Cathepsin K-dependent Toll-like receptor 9 signaling revealed in experimental arthritis

被引：267

作者：

Asagiri, Masataka ^{[1
,2
]}

Hirai, Toshitake ^{[1
,4
]}

Kunigami, Toshihiro ^{[1
,4
]}

Kamano, Shunya ^{[1
,5
]}

Gober, Hans-Juergen ^{[1
]}

Okamoto, Kazuo ^{[1
]}

Nishikawa, Keizo ^{[1
]}

Latz, Eicke ^{[6
]}

Golenbock, Douglas T. ^{[6
]}

Aoki, Kazuhiro ^{[3
]}

Ohya, Keiichi ^{[3
]}

Imai, Yuuki ^{[7
,9
]}

Morishita, Yasuyuki ^{[8
]}

Miyazono, Kohei ^{[8
]}

Kato, Shigeaki ^{[7
,9
]}

Saftig, Paul ^{[10
]}

Takayanagi, Hiroshi ^{[1
,2
]}

机构：

[1] Tokyo Med & Dent Univ, Grad Sch, Dept Cell Signaling, Tokyo 1138549, Japan

[2] Tokyo Med & Dent Univ, Ctr Excellence Program Frontier Res Mol Destruct, Tokyo 1138549, Japan

[3] Tokyo Med & Dent Univ, Grad Sch, Pharmacol Sect, Dept Hard Tissue Engn, Tokyo 1138549, Japan

[4] Nippon Chemiphar Co Ltd, Saitama 3410005, Japan

[5] Juntendo Univ, Sch Med, Dept Orthopaed Surg, Tokyo 1138421, Japan

[6] Univ Massachusetts, Sch Med, Div Infect Dis & Immunol, Worcester, MA 01605 USA

[7] Univ Tokyo, Inst Mol & Cellular Biosci, Tokyo 1130032, Japan

[8] Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Tokyo 1130033, Japan

[9] Japan Sci & Technol Agcy, Exploratory Res Adv Technol, Kawaguchi, Saitama 3320012, Japan

[10] Univ Kiel, Inst Biochem, D-24098 Kiel, Germany

来源：

SCIENCE | 2008年 / 319卷 / 5863期

关键词：

D O I：

10.1126/science.1150110

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 [理学]; 0710 [生物学]; 09 [农学];

摘要：

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.

引用

页码：624 / 627

页数：4

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