Active synovial matrix metalloproteinase-2 is associated with radiographic erosions in patients with early synovitis.
Active synovial matrix metalloproteinase-2 is associated with radiographic erosions in patients with early synovitis.
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DOI：
10.1186/ar79
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
El-Gabalawy HS
中科院分区：
文献类型：
--
作者：
Goldbach-Mansky R;Lee JM;Hoxworth JM;Smith D 2nd;Duray P;Schumacher RH Jr;Yarboro CH;Klippel J;Kleiner D;El-Gabalawy HS
本文检测了28例炎性早期滑膜炎患者和4例健康志愿者血清和滑膜组织中基质金属蛋白酶(MMP)-2和-9及其分子调节因子MMP-14和TIMP-2的表达，并与患者是否存在糜蚀进行了相关性分析。MMP-2、MMP-14和TIMP-2的免疫组织染色定位于滑膜衬里层的相应区域，在正常滑膜中几乎不存在。有影像学糜烂的患者活性MMP-2水平明显高于无糜烂的患者，提示滑膜组织中活性MMP-2水平可能是滑膜病变侵袭性更强的标志。在癌症中，明胶酶[基质金属蛋白酶(MMP)-2和MMP-9]已被证明与组织侵袭和转移性疾病有关。在炎症性关节炎患者中，明胶酶在滑膜中表达，并与滑膜组织侵入相邻软骨和骨有关。据推测，明胶酶的激活剂和抑制剂之间的不平衡导致更高水平的活性，增强局部蛋白质水解和骨侵蚀。确定MMP-2和MMP-9及其调节因子MMP-14和金属蛋白酶组织抑制剂（TIMP）的表达和活性水平是否与新近发病的滑膜炎患者早期糜烂形成有关。根据组织可用性，从较大的早期滑膜炎队列中选择66例患者进行滑膜组织和血清明胶酶表达的研究。持续时间少于1年的周围性关节滑膜炎患者在12个月内的4次就诊中进行了临床和血清学评估。在初次就诊时，患者对一个肿胀的关节进行滑膜组织活检，并在最初和1年时对患者的手脚进行影像学评估。测定血清MMP-1、MMP-2、MMP-9、MMP-14、TIMP-1和TIMP-2水平，并通过免疫组织学检查滑膜组织中MMP-2和MMP-9及其分子调节因子的表达。MMP-2和MMP-9的明胶溶解活性采用灵敏的组织凝胶酶谱技术进行定量。4名健康个体接受闭式滑膜活检，并对其滑膜组织进行类似的分析。在研究的66例患者中，45例符合美国风湿病学会类风湿关节炎（RA）的标准，其中32例（71%）为类风湿因子阳性。在21名非ra患者中，7名患有脊椎关节病，14名患有未分化关节炎。x线摄影显示，12名RA患者在1年内出现多处糜烂，而非RA患者没有发生这种程度的糜烂。在组织中，潜伏性MMP-2广泛表达于滑膜衬里层及下层和间质增生区，而MMP-9表达较为稀疏和局部。在连续的组织学切片上，MMP-14、TIMP-2和MMP-2均在衬里层的相似区域检测到。MMP-14（促mmp -2的激活剂）的组织表达在RA患者中显著高于非RA患者（8.4±5 vs 3.7±4细胞/高倍视野；P = 0.009）。相比之下，MMP-2抑制剂TIMP-2在RA中的表达低于非RA样品（25±12 vs 39±9细胞/高倍视野，P = 0.01）。滑膜组织中MMP-2、MMP-14和TIMP-2的表达在正常滑膜组织样本中几乎检测不到。糜烂性疾病患者的滑膜组织样本中活性MMP-2水平明显高于无糜烂性疾病患者（图1）。然而，MMP-2和MMP-9的组织表达与这些酶的血清水平无关。除血清MMP-2未高于正常水平外，其他所有MMPs和TIMPs的血清水平均有不同程度的升高，并不能预测糜烂性疾病。有趣的是，MMP-1和c反应蛋白，两者都与侵蚀的存在相关，彼此呈正相关（r = 0.42; P < 0.001）。MMP-2和MMP-9被认为在炎症性关节炎患者关节糜烂的演变中起重要作用。大多数研究都集中在MMP-9对滑膜炎的作用上，因为滑膜液和血清MMP-9水平在炎性关节病中显着升高。先前报道的血清MMP-9水平差异很大。在近期发病的滑膜炎患者样本中，血清MMP-9水平升高的仅占21%。此外，这些升高并不是RA特异性的，MMP-9的组织表达是局灶性的，MMP-9活性水平与早期侵蚀没有很好的相关性。虽然血清MMP-2水平不具有预后价值，但高水平的滑膜组织MMP-2活性与早期糜烂的存在显著相关。这可能反映了在这些组织中MMP-14的相对高水平和TIMP-2的低水平增加了MMP-2的激活。我们能够在连续的组织切片中定位这种三分子复合物的成分到滑膜衬里层，这一发现与它们的共定位是一致的。总之，我们提供的证据表明，活跃的MMP-2复合物在炎症类风湿性关节炎滑膜中可检测到，并可能参与早期骨侵蚀的发展。这些结果表明，抑制MMP-2激活的策略可能具有延缓或预防炎症性关节炎患者早期糜烂的潜力。
Serum and synovial tissue expression of the matrix metalloproteinase (MMP)-2 and -9 and their molecular regulators, MMP-14 and TIMP-2 was examined in 28 patients with inflammatory early synovitis and 4 healthy volunteers and correlated with the presence of erosions in the patients. Immunohistological staining of MMP-2, MMP-14 and TIMP-2 localized to corresponding areas in the synovial lining layer and was almost absent in normal synovium. Patients with radiographic erosions had significantly higher levels of active MMP-2 than patients with no erosions, suggesting that activated MMP-2 levels in synovial tissue may be a marker for a more aggressive synovial lesion. In cancer the gelatinases [matrix metalloproteinase (MMP)-2 and MMP-9] have been shown to be associated with tissue invasion and metastatic disease. In patients with inflammatory arthritis the gelatinases are expressed in the synovial membrane, and have been implicated in synovial tissue invasion into adjacent cartilage and bone. It is hypothesized that an imbalance between the activators and inhibitors of the gelatinases results in higher levels of activity, enhanced local proteolysis, and bone erosion. To determine whether the expression and activity levels of MMP-2 and MMP-9, and their regulators MMP-14 and tissue inhibitor of metalloproteinase (TIMP), are associated with early erosion formation in patients with synovitis of recent onset. A subset of 66 patients was selected from a larger early synovitis cohort on the basis of tissue availability for the study of synovial tissue and serum gelatinase expression. Patients with peripheral joint synovitis of less than 1 years' duration were evaluated clinically and serologically on four visits over a period of 12 months. At the initial visit, patients underwent a synovial tissue biopsy of one swollen joint, and patients had radiographic evaluation of hands and feet initially and at 1year. Serum MMP-1, MMP-2, MMP-9, MMP-14, and TIMP-1 and TIMP-2 levels were determined, and synovial tissue was examined by immunohistology for the expression of MMP-2 and MMP-9, and their molecular regulators. Gelatinolytic activity for MMP-2 and MMP-9 was quantified using a sensitive, tissue-based gel zymography technique. Four healthy individuals underwent closed synovial biopsy and their synovial tissues were similarly analyzed. Of the 66 patients studied, 45 fulfilled American College of Rheumatology criteria for rheumatoid arthritis (RA), with 32 (71%) being rheumatoid factor positive. Of the 21 non-RA patients, seven had a spondylarthropathy and 14 had undifferentiated arthritis. Radiographically, 12 of the RA patients had erosions at multiple sites by 1 year, whereas none of the non-RA patients had developed erosive disease of this extent. In the tissue, latent MMP-2 was widely expressed in the synovial lining layer and in areas of stromal proliferation in the sublining layer and stroma, whereas MMP-9 was expressed more sparsely and focally. MMP-14, TIMP-2, and MMP-2 were all detected in similar areas of the lining layer on consecutive histologic sections. Tissue expression of MMP-14, the activator for pro-MMP-2, was significantly higher in RA than in non-RA patients (8.4 ± 5 versus 3.7 ± 4 cells/high-power field; P = 0.009). In contrast, the expression of TIMP-2, an inhibitor of MMP-2, was lower in the RA than in the non-RA samples (25 ± 12 versus 39 ± 9 cells/high-power field; P = 0.01). Synovial tissue expressions of MMP-2, MMP-14, and TIMP-2 were virtually undetectable in normal synovial tissue samples. The synovial tissue samples of patients with erosive disease had significantly higher levels of active MMP-2 than did those of patients without erosions (Fig. 1). Tissue expression of MMP-2 and MMP-9, however, did not correlate with the serum levels of these enzymes. With the exception of serum MMP-2, which was not elevated over normal, serum levels of all of the other MMPs and TIMPs were elevated to varying degrees, and were not predictive of erosive disease. Interestingly, MMP-1 and C-reactive protein, both of which were associated with the presence of erosions, were positively correlated with each other (r = 0.42; P < 0.001). MMP-2 and MMP-9 are thought to play an important role in the evolution of joint erosions in patients with an inflammatory arthritis. Most studies have concentrated on the contribution of MMP-9 to the synovitis, because synovial fluid and serum MMP-9 levels are markedly increased in inflammatory arthropathies. Previously reported serum levels of MMP-9 have varied widely. In the present sample of patients with synovitis of recent onset, serum MMP-9 levels were elevated in only 21%. Moreover, these elevations were not specific for RA, the tissue expression of MMP-9 was focal, and the levels of MMP-9 activity were not well correlated with early erosions. Although serum MMP-2 levels were not of prognostic value, high synovial tissue levels of MMP-2 activity were significantly correlated with the presence of early erosions. This may reflect augmented activation of MMP-2 by the relatively high levels of MMP-14 and low levels of TIMP-2 seen in these tissues. We were able to localize the components of this trimolecular complex to the synovial lining layer in consecutive tissue sections, a finding that is consistent with their colocalization. In conclusion, we have provided evidence that active MMP-2 complexes are detectable in the inflamed RA synovium and may be involved in the development of early bony erosions. These results suggest that strategies to inhibit the activation of MMP-2 may have the potential for retarding or preventing early erosions in patients with inflammatory arthritis.
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影响因子：
--
作者：
DOUGADOS, M;VANDERLINDEN, S;ZEIDLER, H
通讯作者：
ZEIDLER, H
影响因子：
64.5
作者：
Brooks, PC;Stromblad, S;Cheresh, DA
通讯作者：
Cheresh, DA
影响因子：
--
作者：
ELGABALAWY, H;GALLATIN, M;WILKINS, J
通讯作者：
WILKINS, J
影响因子：
6.2
作者：
Nawrocki, B;Polette, M;Adnet, JJ
通讯作者：
Adnet, JJ
影响因子：
6.9
作者：
Konttinen, YT;Ceponis, A;Seiki, M
通讯作者：
Seiki, M