不同干预因素对膝骨关节炎患者滑液中MMP-3和TIMP-1的影响

目的:观察透明质酸钠(hyaluronic acid,HA)、硫酸氨基葡萄糖(glucosamine sulfate,GS)、关节镜下关节清理术(arthroscopic debridment,AD)治疗膝骨关节炎(osteoarthritis,OA)时,对关节液内基质金属蛋白酶-3(matrix metalloproteinase-3,MMP-3)、组织型金属蛋白酶抑制剂-1(tissue inhibitor of metallo-proteinase-1,TIMP-1)水平的影响,并探讨其治疗OA的机制.方法:60例膝OA病人(64关节)分为HA组和GS HA组,并于HA组和GS HA组选取部分病例组成HA'组和GS HA'组,再与AD组比较.于治疗前和治疗后4周、6月抽取关节液样本,采用双抗体夹心ELISA法测定关节液内MMP-3和TIMP-1水平.结果:HA组和GS HA组治疗4周时关节液中MMP-3水平及MMP-3/TIMP-1比值均较治疗前降低(P＜0.01),且在治疗半年后MMP-3水平和MMP-3/TIMP-1比值下降仍有统计学意义(P＜0.01).GS HA组治疗4同时TIMP-1水平较治疗前显著升高(P＜0.01);HA组治疗4周时TIMP-1水平虽较治疗前升高,但无统计学意义(P＞0.05).AD组治疗4周与治疗前比较,关节液中MMP-3水平降低(P＜0.01),TIMP-1水平升高(P＜0.01),MMP-3/TIMP-1比值降低(P＜0.01);且在治疗半年后MMP-3水平、MMP-3/TIMP-1比值下降仍有统计学意义(P＜0.01);但治疗6月后与治疗4周比较,TIMP-1水平降低(P＜0.01),MMP-3/TIMP-1比值升高(P＜0.01).HA组与GS HA组比较,GS HA组治疗4周时TIMP-1升高水平显著高于HA组(P＜0.01).AD组与相应的HA'组、GS HA'组比较,治疗4周时AD组的TIMP-1升高最明显(P＜0.01),其余指标无明显差异.结论:(1)HA,GS和AD治疗均能使膝关节OA患者关节液内的MMP-3水平、MMP-3/TIMP-1比值降低.(2)HA对关节液内的TIMP-1水平无明显影响,但同时应用CS可使关节液内的TIMP-1水平升高.HA和GS可通过不同的机制发挥治疗OA的作用.HA联合GS治疗可能获得更好的疗效.(3)在中、重度膝关节OA患者中,与相应的HA'组、GS HA'组比较,治疗4周后AD组TIMP-1升高最明显,AD可能获得更好的疗效.(4)对MMP-3和TIMP-1的影响,可能是HA,GS和AD改善OA病情的重要机制.

Effect of various intervention factors on MMP-3 and TIMP-1 level in synovial fluid in knee joints with osteroarthritis

OBJECTIVE: To examine the expression of MMP-3 and TIMP-1 in the synovial fluid in knee joints with osteoarthritis before and after being treated with hyaluronic acid(HA), glucosamine sulfate(GS) and arthroscopic de bridment(AD), and to explore the therapeutic mechanism. METHODS: Sixty patients (64 knees) with osteoarthritis(OA) were randomly divided into HA group AD group and GS+AD group. Some patients from the HA group and the GS+HA group were selected, and served as HA' group and GS+HA' group. The expression of MMP-3 and TIMP-1 in the synovial fluid was measured by enzyme-linked immunosorbent assay (ELISA) before and after 4 week and 6 month therapy. RESULTS: The level of MMP-3 and the ratio of MMP-3/TIMP-1 in the synovial fluid decreased after being treated for 4 weeks, and the effect on MMP-3 and MMP-3/TIMP-1 lasted for 6 months in the HA group and the GS+HA groups. The levels of TIMP-1 increased significantly after being treated for 4 weeks only in the GS+HA group. The level of MMP-3 and the ratio of MMP-3/TIMP-1 in the synovial fluid decreased, but the level of TIMP-1 increased after being treated for 4 weeks, and the effect on MMP-3 and MMP-3/TIMP-1 lasted for 6 months. The level of MMP-3 and the ratio of MMP-3/TIMP-1 in the synovial fluid increased after being treated for 6 months compared with those for 4 weeks. The level of TIMP-1 increased in the GS group more than that in the HA group after being treated for 4 weeks. The level of TIMP-1 increased in the AD group more than that in the HA' group and the GS+HA' group after being treated for 4 weeks. CONCLUSION: (1) HA, GS and AD all can decrease the level of of MMP-3 and the ratio of MMP-3/TIMP-1 in the synovial fluid in knee joints with OA. (2) The level of TIMP-1 in the synovial fluid has no difference before and after being treated with HA. The AD group and GS group can increase the level of TIMP-1, which indicates that the AD group or GS group might produce better therapeutic effect. (3) The level of TIMP-1 increased in the AD group is more than that in the HA' group and the GS+HA' group after being treated for 4 weeks, which indicates that the AD group might get better therapeutic effect than the other 2 groups. (4) One of the most important mechanisms of HA, GS and AD in treating OA might be attributed to the expression of MMPs and TIMPs in knee joints with OA.