Decreased levels of metalloproteinase-9 and angiogenic factors in skin lesions of patients with psoriatic arthritis after therapy with anti-TNF-alpha.
Decreased levels of metalloproteinase-9 and angiogenic factors in skin lesions of patients with psoriatic arthritis after therapy with anti-TNF-alpha.
复制标题
DOI：
10.1186/1740-2557-3-5
复制
发表时间：
2006-10-05
期刊：
影响因子：
--
通讯作者：
Ensoli F
中科院分区：
文献类型：
--
作者：
Cordiali-Fei P;Trento E;D'Agosto G;Bordignon V;Mussi A;Ardigò M;Mastroianni A;Vento A;Solivetti F;Berardesca E;Ensoli F
炎症是皮肤银屑病和银屑病关节炎发展过程中的早期和关键事件。令人信服的证据表明，肿瘤坏死因子-α的产生在银屑病中起着核心作用，它维持了皮肤和关节的炎症过程。在肿瘤坏死因子-α对角质形成细胞的多种作用中，基质金属蛋白酶-9(MMP9)的诱导可能是该病发病的关键机制之一。本研究的目的是通过检测银屑病患者皮损和血清中基质金属蛋白酶-9的表达，探讨基质金属蛋白酶-9在银屑病发生发展中的作用；(2)基质金属蛋白酶-9与银屑病活动性的关系；(3)基质金属蛋白酶-9与肿瘤坏死因子-α产生的关系。11名临床表现与皮肤病有关的关节症状的牛皮癣患者被纳入一项基于给予抗肿瘤坏死因子-α单抗(英夫利昔单抗)的治疗方案。分别于治疗前和治疗6周后采集血清和皮肤活检标本。组织短期培养，免疫酶法测定培养上清液中肿瘤坏死因子-α、基质金属蛋白酶-9、基质金属蛋白酶-2、血管内皮生长因子和E-选择素等与斑块型银屑病发病相关的血管生成分子的含量。同时检测血清中基质金属蛋白酶-9的浓度。用银屑病面积和严重程度指数(PASI)评价疾病的皮肤活动性。临床和实验室评估表明，除一名患者外，所有患者在治疗三个月后PASI评分均有显著改善。治疗前后皮损活检自发释放的基质金属蛋白酶-9(P=0.017)、肿瘤坏死因子-α(P=0.005)和E-选择素(P=0.018)水平显著降低。此外，PASI与肿瘤坏死因子-α(R2=0.33，P=0.005)、基质金属蛋白酶-9(R2=0.25，P=0.017)、E-选择素(R2=0.24，P=0.018)的产生呈显著正相关。MMP9与肿瘤坏死因子α水平呈显著正相关(R2=0.3，P=0.008)。随着临床症状的改善，血清中的基质金属蛋白酶-9水平也显著降低。我们的研究结果表明，基质金属蛋白酶-9和肿瘤坏死因子-α的产生之间存在直接的关系，强烈提示基质金属蛋白酶-9可能在银屑病的皮肤炎症过程中发挥关键作用。
Inflammation represents an early and key event in the development of both the cutaneous psoriasis and psoriatic arthritis. Compelling evidences indicate that the production of TNF-α plays a central role in psoriasis by sustaining the inflammatory process in the skin as well as in the joints. Among the multiple effects produced by TNF-α on keratinocytes, the induction of matrix metalloproteinase-9 (MMP-9), a collagenase implicated in joint inflammatory arthritis which acts as an angiogenesis promoting factor, might represent a key mechanism in the pathogenesis of the disease. Aims of the present study were to investigate a) the role of MMP-9 in the development of psoriasis by assessing the presence of MMP-9 in lesional skin and in sera of psoriatic patients; b) the association of MMP-9 with the activity of the disease; c) the relationship between MMP-9 and TNF-α production. Eleven psoriatic patients, clinically presenting joint symptoms associated to the cutaneous disease, were included in a therapeutic protocol based on the administration of anti-TNF-α monoclonal antibody (Infliximab). Sera and skin biopsies were collected before treatment and after 6 weeks of therapy. Tissues were kept in short term cultures and production soluble mediators such as TNF-α, MMP-9, MMP-2, VEGF and E-Selectin, which include angiogenic molecules associated to the development of plaque psoriasis, were measured in the culture supernatants by immunoenzymatic assays (ng/ml or pg/ml per mg of tissue). MMP-9 concentrations were also measured in the sera. The cutaneous activity of disease was evaluated by the Psoriasis Area and Severity Index (PASI). Clinical and laboratory assessment indicated that all but one patients had a significant improvement of the PASI score after three months of therapy. The clinical amelioration was associated to a significant decrease of MMP-9 (P = 0.017), TNF-α (P = 0.005) and E-selectin (P = 0.018) levels, spontaneously released by lesional biopsies before and after therapy. In addition, significant correlations were found between the PASI measurements and TNF-α (r2 = 0.33, P = 0.005), MMP-9 (r2 = 0.25, P = 0.017), E-selectin (r2 = 0.24, P = 0.018) production. MMP-9 levels were significantly correlated with those of TNF-α (r2 = 0.30, P = 0.008). A significant decrease of MMP-9 in the sera, associated to the clinical improvement was also found. Our findings show the existence of a direct relationship between MMP-9 and TNF-α production strongly suggesting that MMP-9 may play a key role in the skin inflammatory process in psoriasis.