Cathepsin K-dependent Toll-like receptor 9 signaling revealed in experimental arthritis
Cathepsin K-dependent Toll-like receptor 9 signaling revealed in experimental arthritis
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DOI：
10.1126/science.1150110
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发表时间：
2008-02-01
期刊：
影响因子：
56.9
通讯作者：
Takayanagi, Hiroshi
中科院分区：
文献类型：
--
作者：
Asagiri, Masataka;Hirai, Toshitake;Takayanagi, Hiroshi
组织蛋白酶K最初被鉴定为一种破骨细胞特异性溶酶体蛋白酶，其抑制剂被认为可能具有治疗潜力。我们表明，抑制组织蛋白酶K可有效抑制关节的自身免疫性炎症以及自身免疫性关节炎中的破骨细胞性骨吸收。此外，组织蛋白酶K基因敲除小鼠对实验性自身免疫性脑脊髓炎具有抵抗力。对组织蛋白酶K的药理抑制或靶向破坏导致树突状细胞在对未甲基化CpG DNA应答时Toll样受体9信号传导缺陷，这进而导致辅助性T细胞17的诱导减弱，而不影响树突状细胞的抗原呈递能力。这些结果表明组织蛋白酶K在免疫系统中起重要作用，并可作为自身免疫性疾病的一个有效治疗靶点。
Cathepsin K was originally identified as an osteoclast- specific lysosomal protease, the inhibitor of which has been considered might have therapeutic potential. We show that inhibition of cathepsin K could potently suppress autoimmune inflammation of the joints as well as osteoclastic bone resorption in autoimmune arthritis. Furthermore, cathepsin K-/- mice were resistant to experimental autoimmune encephalomyelitis. Pharmacological inhibition or targeted disruption of cathepsin K resulted in defective Toll- like receptor 9 signaling in dendritic cells in response to unmethylated CpG DNA, which in turn led to attenuated induction of T helper 17 cells, without affecting the antigen- presenting ability of dendritic cells. These results suggest that cathepsin K plays an important role in the immune system and may serve as a valid therapeutic target in autoimmune diseases.