Collagen and aggrecan degradation is blocked in interleukin-1-treated cartilage explants by an inhibitor of IκB kinase through suppression of metalloproteinase expression
Collagen and aggrecan degradation is blocked in interleukin-1-treated cartilage explants by an inhibitor of IκB kinase through suppression of metalloproteinase expression
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DOI：
10.1124/jpet.105.087569
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发表时间：
2005-10-01
影响因子：
3.5
通讯作者：
Burke, JR
中科院分区：
文献类型：
--
作者：
Pattoli, MA;MacMaster, JF;Burke, JR
先前已显示BMS-345541 [4（2 '-氨乙基）氨基-1，8-二甲基咪唑（1，2-a）喹喔啉]（I κ B激酶（IKK）的高选择性抑制剂）可阻断鼠胶原诱导关节炎中的炎症和关节破坏。虽然这种药物已被证明可以抑制小鼠中核因子-κ B依赖性细胞因子的表达，但我们研究了这种抑制剂是否直接抑制精氨酸驱动的金属蛋白酶表达和软骨降解。在SW-1353人软骨肉瘤细胞中，BMS-345541以浓度依赖性方式抑制基质金属蛋白酶（MMP）-1，MMP-3和MMP-13的白细胞介素-1（IL-1）依赖性表达。IL-1处理未能诱导且BMS-345541未抑制聚集蛋白聚糖酶ADAMTS-4（具有血小板反应蛋白基序的去整合素和金属蛋白酶结构域）和ADAMTS-5以及金属蛋白酶组织抑制剂-3的表达。在用IL-1刺激以诱导聚集蛋白聚糖和胶原降解的牛软骨外植体培养物中，培养3周后，BMS-345541可有效抑制聚集蛋白聚糖和胶原降解。在这些外植体中，分泌的ADAMTS-4不受BMS-345541的抑制，而ADAMTS-5的分泌在抑制聚集蛋白聚糖降解的相同浓度范围内被阻断。IKK抑制剂通过抑制金属蛋白酶表达阻断聚集蛋白聚糖和胶原降解的能力，加上其阻断炎性细胞因子产生的能力，表明IKK是开发治疗关节炎疾病的新型药物的有希望的靶点。
It has previously been shown that BMS-345541 [4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline], a highly-selective inhibitor of I kappa B kinase (IKK), blocks both inflammation and joint destruction in murine collagen-induced arthritis. Although this agent has been shown to inhibit nuclear factor-kappa B-dependent cytokine expression in mice, we examined whether the inhibitor directly inhibits cytokine-driven metalloproteinase expression and cartilage degradation. In SW-1353 human chondrosarcoma cells, BMS-345541 inhibited interleukin-1 (IL-1)- dependent expression of matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13 in a concentration-dependent manner. IL-1 treatment failed to induce and BMS-345541 did not inhibit the expression of aggrecanases ADAMTS-4 ( a disintegrin and metalloproteinase domain with thrombospondin motif) and ADAMTS-5, as well as the tissue inhibitor of metalloproteinase-3. In bovine cartilage explant cultures stimulated with IL-1 to induce aggrecan and collagen degradation over 3 weeks of culture, BMS-345541 was effective in inhibiting the degradation of both aggrecan and collagen. Secreted ADAMTS-4 was not inhibited by BMS-345541 in these explants, whereas ADAMTS-5 secretion was blocked in the same concentration range that inhibited aggrecan degradation. The ability of the IKK inhibitor to block aggrecan and collagen degradation through suppression of metalloproteinase expression, coupled with its ability to block inflammatory cytokine production, shows IKK to be a promising target for the development of novel agents to treat arthritic diseases.