Lack of tissue inhibitor of metalloproteinases-3 results in an enhanced inflammatory response in antigen-induced arthritis
Lack of tissue inhibitor of metalloproteinases-3 results in an enhanced inflammatory response in antigen-induced arthritis
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DOI：
10.1016/s0002-9440(10)62483-2
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发表时间：
2005-06-01
影响因子：
6
通讯作者：
Mort, JS
中科院分区：
文献类型：
--
作者：
Mahmoodi, M;Sahebjam, S;Mort, JS
金属蛋白酶组织抑制因子-3(TIMP-3)可抑制基质金属蛋白酶、肿瘤坏死因子-α转换酶(TACE，ADAM17)、肿瘤坏死因子-α转换酶(TACE，ADAM17)。这些金属蛋白参与炎性关节炎关节破坏的不同方面。为了确定该抑制物在关节病理中的相对重要性，用甲基化牛血清白蛋白免疫野生型和TIMP3(-/-)小鼠，然后用相同的抗原关节内注射诱导关节炎。动物在攻击后被监测长达14天，关节组织通过常规和藏红素0染色进行分析，并观察金属蛋白酶裂解产生的聚集素新表位的存在。免疫分析法检测血清肿瘤坏死因子-α水平。与野生型动物相比，TIMP3(-/-)小鼠关节腔内注射抗原后的初始炎症反应显著增加，免疫后TIMP3(-/-)小鼠血清中的肿瘤坏死因子-α水平显著升高。然而，这些临床特征的差异在第7天到第14天就消失了。在藏红花0染色或聚集素裂解部位新表位丰度方面没有发现差异。因此，在炎症性关节疾病中，TIMP-3可能通过降低ADAM17的活性来抑制肿瘤坏死因子-α的炎症反应。
Tissue inhibitor of metalloproteinases-3 (TIMP-3) is known to inhibit matrix metalloproteinases, aggre-canases, and tumor necrosis factor (TNF)-alpha-converting enzyme (TACE, ADAM17). These metalloproteases participate in different aspects of joint destruction in inflammatory arthritis. To determine the relative importance of this inhibitor in joint pathology, wildtype and Timp3(-/-) mice were immunized with methylated bovine serum albumin followed by arthritis induction by intra-articular injection of the same antigen. Animals were monitored for up to 14 days after challenge, and joint tissues were analyzed by routine and Safranin 0 staining and for the presence of aggrecan neoepitopes produced by metalloprotease cleavage. Serum TNF-alpha was measured by immunoassay. Compared to wild-type animals, Timp3(-/-) mice showed a dramatic increase in the initial inflammatory response to intra-articular antigen injection, and serum TNF-a levels were greatly elevated in the Timp3(-/-) animals after immunization. However, these differences in clinical features disappeared by days 7 to 14. No difference in Safranin 0 staining or aggrecan cleavage site neoepitope abundance was seen. Thus, in inflammatory joint disease TIMP-3 likely dampens the inflammatory response of TNF-a by reducing ADAM17 activity.