The chondroprotective agent ITZ-1 inhibits interleukin-1beta-induced matrix metalloproteinase-13 production and suppresses nitric oxide-induced chondrocyte death.
In a screening program aimed at discovering anti-osteoarthritis (OA) drugs, we identified an imidazo[5,1-c][1,4]thiazine derivative, ITZ-1, that suppressed both interleukin-1beta (IL-1beta)-induced proteoglycan and collagen release from bovine nasal cartilage in vitro and suppressed intra-articular infusion of IL-1beta-induced cartilage proteoglycan degradation in rat knee joints. ITZ-1 did not inhibit enzyme activities of various matrix metalloproteinases (MMPs), which have pivotal roles in cartilage degradation, while it selectively inhibited IL-1beta-induced production of MMP-13 in human articular chondrocytes (HAC). IL-1beta-induced MMP production has been shown to be mediated by extracellular signal-regulated protein kinase (ERK), p38 kinase, and c-Jun N-terminal kinase (JNK) of the mitogen-activated protein kinase (MAPK) family signal transduction molecules. An ERK-MAPK pathway inhibitor (U0126), but not a p38 kinase inhibitor (SB203580) or a JNK inhibitor (SP600125), also selectively inhibited IL-1beta-induced MMP-13 production in HAC. Furthermore, ITZ-1 selectively inhibited IL-1beta-induced ERK activation without affecting p38 kinase and JNK activation, which may account for its selective inhibition of MMP-13 production. Inhibition of nitric oxide (NO)-induced chondrocyte apoptosis has been another area of interest as a therapeutic strategy for OA, and ITZ-1 also suppressed NO-induced death in HAC. These results suggest that ITZ-1 is a promising lead compound for a disease modifying anti-OA drug program.
Kimura
Haruhide
H
Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Japan. Kimura_Haruhide@takeda.co.jp
Yukitake
Hiroshi
H
Suzuki
Hirobumi
H
Tajima
Yasukazu
Y
Gomaibashi
Koyo
K
Morimoto
Shinji
S
Funabashi
Yasunori
Y
Yamada
Kiyofumi
K
Takizawa
Masayuki
M
D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D016923:Cell Death / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000008:administration & dosage*; D007719:Knee Joint / Q000187:drug effects / Q000378:metabolism; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000187:drug effects* / Q000378:metabolism; D055171:Nasal Cartilages / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000008:administration & dosage; D010003:Osteoarthritis / Q000188:drug therapy / Q000503:physiopathology; D011509:Proteoglycans / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013843:Thiazines / Q000494:pharmacology*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D003094:Collagen; D007093:Imidazoles; D053583:Interleukin-1beta; D053509:Matrix Metalloproteinase 13; D009569:Nitric Oxide; D011509:Proteoglycans; D013843:Thiazines; C542558:N-(5,6-dimethyl-3-oxo-8-((4,4,5,5,5-pentafluoropentyl)thio)-2,3-dihydro-1H-imidazo(5,1-c)(1,4)thiazin-1-ylidene)-4-methylbenzenesulfonamide; D005466:Fluorocarbons; D000096926:Benzenesulfonamides