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

被引：259

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 ; 0710 ; 09 ;

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

共 25 条

[1] Pathogen recognition and innate immunity [J].

Akira, S ;

Uematsu, S ;

Takeuchi, O .

CELL, 2006, 124 (04) :783-801

[2] The molecular understanding of osteoclast differentiation [J].

Asagiri, Masataka ;

Takayanagi, Hiroshi .

BONE, 2007, 40 (02) :251-264

[3] Autoimmunity through cytokine-induced dendritic cell activation [J].

Banchereau, J ;

Pascual, V ;

Palucka, AK .

IMMUNITY, 2004, 20 (05) :539-550

[4] Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells [J].

Bettelli, E ;

Carrier, YJ ;

Gao, WD ;

Korn, T ;

Strom, TB ;

Oukka, M ;

Weiner, HL ;

Kuchroo, VK .

NATURE, 2006, 441 (7090) :235-238

[5] Novel pycnodysostosis mouse model uncovers cathepsin K function as a potential regulator of osteoclast apoptosis and senescence [J].

Chen, Wei ;

Yang, Shuying ;

Abe, Yoke ;

Li, Ming ;

Wang, Yucheng ;

Shao, Jianzhong ;

Li, En ;

Li, Yi-Ping .

HUMAN MOLECULAR GENETICS, 2007, 16 (04) :410-423

[6] Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency [J].

Gelb, BD ;

Shi, GP ;

Chapman, HA ;

Desnick, RJ .

SCIENCE, 1996, 273 (5279) :1236-1238

[7] Arthritis induced in rats with non-immunogenic adjuvants as models for rheumatoid arthritis [J].

Holmdahl, R ;

Lorentzen, JC ;

Lu, SM ;

Olofsson, P ;

Wester, L ;

Holmberg, J ;

Pettersson, U .

IMMUNOLOGICAL REVIEWS, 2001, 184 :184-202

[8] Lysosomal cysteine proteases regulate antigen presentation [J].

Honey, K ;

Rudensky, AY .

NATURE REVIEWS IMMUNOLOGY, 2003, 3 (06) :472-482

[9] Toll-like receptor control of the adaptive immune responses [J].

Iwasaki, A ;

Medzhitov, R .

NATURE IMMUNOLOGY, 2004, 5 (10) :987-995

[10] CpG motifs in bacterial DNA and their immune effects [J].

Krieg, AM .

ANNUAL REVIEW OF IMMUNOLOGY, 2002, 20 :709-760

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