Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis |
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| Authors: | Asagiri Masataka Hirai Toshitake Kunigami Toshihiro Kamano Shunya Gober Hans-Jürgen Okamoto Kazuo Nishikawa Keizo Latz Eicke Golenbock Douglas T Aoki Kazuhiro Ohya Keiichi Imai Yuuki Morishita Yasuyuki Miyazono Kohei Kato Shigeaki Saftig Paul Takayanagi Hiroshi |
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| Institution: | Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8549, Japan. |
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| 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. |
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