Mahmoodi Mandana, Sahebjam Solmaz, Smookler David, Khokha Rama, Mort John S
Joint Diseases Laboratory, Shriners Hospital for Children, 1529 Cedar Ave., Montreal, Quebec, Canada H3G 1A6.
Am J Pathol. 2005 Jun;166(6):1733-40. doi: 10.1016/S0002-9440(10)62483-2.
Tissue inhibitor of metalloproteinases-3 (TIMP-3) is known to inhibit matrix metalloproteinases, aggrecanases, 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, wild-type 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 O 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-alpha 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 O staining or aggrecan cleavage site neoepitope abundance was seen. Thus, in inflammatory joint disease TIMP-3 likely dampens the inflammatory response of TNF-alpha by reducing ADAM17 activity.
金属蛋白酶组织抑制剂-3（TIMP-3）已知可抑制基质金属蛋白酶、聚集蛋白聚糖酶和肿瘤坏死因子（TNF）-α转换酶（TACE，ADAM17）。这些金属蛋白酶参与炎症性关节炎关节破坏的不同方面。为了确定这种抑制剂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基因敲除小鼠，随后通过关节内注射相同抗原诱导关节炎。在激发后对动物进行长达14天的监测，并通过常规和番红O染色以及检测金属蛋白酶切割产生的聚集蛋白聚糖新表位的存在情况来分析关节组织。通过免疫测定法测量血清TNF-α。与野生型动物相比，Timp3基因敲除小鼠对关节内抗原注射的初始炎症反应显著增加，免疫后Timp3基因敲除动物的血清TNF-α水平大幅升高。然而，这些临床特征的差异在第7至14天消失。在番红O染色或聚集蛋白聚糖切割位点新表位丰度方面未观察到差异。因此，在炎症性关节疾病中，TIMP-3可能通过降低ADAM17活性来减轻TNF-α的炎症反应。
