Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis.
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.
Asagiri
Masataka
M
Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8549, Japan.
Hirai
Toshitake
T
Kunigami
Toshihiro
T
Kamano
Shunya
S
Gober
Hans-Jürgen
HJ
Okamoto
Kazuo
K
Nishikawa
Keizo
K
Latz
Eicke
E
Golenbock
Douglas T
DT
Aoki
Kazuhiro
K
Ohya
Keiichi
K
Imai
Yuuki
Y
Morishita
Yasuyuki
Y
Miyazono
Kohei
K
Kato
Shigeaki
S
Saftig
Paul
P
Takayanagi
Hiroshi
H
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D001862:Bone Resorption; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D015226:Dinucleoside Phosphates / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D005620:Freund's Adjuvant / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D010024:Osteoporosis / Q000188:drug therapy; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
D015703:Antigens, CD; D056657:Cathepsin K; D002403:Cathepsins; D016207:Cytokines; D004247:DNA; D015226:Dinucleoside Phosphates; D005620:Freund's Adjuvant; D011480:Protease Inhibitors; D051217:Toll-Like Receptor 9; C495370:Tlr9 protein, mouse; C015772:CpG dinucleotide; C534132:Ctsk protein, mouse; C534133:Ctsk protein, rat