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Science 319 (5863): 624-627

Copyright © 2008 by the American Association for the Advancement of Science

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*

Abstract: 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

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