Cerebrospinal fluid and serum levels and intrathecal production of active matrix metalloproteinase-9 (MMP-9) as markers of disease activity in patients with multiple sclerosis
Cerebrospinal fluid and serum levels and intrathecal production of active matrix metalloproteinase-9 (MMP-9) as markers of disease activity in patients with multiple sclerosis
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DOI：
10.1191/135248506ms1274oa
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发表时间：
2006-01-01
影响因子：
5.8
通讯作者：
Dallocchio, F
中科院分区：
文献类型：
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作者：
Fainardi, E;Castellazzi, M;Dallocchio, F
本研究采用灵敏的活性检测系统，对37例复发缓解期(RR)、15例继发性进展期(SP)和9例原发进展期(PP)多发性硬化症(MS)患者的脑脊液(CSF)和血清活性基质金属蛋白酶-9(MMP9)水平进行了检测。我们还研究了48例其他炎症性神经疾病(OIND)患者和48例非炎症性神经疾病(NIND)患者作为神经对照。采用双抗体夹心酶联免疫吸附试验检测同一患者组脑脊液和血清中基质金属蛋白酶9组织抑制物TIMP-1的水平，以评价其活性。脑脊液中活性基质金属蛋白酶-9、脑脊液活性基质金属蛋白酶-9/TIMP-1比值和鞘内活性基质金属蛋白酶-9的合成以特异性指数表示，MS组高于NIND组(P<0.05)，血清活性MMP9/TIMP-1比值高于NIND组(P<0.05)，血清TIMP-1浓度低于NIND组(P<；0.05)。更重要的是，在临床(分别为0.001，0.001和0.05)和核磁共振(分别为0.001，0.001和0.02)的MS患者中，血清活性MMP9的平均水平、血清活性MMP9/TIMP-1的比值和鞘内活性MMP9的产生均增加，而只有在MMRI有疾病活动证据的MS患者中，脑脊液中活性MMP9的平均浓度和脑脊液中活性MMP9/TIMP-1的比值才增加(P<；0.02和<；0.01)。综上所述，这些发现提示，基质金属蛋白酶-9/TIMP-1平衡向基质金属蛋白酶-9蛋白分解活性的转变可能与MS免疫失调有关。此外，我们的结果表明，脑脊液和血清活性基质金属蛋白酶-9水平可能是监测MS疾病活动性的潜在替代生物标志物。特别是，血清活性基质金属蛋白酶-9/TIMP-1比值似乎是一个非常合适的持续MS炎症的指标，因为它很容易测量。
In this study, we employed a sensitive activity assay system to measure cerebrospinal fluid (CSF) and serum levels of active matrix metalloproteinase-9 (MMP-9) in 37 relapsing-remitting (RR), 15 secondary progressive (SP) and nine primary progressive ( PP) multiple sclerosis (MS) patients, grouped according to clinical and magnetic resonance imaging (MRI) evidence of disease activity. We also studied, as neurological controls, 48 patients with other inflammatory neurological disorders (OIND) and 48 with non-inflammatory neurological disorders (NIND). To assess active MMP-9/TIMP-1 circuit, CSF and serum levels of MMP-9 tissue inhibitor TIMP-1 were quantified by ELISA in the same patient population. CSF mean levels of active MMP-9, CSF active MMP-9/TIMP-1 ratios and intrathecal active MMP-9 synthesis, as indicated by specific index, were more elevated in MS than in NIND (P < 0.05, < 0.02 and < 0.02, respectively), serum active MMP-9/TIMP-1 ratio was higher in MS (P < 0.01) and OIND (P < 0.02) than in NIND, and serum TIMP-1 concentrations were lower in MS than in NIND (P < 0.05). More importantly, serum active MMP-9 mean levels, serum active MMP-9/TIMP-1 ratio and intrathecal production of active MMP-9 were increased in MS patients with clinical (P < 0.001, < 0.001 and < 0.05, respectively) and MRI (P < 0.001, < 0.001 and < 0.02, respectively) disease activity, whereas CSF mean concentrations of active MMP-9 and CSF active MMP-9/TIMP-1 ratio were enhanced only in MS patients with MRI evidence of disease activity (P < 0.02 and < 0.01, respectively). Altogether, these findings suggest that a shift in MMP-9/TIMP-1 balance towards proteolytic activity of MMP-9 could be relevant in MS immune dysregulation. In addition, our results indicate that CSF and serum levels of active MMP-9 may represent a potential surrogate biomarker for monitoring MS disease activity. In particular, serum active MMP-9/TIMP-1 ratio seems to be a very appropriate indicator of ongoing MS inflammation, since it is easily measurable.