The Chondroprotective Agent ITZ-1 Inhibits Interleukin-1β–Induced Matrix Metalloproteinase–13 Production and Suppresses Nitric Oxide–Induced Chondrocyte Death

Journal of Pharmacological Sciences

Yasukazu Tajima¹  Hirobumi Suzuki¹  Haruhide Kimura¹  Kiyofumi Yamada²  Yasunori Funabashi¹  Hiroshi Yukitake¹  Koyo Gomaibashi¹  Shinji Morimoto¹  Masayuki Takizawa¹ 

[1] Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Japan;Laboratory of Neuropsychopharmacology, Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Japan

关键词: ITZ-1;    cartilage degradation;    chondrocyte;    matrix metalloproteinase (MMP)-13;    cell death;   

DOI  :  10.1254/jphs.09076FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(38)Cited-By(8)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-1β (IL-1β)-induced proteoglycan and collagen release from bovine nasal cartilage in vitro and suppressed intra-articular infusion of IL-1β–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-1β–induced production of MMP-13 in human articular chondrocytes (HAC). IL-1β–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-1β–induced MMP-13 production in HAC. Furthermore, ITZ-1 selectively inhibited IL-1β–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.

【 授权许可】

Unknown