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

Science. 2008 Feb 1;319(5863):624-7. doi: 10.1126/science.1150110.

Masataka Asagiri ¹, Toshitake Hirai, Toshihiro Kunigami, Shunya Kamano, Hans-Jürgen Gober, Kazuo Okamoto, Keizo Nishikawa, Eicke Latz, Douglas T Golenbock, Kazuhiro Aoki, Keiichi Ohya, Yuuki Imai, Yasuyuki Morishita, Kohei Miyazono, Shigeaki Kato, Paul Saftig, Hiroshi Takayanagi

Affiliations

Affiliation

1 Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8549, Japan.

PMID: 18239127 DOI: 10.1126/science.1150110

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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