Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Science 1 February 2008:
Vol. 319. no. 5863, pp. 624 - 627
DOI: 10.1126/science.1150110
Prev | Table of Contents | Next

Reports

Cathepsin K-Dependent Toll-Like Receptor 9 Signaling Revealed in Experimental Arthritis

Masataka Asagiri,1,2 Toshitake Hirai,1,4 Toshihiro Kunigami,1,4 Shunya Kamano,1,5 Hans-Jürgen Gober,1 Kazuo Okamoto,1 Keizo Nishikawa,1 Eicke Latz,6 Douglas T. Golenbock,6 Kazuhiro Aoki,3 Keiichi Ohya,3 Yuuki Imai,7,9 Yasuyuki Morishita,8 Kohei Miyazono,8 Shigeaki Kato,7,9 Paul Saftig,10 Hiroshi Takayanagi1,2*

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.

1 Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8549, Japan.
2 Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, Tokyo 113-8549, Japan.
3 Department of Hard Tissue Engineering, Section of Pharmacology, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8549, Japan.
4 Nippon Chemiphar Co., Ltd., Saitama 341-0005, Japan.
5 Department of Orthopaedic Surgery, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
6 Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
7 Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan.
8 Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
9 Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan.
10 Biochemical Institute, Christian-Albrechts-University Kiel, D-24098 Kiel, Germany.

* To whom correspondence should be addressed. E-mail: taka.csi{at}tmd.ac.jp

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
ATP-induced osteoclast function: the formation of sealing-zone like structure and the secretion of lytic granules via microtubule-deacetylation under the control of Syk.
R. Hazama, X. Qu, K. Yokoyama, C. Tanaka, E. Kinoshita, J. He, S. Takahashi, K. Tohyama, H. Yamamura, and Y. Tohyama (2009)
Genes Cells 14, 871-884
   Abstract »    Full Text »    PDF »
Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing.
R. Fukui, S.-i. Saitoh, F. Matsumoto, H. Kozuka-Hata, M. Oyama, K. Tabeta, B. Beutler, and K. Miyake (2009)
J. Exp. Med. 206, 1339-1350
   Abstract »    Full Text »    PDF »
Endocytic sequestration of the B cell antigen receptor and toll-like receptor 9 in anergic cells.
S. K. O'Neill, M. L. Veselits, M. Zhang, C. Labno, Y. Cao, A. Finnegan, M. Uccellini, M.-L. Alegre, J. C. Cambier, and M. R. Clark (2009)
PNAS 106, 6262-6267
   Abstract »    Full Text »    PDF »
The roles of TLRs, RLRs and NLRs in pathogen recognition.
T. Kawai and S. Akira (2009)
Int. Immunol. 21, 317-337
   Abstract »    Full Text »    PDF »
Fra-1 negatively regulates lipopolysaccharide-mediated inflammatory responses.
H. Morishita, F. Saito, H. Kayama, K. Atarashi, H. Kuwata, M. Yamamoto, and K. Takeda (2009)
Int. Immunol. 21, 457-465
   Abstract »    Full Text »    PDF »
Response to Letter by Yetkin and Waltenberger.
H. Kataoka (2009)
Stroke 40, e28
   Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)