing spondylitis: is it yet established? Adv Inflam Res 1985, 9:1-13.
80. Rudwaleit M, Siegert S, Yin Z, et al. Low T cell production of TNF alpha and IFN gamma in ankylosing spondylitis: its relation to HLA-B27 and influence of the TNF-308 gene polymorphism. Ann Rheum Dis 2001, 60:36-42.
81. Baeten D, Damme VN, Bosch VF, et al. Impaired Th1 cytokine production in spondyloarthropathy is restored by anti-TNF alpha. Ann Rheum Dis 2001, 60:750-5.
82. Baeten D, Elli K, Filip V B, et al. Immunomodulatory Effects of Anti-Tumor Necrosis Factor a Therapy on Synovium in Spondylarthropathy Arthritis Rheum 2001, 44: 186-195.
83. Kurt R, Silvia H, Andrea M, et al. Tumor Necrosis Factor α-Mediated Joint Destruction Is Inhibited by Targeting Osteoclasts With Osteoprotegerin. Arthritis Rheum 2002, 46:785-792.
84. Ross FP, Chappel J, Alvarez JI, et al. Interactions between the bone matrix proteins osteopontin and bone sialoprotein and the osteoclast integrin alpha v beta 3 potentiate bone resorption: J Biol Chem 1993, 268:9901-9907.
85. Vaananen HK, Horton M. The osteoclast clear zone is a specialized cell-extracellular matrix adhesion structure. J Cell Sci 1995, 108:2729-2732.
86.Haynes DR, Crotti TN, Loric M, et al. Osteoprotegerin and receptor activator of nuclear factor kappaB ligand (RANKL) regulate osteoclast formation by cells in the human rheumatoid arthritic joint. Rheumatol 2001, 40:623-30.
87.Akatstu T, Murakami T, Nishikawa M, et al. Osteoclastogenesis inhibitory factor suppresses osteoclast survial by interfering in the interaction of steromal cells with osteoclast. Biochem Biophys Res Commun 1998, 250:229-34.
88.Bucay N, Sarosi I, Dunstan CR, et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev, 1998, 12:1260-1268.
89.Simoner WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997, 89:309-319.
90.Kong YY, Feige U, Sarosi I, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999, 402:304-309.
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96．赵伟，黄烽，徐明等．血清及关节液中单核因子表达水平的测定及其在幼年脊柱关节病中的临床意义．中华风湿病学杂志，2001，5(6)：346-349．
97．赵伟，黄烽，徐明等．幼年脊柱关节病患者血液及关节液中单核因子mRNA表达水平的测定．中华微生物和免疫学杂志，2002，22(1)：80-81．
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35. Mori H, Kitazawa R, Maeda S, et al. RANK ligand, RANK, and OPG expression in type Ⅱ collagen-induced arthritis mouse.2002, 117:283-292.
36. Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998, 93:165-76.
37. Bogoch ER, Moran E. Abnormal bone remodelling in inflammatory arthritis. Can J Surg 1998, 41:264-71.
38. Tak PP, Breedveld FC. Analysis of serial synovial biopasies as a screening method for predicting the effects of therapeutic interventions, J Clin Rheumatol 1997; 3: 186-7
39. Youssef PP, Triantafillou S, Parker A, et al. Variability in cytokine and cell adhesion molecule staining in arthroscopic synovial biopsies: quatification using color video image analysis. J Rheumatol 1997, 24:2291-8.
40. Youssef PP, Triantafillou S, Parker A, et al. Efects of pulse
methylprednisolone on cell adhesion molecules in the synovial membrane in rheumatoid arthritis. Arthritis Rheum 1996, 39:1970-9
41. Krnna MC, Versendaal H, Jonker M, et al. Asymoptomatic synovitis precedes clinical manifest arthritis. Arthritis Rheum 1998, 41:1481-8.
42. Tak PP, Smeets TJM, Daha MR, et al. Analysis of the synotial cellular infiltrate in early rheumatoid synovial tissue in relation to disease activity. Arthritis Rheum 1997, 40:217-25.
43. Tak PP, Smeets TJM, Daha MR, et al. Analysis of the synotial cellular infiltrate in early rheumatoid synovial tissue in relation to disease activity. Arthritis Rheum 1997, 40:217-25.
44. Bresnihan B, Cunnane G, Youssef P, et al. Microscopic messurement of synovial memvrane inflammation in rheumatoid arthritis: proposals for the evaluation of tissue samples by quantitative analysis. Br J Rheumatol 1998, 37:636-42.
45. Youssef PP. Smeets TJM, Bresnihan B, et al. Microscopic measurement of inflammation in the rheumatoid arthritis synovial membrane: a comparison of semiquantiative and quantitatice analysis. Br J Rheumatol 1998, 37:1003-7.
46. Yasuda H, Shima N, Nakagawa N, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteo clastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA, 1998, 95:3597-602.
47.Wong BR, Rho J, Arron J, et al. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J Biol Chem 1997, 272:25190-94.
48.Roodman GD. Cell biology of the osteoclast. Exp Hematol 1999, 27:1229-41.
49.Anderson DM, Maraskovsky E, Billingsley WL, et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 1997, 390: 175-79.
50.Kong YY, Feige U, Sarosi I, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999, 402:304-09.
51.Hofbauer LC, Khosla S, Dunstan CR, et al. The role of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res 2000, 15:2-12.
52.Hofbauer LC, Heufelder AE. The role of receptor activator of nuclear factor-B ligand and osteoproteferin in the pathogentsis and treatment of metabolic bone disease. J Clin Endocr Metab 2000, 85:2355-2363.
53.Redlich K, Hayer S, Ricci R, et al. Ostedclasts are essential for TNF-α mediated joint destruction. J Clin Invest 2002, 110:1419-1427.
54.Lacey DL, Timms E, Tan KL, et al. Osteoprotegeriin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998, 96:3540-3545.
55.Kotake S, Sato K, Kim KJ, et al. Interleukin-6 and soluble
interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res 1996, 11:88-95.
56.Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 1996, 14:397-440.
57.Bendele A, McComb J, Gould T, et al. Animal models of arthritis: relevance to human disease. Toxicol Pathol 1999, 27:134-42.
58.Panayi GS, Lanchbury JS, Kingsley GH. The importance of the T cell in initiating and maintaining the chronic synovitis of rheumatoid arthritis. Arthritis Rheum 1992, 35:729-35.
59.Fazzalari NL, Kuliwaba JS, Arkins GJ, et al. The ratio of messenger RNA levels of receptor activator of nuclear factor kappaB ligand to osteoprolege in correlates with bone remodeling indices in normal human cancellous cone but not in ostearthritis. J Bone Miner Res 2001, 16:1015-27.
60.Kong YY, Feige U, Sarosi L, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999,403:304-9.
61.Harwood NJ, Kartsogiannis V, Quinn JMW, et al. Activated T lymphocytes support osteoclast formation in vitro. Biochem Biophys Res Commun 1999, 265:144-50.
62.Ji H, Pettit A, Ohmura K, et al. Critical roles for interleukin 1 and tumor necrosis factor a in antibody-induced arthritis. J Exp Med 2002, 196:77-85.
63.Redlich K, Hayer S, Maier A, et al. Tumor necrosis factor
alpha-mediated joint destruction is inhibited by targeting osteoclasts with osteoprotegerin. Arthritis Rheum 2002, 46:785-92.
64.Mori H, Kitazawa R, Mizuki S, et al. RANK ligand, RANK, and OPG expression in type Ⅱ collagen-induced arthritis mouse. Histochem Cell Biol 2002, 117:283-92.
65.Takayanagi H, Lizuka H, Nakagawa T, et al. Involvement of receptor activator of nuclear factor κ B ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum 2000, 43:259-269.
66.Shigeyama Y, PaP T, Kunzler P, et al. Expression of osteoclast differentiation factor in rheumatoid arthritis. Arthritis Rheum 2000, 43:2523-30.
67.Katake S, Udagawa N, Harkada M, et al. Activated human T cells directly induce osteoclastogenesis from human monocytes: possible role of T cells in bone destruction in rheumatoid arthritis patients. Arthritis Rheum 2001, 44:1003-12.
68.Itanaga I, Fujikawa Y, Sabakbar A, et al. Rheumatoid arthritis synovial macrophage-osteoclast differentiation is osteoprotegerin ligand-dependent, J Pathol 2000, 192:97-104.
69.Haynes DR, Crotti TN, Loric M, et al. Osteoprotegerin and receptor activator of nuclear factor kappaB ligand regulate osteoclast formation by cells in the human rheumatoid arthiritic joint. Rheumatol (Oxford) 2001, 40:623-30.
70.Suzuki Y, Tsutmi Y, Nakagawa M, et al. Osteoclast-like cells in an in vitro model of bone destruction by rheumatoid synovuim.
Rheumatol (Oxford) 2001, 40:672-82.
71.Koch A, Campagnuolo G, Bolon B, et al. Kinetics of bone protection by recombinant osteoprotogerin therapy in Lewis rats with mycobacteria-induced adjuvant arthritis. Arthritis Rheum 2001, 44:S267.
72.Romas E, Gillespie MT, Martin TJ. Involvement of receptor activator of NfkappaB ligand and tumor necrosis factor-alpha in bone destruction in rheumatoid arthritis. Bone 2002, 30:340-6.
73.Olee T, Kuhn K, Brinson DC, et al. The osteoprotegerin/ receptor activator of nuclear factor kappaB/receptor activator of nuclear factor kappaB ligand system in cartilage. Arthritis Rheum 2001, 44:2768-76.
74.Pettit AR, Ji H, von Stechow D, et al. TRANCE/RANKL knockout mice are protected from bone erosion in the K/BxN serum transfer model of arthritis. Am J Pathol 2001, 159:1689-1699.
75.Kotake S, Udagawa N, Hakoda M, et al. Activated human T cells directly induce osteoclastogenesis from human monocytes: possible role of T cells in bone destruction in rheumatoid arthritis patients. Arthritis Rheum 2001, 44:1003-12.
76.Kontoyiannis D, Kollias G. Fibroblast biology: synovial fibroblasts in rheumatoid arthritis: leading role or chorus line? Arthritis Res 2000, 2:342-343.
77.Gravallese EM, Manning C, Tsay A, et al. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum 2000, 43:250-258.
78．戴冽，汤美安，尹培达．滑膜巨噬细胞与类风湿关节炎病情活动及关节破坏的相关性．中华风湿病学杂志 1999；2(4)：229-231．
79. Bywaters EGL. Pathological specificity of ankylosing spondylitis: is it yet established? Adv Inflam Res 1985, 9:1-13.
80. Rudwaleit M, Siegert S, Yin Z, et al. Low T cell production of TNF alpha and IFN gamma in ankylosing spondylitis: its relation to HLA-B27 and influence of the TNF-308 gene polymorphism. Ann Rheum Dis 2001, 60:36-42.
81. Baeten D, Damme VN, Bosch VF, et al. Impaired Th1 cytokine production in spondyloarthropathy is restored by anti-TNF alpha. Ann Rheum Dis 2001, 60:750-5.
82. Baeten D, Elli K, Filip V B, et al. Immunomodulatory Effects of Anti-Tumor Necrosis Factor a Therapy on Synovium in Spondylarthropathy Arthritis Rheum 2001, 44: 186-195.
83. Kurt R, Silvia H, Andrea M, et al. Tumor Necrosis Factor α-Mediated Joint Destruction Is Inhibited by Targeting Osteoclasts With Osteoprotegerin. Arthritis Rheum 2002, 46:785-792.
84. Ross FP, Chappel J, Alvarez JI, et al. Interactions between the bone matrix proteins osteopontin and bone sialoprotein and the osteoclast integrin alpha v beta 3 potentiate bone resorption: J Biol Chem 1993, 268:9901-9907.
85. Vaananen HK, Horton M. The osteoclast clear zone is a specialized cell-extracellular matrix adhesion structure. J Cell Sci 1995, 108:2729-2732.
86.Haynes DR, Crotti TN, Loric M, et al. Osteoprotegerin and receptor activator of nuclear factor kappaB ligand (RANKL) regulate osteoclast formation by cells in the human rheumatoid arthritic joint. Rheumatol 2001, 40:623-30.
87.Akatstu T, Murakami T, Nishikawa M, et al. Osteoclastogenesis inhibitory factor suppresses osteoclast survial by interfering in the interaction of steromal cells with osteoclast. Biochem Biophys Res Commun 1998, 250:229-34.
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