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

M Asagiri, T Hirai, T Kunigami, S Kamano, HJ Gober… - Science, 2008 - science.org
M Asagiri, T Hirai, T Kunigami, S Kamano, HJ Gober, K Okamoto, K Nishikawa, E Latz
Science, 2008science.org
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 …
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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