Publication Date:
2008-02-02
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Asagiri, Masataka -- Hirai, Toshitake -- Kunigami, Toshihiro -- Kamano, Shunya -- Gober, Hans-Jurgen -- 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 -- New York, N.Y. -- Science. 2008 Feb 1;319(5863):624-7. doi: 10.1126/science.1150110.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8549, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18239127" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antigens, CD/metabolism
;
Arthritis, Experimental/drug therapy/*immunology/*metabolism
;
Autoimmune Diseases/drug therapy/immunology/*metabolism
;
Bone Resorption
;
Cathepsin K
;
Cathepsins/antagonists & inhibitors/deficiency/*metabolism
;
Cytokines/metabolism
;
DNA/immunology/metabolism
;
Dendritic Cells/drug effects/immunology
;
Dinucleoside Phosphates/immunology/metabolism
;
Encephalomyelitis, Autoimmune, Experimental/immunology/metabolism
;
Endosomes/metabolism
;
Freund's Adjuvant/immunology
;
Lymphocyte Activation/drug effects
;
Male
;
Mice
;
Osteoporosis/drug therapy
;
Protease Inhibitors/pharmacology
;
Rats
;
*Signal Transduction
;
T-Lymphocytes/drug effects/enzymology/immunology
;
Toll-Like Receptor 9/*metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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