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壳聚糖膝关节腔内注射疗法对兔骨关节炎关节软骨的影响 总被引:4,自引:4,他引:4
目的观察关节内注射羧甲基壳聚糖(CMCTS)对兔骨关节炎(OA)关节软骨退变及软骨基质金属蛋白酶(MMP)-1,-3mRNA表达的影响。方法24只大耳白兔行单侧膝关节前交叉韧带切断术,术后5周将动物随机分为3组,A组关节内注射2%CMCTS0.3ml,每2周1次;B组关节内注射1%透明质酸钠(HA)0.3ml,每周1次;C组关节内不注射药物。术后11周处死动物,观察各组股骨内髁关节软骨的大体变化,采用反转录-聚合酶链反应(RT-PCR)方法检测股骨内髁退变软骨中MMP-1和MMP-3的mRNA表达。结果CMCTS和HA注射组软骨退变程度较不用药组明显减轻,CMCTS注射组软骨MMP-1、MMP-3的mRNA表达明显低于HA注射组和不用药组。HA注射组软骨MMP-1和MMP-3的mRNA表达与不用药组比较,差异没有显著性意义。结论CMCTS能够明显抑制OA软骨MMP-1和MMP-3的mRNA表达,明显减轻软骨退变的程度,CMCTS对早期OA软骨有修复保护作用。 相似文献
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The aim of this study was to investigate the effects of intra-articular injection of dehydroepiandrosterone (DHEA) on cartilage and synovium of knee joints with osteoarthritis (OA) in rabbits and the underlying mechanism. Forty rabbits underwent unilateral anterior cruciate ligament transaction and were divided into two groups. Rabbits were injected with 100 μmol/l DHEA dissolved in the dimethylsulphoxide (DMSO) in the knee joints 5 weeks after transaction, once a week for 5 weeks. Rabbits injected with DMSO under the same condition were served as a control. All rabbits were killed 1 week after the last injection. The knee joints were evaluated by gross morphology, histology, and gene expression analysis. Gross morphologic inspection and histological evaluation showed that the DHEA group appeared less damage in cartilage and synovium as compared with the control. Gene expression analysis revealed that the mRNA expression of matrix metalloproteinase-3 (MMP-3) in cartilage and synovium decreased significantly in the DHEA group and that of tissue inhibitor of metalloproteinase-1 (TIMP-1) increased. No significant difference of interleukin-1 beta (IL-1β) mRNA expression was found in the cartilage between two groups while the mRNA expression of IL-1β in the synovium was largely suppressed in the DHEA group. The study suggests that DHEA plays a protective role against cartilage degradation and synovium inflammation in rabbits with OA. This role may be achieved through the regulation of the MMP-3, TIMP-1, and IL-1β gene expression in the cartilage and synovium. 相似文献
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目的观察高脱乙酰度羧甲基壳聚糖(HD-CMC)经关节腔注射后对兔膝骨关节炎(OA)软骨诱导型一氧化氮合酶(iNOS)的mRNA和蛋白表达的影响,探讨其用于OA防治的机制及可能性。方法36只日本大耳白兔,行右侧膝关节前交叉韧带切断术(ACLT),术后随机分为2组,实验组于术后当天开始关节腔内注射2%HD-CMC 0.15mg/kg,每2周给药1次,对照组同一时间点关节腔内注射0.9%生理盐水0.15mg/kg。实验组与对照组于第6周分别随机处死大白兔各9只,剩余大白兔于第12周处死,对比两组大白兔股骨髁关节软骨的大体改变,用反转录聚合酶链反应(RT-PCR)及免疫组织化学的方法检测iNOS在软骨中的mRNA和蛋白的表达。结果实验组退变软骨的大体评分轻于对照组,NOS的mRNA和蛋白表达水平均低于对照组。结论HD-CMC能够降低OA退变软骨iNOS的表达,并延缓软骨的退行性变,对OA退变软骨具有修复保护作用。 相似文献
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目的 观察关节腔内注射透明质酸钠(Na-HA)对骨关节炎(OA)软骨的保护作用及对过氧化物酶体增殖物激活受体γ(PPAR-γ)mRNA表达的影响,探讨Na-HA治疗OA的机制.方法 48只大耳白兔随机分为A、B、C 3组,每组16只,A组为正常对照组,B、C两组行单膝前交叉韧带切断术,术后第5周开始,B组关节腔内注射0.3 ml生理盐水;C组注射等量的高分子量1%Na-HA,每周1次,连续5周.术后11周处死动物,比较各组股骨内髁关节软骨的大体变化,苏木素-伊红(HE)染色观察股骨内髁软骨的病理变化,番红O染色观察软骨基质的改变,采用实时定量聚合酶链反应(Real-Time PCR)方法检测软骨PPAR-γ mRNA的表达水平.结果 大体评分显示B组软骨退变的程度明显重于A组和C组(P<0.05);HE染色与A、C两组比较,B组软骨明显溃疡形成;番红O染色平均灰度值B组软骨基质染色明显高于A、c两组(P<0.05);B组软骨PPAR-γ mRNA表达量明显高于A、C两组(P<0.05);A、C两组大体评分和PPAR-γ mRNA表达量差异无统计学意义.结论 关节腔注射Na-HA可以抑制软骨PPAR-γmRNA表达,减轻软骨退变的程度,可能是其治疗骨关节炎的机制之一. 相似文献
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Wei-Ping Chen Jia-Peng Bao Jin-Li Tang Peng-Fei Hu Li-Dong Wu 《Rheumatology international》2011,31(10):1325-1331
The aim of this study was to investigate the effects of trichostatin A (TSA) on expression of cathepsins in cartilage in experimental
osteoarthritis (OA). OA was induced in 18 rabbits by bilateral anterior cruciate ligament transection (ACLT). Four weeks after
surgery, rabbits received intra-articular injection with TSA dissolved in the dimethylsulphoxide (DMSO) in the right knees
and DMSO in the left knees once a week for 5 weeks. Rabbits were killed 7 days after the last injection. The knee joints were
assessed by morphological and histological examination. Messenger RNA expression of cathepsins K, B, L, S and cystatin C was
studied by real-time PCR. TSA inhibited the expression of cathepsins K, B, L, S and cystatin C accompanied with the less degradation
in cartilage. The results suggest that TSA exhibits protective effects against cartilage degradation in rabbits with OA and
the effects may be associated with the inhibition of cathepsins. 相似文献
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Role of apoptotic and matrix-degrading genes in articular cartilage and meniscus of mature and aged rabbits during development of osteoarthritis 总被引:1,自引:0,他引:1
Pennock AT Robertson CM Emmerson BC Harwood FL Amiel D 《Arthritis and rheumatism》2007,56(5):1529-1536
OBJECTIVE: To determine expression patterns of apoptotic and matrix-degrading genes during aging and development of osteoarthritis (OA), using a rabbit model of induced OA. METHODS: Six mature and 6 aged rabbits underwent anterior cruciate ligament transection and were killed 4 and 8 weeks after surgery, respectively, to create early-grade and advanced-grade OA. RNA from articular cartilage and menisci was examined for expression of the genes caspase 8, Fas, Fas ligand, p53, aggrecanase, matrix metalloproteinase 1 (MMP-1), and MMP-3. A second cohort of animals that had undergone no intervention in the joint was also killed. Parametric data were analyzed with analysis of variance and Student's t-tests, while nonparametric data were assessed with the Mann-Whitney U test. RESULTS: Expression levels of Fas, caspase 8, FasL, and MMP-1 were significantly higher (>100%) in aged cartilage compared with mature cartilage (P < 0.05). After induction of OA, expression of apoptotic genes in aged rabbits remained high, while significant up-regulation of Fas and caspase 8 (nearly 150% increase) was observed in mature rabbits (P < 0.05). No significant up-regulation of these genes was observed in the menisci of aged or mature rabbits prior to or after induction of OA. Development of OA occurred more rapidly in aged cartilage compared with mature cartilage (P < 0.05). CONCLUSION: Differential expression of apoptotic and matrix-degrading genes occurs in aged compared with mature cartilage, both at baseline and during development of OA. This may be responsible for faster degradation of aged cartilage and its predisposition for developing OA. 相似文献
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Hayami T Pickarski M Wesolowski GA McLane J Bone A Destefano J Rodan GA Duong le T 《Arthritis and rheumatism》2004,50(4):1193-1206
OBJECTIVE: It has been suggested that subchondral bone remodeling plays a role in the progression of osteoarthritis (OA). To test this hypothesis, we characterized the changes in the rat anterior cruciate ligament transection (ACLT) model of OA and evaluated the effects of alendronate (ALN), a potent inhibitor of bone resorption, on cartilage degradation and on osteophyte formation. METHODS: Male Sprague-Dawley rats underwent ACLT or sham operation of the right knee. Animals were then treated with ALN (0.03 and 0.24 microg/kg/week subcutaneously) and necropsied at 2 or 10 weeks postsurgery. OA changes were evaluated. Subchondral bone volume and osteophyte area were measured by histomorphometric analysis. Coimmunostaining for transforming growth factor beta (TGF beta), matrix metalloproteinase 9 (MMP-9), and MMP-13 was performed to investigate the effect of ALN on local activation of TGF beta. RESULTS: ALN was chondroprotective at both dosages, as determined by histologic criteria and collagen degradation markers. ALN suppressed subchondral bone resorption, which was markedly increased 2 weeks postsurgery, and prevented the subsequent increase in bone formation 10 weeks postsurgery, in the untreated tibial plateau of ACLT joints. Furthermore, ALN reduced the incidence and area of osteophytes in a dose-dependent manner. ALN also inhibited vascular invasion into the calcified cartilage in rats with OA and blocked osteoclast recruitment to subchondral bone and osteophytes. ALN treatment reduced the local release of active TGF beta, possibly via inhibition of MMP-13 expression in articular cartilage and MMP-9 expression in subchondral bone. CONCLUSION: Subchondral bone remodeling plays an important role in the pathogenesis of OA. ALN or other inhibitors of bone resorption could potentially be used as disease-modifying agents in the treatment of OA. 相似文献
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《Modern rheumatology / the Japan Rheumatism Association》2013,23(5):768-771
AbstractPurpose. Astaxanthin is a red-pigment carotenoid found in certain marine animals and plants. Astaxanthin has been shown to inhibit matrix metalloproteinases (MMPs) expression in vitro. However, the effect of astaxanthin on cartilage is still unclear. The aim of this study was to investigate the effects of astaxanthin on cartilage in experimental osteoarthritis (OA).Methods. New Zealand rabbits underwent anterior cruciate ligament transection to induce OA in right knee. Rabbits received intra-articular injection containing 0.3 ml of vehicle (dimethyl sulfoxide) or astaxanthin (50 μM). Injection was started on the day of operation, and the injection were performed once weekly for six consecutive weeks. Then, rabbits were sacrificed and the right knees were harvested for study.Results. Cartilage degradation was reduced by astaxanthin, as assessed by morphological and histological examination. Astaxanthin inhibited the gene expression of MMP-1, MMP-3, and MMP-13 in cartilage as compared with the vehicle group.Conclusions. The results suggest that astaxanthin may be considered as pharmaceutical agent in OA treatment. 相似文献
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Inoue A Takahashi KA Arai Y Tonomura H Sakao K Saito M Fujioka M Fujiwara H Tabata Y Kubo T 《Arthritis and rheumatism》2006,54(1):264-270
OBJECTIVE: To investigate the therapeutic effects of basic fibroblast growth factor (bFGF) contained in gelatin hydrogel microspheres on osteoarthritis (OA) development in rabbit knee joints. METHODS: (125)I-labeled bFGF contained in gelatin hydrogel microspheres was administered to the knee joints of normal rabbits to confirm the sustained-release kinetics of bFGF in the knee joint. In addition, the expression of proteoglycan core protein messenger RNA was examined using real-time polymerase chain reaction to confirm the anabolic effects on the cartilage treated with the sustained release of bFGF. The bFGF in gelatin hydrogel microspheres was administered to the knee joint once every 3 weeks (a total of twice) from 4 weeks after anterior cruciate ligament transection (ACLT). Ten weeks after ACLT, gross morphologic and histologic examinations were performed. RESULTS: Sustained release of bFGF in the knee joint continued for >7 days and induced the anabolic effects on the cartilage. Intraarticular injections of bFGF contained in gelatin hydrogel microspheres suppressed the progression of OA in the ACLT rabbit model. CONCLUSION: Our findings demonstrated that sustained release of bFGF into the joint had therapeutic effects on OA development in a rabbit model. Our results suggest the potential feasibility of a new conservative treatment for OA. 相似文献
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Effect of hyaluronan on chondrocyte apoptosis and nitric oxide production in experimentally induced osteoarthritis 总被引:22,自引:0,他引:22
Takahashi K Hashimoto S Kubo T Hirasawa Y Lotz M Amiel D 《The Journal of rheumatology》2000,27(7):1713-1720
OBJECTIVE: Nitric oxide (NO) plays an important role in cartilage degeneration, and NO donors induce chondrocyte apoptosis. This study evaluated the effect of intraarticular injections of hyaluronan (HA) on chondrocyte apoptosis and NO production using an experimental osteoarthritis (OA) model. METHODS: Thirty-six New Zealand white rabbits underwent unilateral anterior cruciate ligament transection (ACLT), and were divided into 3 groups. Four weeks after ACLT, the HA group started intraarticular HA injections once a week for 5 weeks; the vehicle group started to receive the carrier of HA; the no injection group received no treatment. All ACLT knees were harvested at Week 9 and evaluated for OA severity. Culture supernatants of the cartilage were analyzed for nitrite concentration. Cartilage sections were analyzed by TUNEL for apoptosis and by immunohistochemistry for nitrotyrosine. RESULTS: OA in the HA group was less severe than the other 2 groups. The number of apoptotic chondrocytes was significantly lower in the HA group. HA injection did not influence NO production in cartilage. CONCLUSION: HA protects against chondrocyte apoptosis during the development of OA, while it may not have definite effects on NO production in the joints. These inhibitory effects of HA on chondrocyte apoptosis may play a role in its mechanism of action in chondroprotection. 相似文献
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Effects of dehydroepiandrosterone on articular cartilage during the development of osteoarthritis 总被引:5,自引:0,他引:5
OBJECTIVE: To investigate the in vivo effects of dehydroepiandrosterone (DHEA) on knee joints during the development of experimentally induced osteoarthritis (OA). METHODS: Twenty-two mature NZW rabbits underwent bilateral anterior cruciate ligament transection (ACLT) and received 0.3-ml intraarticular injections of DHEA (at a concentration of 100 microM in phosphate buffered saline) and control solution in the right and left knees, respectively, beginning 4 weeks after ACLT and continuing once weekly for 5 weeks. All animals were killed 9 weeks after surgery, and the knee joints were assessed by gross morphologic, histologic, histomorphometric, and biochemical methods. RESULTS: Gross morphologic inspection following India ink application showed that the right femoral condyles, which received DHEA, demonstrated less severe cartilage damage than did the contralateral condyles. The thickness, area, and roughness of the DHEA-treated femoral condyles provided evidence of a cartilage-protecting effect of DHEA following ACLT. These results were supported by gene expression analysis. Messenger RNA expression of a proinflammatory cytokine, interleukin-1beta, and catabolic enzymes, matrix metalloproteinases 1 and 3, was reduced in the cartilage of the DHEA-treated knee joints, and expression of tissue inhibitor of metalloproteinase 1 was increased. CONCLUSION: Results of the present study demonstrate a cartilage-protecting effect of DHEA during the development of OA following ACLT in a rabbit model. 相似文献
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Blom AB van Lent PL Libregts S Holthuysen AE van der Kraan PM van Rooijen N van den Berg WB 《Arthritis and rheumatism》2007,56(1):147-157
OBJECTIVE: To explore the involvement of synovial macrophages in early cartilage damage in osteoarthritis (OA), and to identify the role of matrix metalloproteinase 3 (MMP-3) in the pathology of early and late OA. METHODS: The role of synovial macrophages in MMP-mediated damage in OA was studied by depleting synovial macrophages prior to elicitation of a collagenase-induced instability model of OA. The expression of MMP in synovium and cartilage was monitored using TaqMan analysis. In spontaneous and induced OA, cartilage pathology was scored in MMP-3-knockout mice and control mice, by histologic assessment and VDIPEN staining. RESULTS: On day 14 following induction of OA, MMP-mediated neoepitopes were detected in cartilage from mice with mild experimental OA (mean +/- SD positively stained surface area 20 +/- 3.2%). Remarkably, by depleting synovial macrophages prior to induction of OA, the generation of MMP-induced neoepitopes was largely prevented (mean +/- SD positively stained surface area 5 +/- 1%; P< 0.001), indicating an important role for synovial macrophages in the occurrence of MMP-mediated cartilage damage. We observed a strong decrease in MMP-3 and MMP-9 expression in synovial but not cartilage tissue in macrophage-depleted joints. Among 2-year-old mice, spontaneous OA-like changes in the lining layer were significantly decreased in MMP-3-knockout mice compared with control mice. Even more striking was the 67% reduction in the occurrence of severe cartilage damage in MMP-3-knockout mice. In addition, MMP-mediated VDIPEN expression was significantly decreased, indicating reduced MMP-mediated cartilage breakdown. CONCLUSION: The results of this study prove that MMP-3 is involved in the generation of severe cartilage damage in murine OA. Synovial macrophages are crucial in early MMP activity and appear to mediate MMP production in synovium rather than cartilage. 相似文献
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The effects of glucosamine hydrochloride on subchondral bone changes in an animal model of osteoarthritis 总被引:1,自引:0,他引:1
OBJECTIVE: To quantify periarticular subchondral bone changes in a rabbit model of experimental osteoarthritis (OA), and to determine the effects of continuous administration of a clinically relevant dose of glucosamine HCl on subchondral bone changes in this model. METHODS: Anterior cruciate ligament transection (ACLT) was performed on the left femorotibial joints of 16 rabbits to induce OA. Ten rabbits that did not undergo ACLT served as unoperated controls. Eight rabbits that underwent ACLT and 6 control rabbits were treated with 100 mg of glucosamine daily, and the others were given a placebo. The articular cartilage was evaluated macroscopically and graded at the time of necropsy, 8 weeks after ACLT. Bone mineral density (BMD) was measured using dual-energy x-ray absorptiometry on the dissected distal femur and proximal tibia. Subchondral trabecular bone turnover, architecture, and connectivity, as well as subchondral plate thickness and mineralization were studied on the undecalcified tibia sections from each animal. RESULTS: Eight weeks after ACLT, most of the operated joints had various degrees of cartilage damage and fibrillation. Compared with the control group, the ACLT group had significantly increased subchondral bone turnover and lower BMD, bone volume, connectivity, and bone mineralization. The high bone turnover was significantly reduced in glucosamine-treated animals that underwent ACLT. In fact, there were no significant differences between the ACLT/glucosamine group and the control/glucosamine group in most of the bone parameters studied. CONCLUSION: This study shows that subchondral bone turnover, structure, and mineralization are significantly altered in the early stages of experimental OA, and that these changes are attenuated by glucosamine treatment. 相似文献
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透明质酸钠对兔骨关节炎软骨诱导型NO合酶基因表达的影响 总被引:7,自引:1,他引:7
目的观察透明质酸钠(Na—HA)关节腔注射对骨关节炎(OA)模型关节软骨中诱导型NO合酶(iNOS) mRNA表达水平的影响。方法16只大耳白兔行单侧前交叉韧带切断术,术后5周将动物随机分为实验组和对照组,实验组关节腔注射1%Na—HA 0.3ml,每周1次,连续5周,对照组则注射等量生理盐水。术后10周处死动物,观察两组股骨内髁关节软骨的大体形态学和组织学病理改变,采用反转录一聚合酶链反应(RT—PCR)方法检测软骨iNOS mRNA的表达。结果实验组软骨退变程度较对照组明显减轻,实验组软骨中iNOS mRNA的表达水平与对照组比较差异无统计学意义。结论Na—HA能有效地减轻早期OA关节软骨的退变程度,Na—HA对早期OA软骨中的iNOS的表达没有下调作用。 相似文献
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Anabolic and catabolic gene expression pattern analysis in normal versus osteoarthritic cartilage using complementary DNA-array technology. 总被引:11,自引:0,他引:11
OBJECTIVE: To understand changes in gene expression levels that occur during osteoarthritic (OA) cartilage degeneration, using complementary DNA (cDNA)-array technology. METHODS: Nine normal, 6 early degenerated, and 6 late-stage OA cartilage samples of human knee joints were analyzed using the Human Cancer 1.2 cDNA array and TaqMan analysis. RESULTS: In addition to a large variability of expression levels between different patients, significant expression patterns were detectable for many genes. Cartilage types II and VI collagen were strongly expressed in late-stage specimens, reflecting the high matrix-remodeling activity of advanced OA cartilage. The increase in fibronectin expression in early degeneration suggests that fibronectin is a crucial regulator of matrix turnover activity of chondrocytes during early disease development. Of the matrix metalloproteinases (MMPs), MMP-3 appeared to be strongly expressed in normal and early degenerative cartilage and down-regulated in the late stages of disease. This indicates that other degradation pathways might be more important in late stages of cartilage degeneration, involving other enzymes, such as MMP-2 and MMP-11, both of which were up-regulated in late-stage disease. MMP-11 was up-regulated in OA chondrocytes and, interestingly, also in the early-stage samples. Neither MMP-1 nor MMP-8 was detectable, and MMP-13 and MMP-2 were significantly detectable only in late-stage specimens, suggesting that early stages are characterized more by degradation of other matrix components, such as aggrecan and other noncollagenous molecules, than by degradation of type II collagen fibers. CONCLUSION: This investigation allowed us to identify gene expression profiles of the disease process and to get new insights into disease mechanisms, for example, to develop a picture of matrix proteinases that are differentially involved in different phases of the disease process. 相似文献
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Connective tissue growth factor/CCN2 overexpression in mouse synovial lining results in transient fibrosis and cartilage damage 总被引:5,自引:0,他引:5
Blaney Davidson EN Vitters EL Mooren FM Oliver N Berg WB van der Kraan PM 《Arthritis and rheumatism》2006,54(5):1653-1661
OBJECTIVE: Characteristics of osteoarthritis (OA) include cartilage damage, fibrosis, and osteophyte formation. Connective tissue growth factor (CTGF; also known as CCN2), is found in high levels in OA chondrocytes and is frequently involved in fibrosis, bone formation, and cartilage repair. The present study was therefore undertaken to investigate the potential role of CTGF in OA pathophysiology. METHODS: We transfected the synovial lining of mouse knee joints with a recombinant adenovirus expressing human CTGF and measured synovial fibrosis and proteoglycan content in cartilage on days 1, 3, 7, 14, and 28. Messenger RNA (mRNA) expression in synovium and cartilage was measured on days 3, 7, and 21. RESULTS: CTGF induced synovial fibrosis, as indicated by accumulation of extracellular matrix and an increase in procollagen type I-positive cells. The fibrosis reached a maximum on day 7 and had reversed by day 28. Levels of mRNA for matrix metalloproteinase 3 (MMP-3), MMP-13, ADAMTS-4, ADAMTS-5, tissue inhibitor of metalloproteinases 1 (TIMP-1), and transforming growth factor beta were elevated in the fibrotic tissue. TIMP-1 expression was elevated on day 3, while expression of other genes did not increase until day 7 or later. CTGF induced proteoglycan depletion in cartilage as early as day 1. Maximal depletion was observed on days 3-7. Cartilage damage was reduced by day 28. A high level of MMP-3 mRNA expression was found in cartilage. CTGF overexpression did not induce osteophyte formation. CONCLUSION: CTGF induces transient fibrosis that is reversible within 28 days. Overexpression of CTGF in knee joints results in reversible cartilage damage, induced either by the high CTGF levels or via factors produced by the CTGF-induced fibrotic tissue. 相似文献
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目的 观察盘状结构域受体(DDR)2和基质金属蛋白酶(MMP)-13在膝骨关节炎(OA)大鼠不同时期软骨及滑膜中的表达,探讨DDR2与关节软骨破坏之间的关系.方法 采用改良膝关节腔内注射木瓜蛋白酶法制作OA大鼠模型,从蛋白水平检测造模后不同病理阶段关节软骨及滑膜中DDR2和MMP-13的表达规律和分布特点.结果 DDR2在各模型组关节软骨及滑膜中的表达较健康组增高(P<0.01),并且各组中软骨表达高于相应滑膜,MMP-13表达呈现与DDR2相同的特点,二者相关系数r=0.93(P<0.01).结论 初步证明"DDR2-MMP-13-软骨破坏"途径在OA病理过程中起重要作用.软骨和滑膜DDR2的表达升高共同促进软骨退变. 相似文献
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Seisuke Tanaka MD Professor Chairman President of the th Meeting of the Japanese Orthopaedic Research Society Chiaki Hamanishi MD Assistant Professor Hiraku Kikuchi MD Lecturer Kanji Fukuda MD Lecturer 《Seminars in arthritis and rheumatism》1998,27(6):392-399