Fainardi E, Castellazzi M, Bellini T, Manfrinato M C, Baldi E, Casetta I, Paolino E, Granieri E, Dallocchio F
Multiple Sclerosis Center, Section of Neurology, University of Ferrara, Arcispedale S. Anna, Corso della Giovecca 203, Ferrara 1-44100, Italy.
Mult Scler. 2006 Jun;12(3):294-301. doi: 10.1191/135248506ms1274oa.
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.
在本研究中，我们采用一种灵敏的活性检测系统，对37例复发缓解型（RR）、15例继发进展型（SP）和9例原发进展型（PP）多发性硬化（MS）患者的脑脊液（CSF）和血清中活性基质金属蛋白酶-9（MMP-9）水平进行了检测，这些患者根据疾病活动的临床和磁共振成像（MRI）证据分组。我们还将48例患有其他炎性神经系统疾病（OIND）的患者和48例患有非炎性神经系统疾病（NIND）的患者作为神经学对照进行了研究。为评估活性MMP-9/TIMP-1通路，通过酶联免疫吸附测定（ELISA）对同一批患者群体的脑脊液和血清中MMP-9组织抑制剂TIMP-1水平进行了定量。MS患者脑脊液中活性MMP-9的平均水平、脑脊液活性MMP-9/TIMP-1比值以及鞘内活性MMP-9合成（由特定指标表明）均高于NIND患者（分别为P < 0.05、< 0.02和< 0.02），MS患者（P < 0.01）及OIND患者（P < 0.02）血清活性MMP-9/TIMP-1比值高于NIND患者，且MS患者血清TIMP-1浓度低于NIND患者（P<0.05）。更重要的是，临床（分别为P < 0.001、< 0.001和< 0.05）及MRI（分别为P < 0.001、< 0.001和< 0.02）有疾病活动的MS患者血清活性MMP-9平均水平、血清活性MMP-9/TIMP-1比值及鞘内活性MMP-9生成均升高，而仅MRI有疾病活动证据的MS患者脑脊液中活性MMP-9平均浓度及脑脊液活性MMP-9/TIMP-1比值升高（分别为P < 0.02和< 0.01）。总之，这些发现表明MMP-9/TIMP-1平衡向MMP-9的蛋白水解活性转变可能与MS免疫失调相关。此外，我们的结果表明脑脊液和血清中活性MMP-9水平可能代表监测MS疾病活动的潜在替代生物标志物。特别是，血清活性MMP-9/TIMP-1比值似乎是正在进行的MS炎症的一个非常合适的指标，因为它易于测量。
