The Experts below are selected from a list of 168 Experts worldwide ranked by ideXlab platform
Masayuki Takizawa - One of the best experts on this subject based on the ideXlab platform.
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the Chondroprotective Agent itz 1 inhibits interleukin 1β induced matrix metalloproteinase 13 production and suppresses nitric oxide induced chondrocyte death
Journal of Pharmacological Sciences, 2009Co-Authors: Haruhide Kimura, Hiroshi Yukitake, Yasukazu Tajima, Hirobumi Suzuki, Shinji Morimoto, Yasunori Funabashi, Koyo Gomaibashi, Kiyofumi Yamada, Masayuki TakizawaAbstract:Abstract. 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.
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The Chondroprotective Agent ITZ-1 Inhibits Interleukin-1β–Induced Matrix Metalloproteinase–13 Production and Suppresses Nitric Oxide–Induced Chondrocyte Death
Journal of pharmacological sciences, 2009Co-Authors: Haruhide Kimura, Hiroshi Yukitake, Yasukazu Tajima, Hirobumi Suzuki, Shinji Morimoto, Yasunori Funabashi, Koyo Gomaibashi, Kiyofumi Yamada, Masayuki TakizawaAbstract:Abstract. 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.
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calcium pentosan polysulfate directly inhibits enzymatic activity of adamts4 aggrecanase 1 in osteoarthritic chondrocytes
FEBS Letters, 2008Co-Authors: Masayuki Takizawa, Taku Yatabe, Aiko Okada, Miyuki Chijiiwa, Satsuki Mochizuki, Peter Ghosh, Yasunori OkadaAbstract:Aggrecanases that include ADAMTS1, 4, 5, 8, 9 and 15 are considered to play key roles in aggrecan degradation in osteoarthritic cartilage. Here we demonstrate that calcium pentosan polysulfate (CaPPS) directly inhibits the aggrecanase activity of ADAMTS4 without affecting the mRNA expression of the ADAMTS species in interleukin-1α-stimulated osteoarthritic chondrocytes. Synthetic peptides corresponding to specific regions of the thrombospondin type 1 repeat, cysteine-rich or spacer domain of ADAMTS4 inhibit the binding to immobilized CaPPS. These data suggest that CaPPS could function as Chondroprotective Agent for the treatment of osteoarthritis by inhibition of ADAMTS4 through interaction with the C-terminal ancillary domain.
Haruhide Kimura - One of the best experts on this subject based on the ideXlab platform.
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ITZ-1, a Client-Selective Hsp90 Inhibitor, Efficiently Induces Heat Shock Factor 1 Activation
Chemistry & biology, 2010Co-Authors: Haruhide Kimura, Hiroshi Yukitake, Yasukazu Tajima, Hirobumi Suzuki, Tomoko Chikatsu, Shinji Morimoto, Yasunori Funabashi, Hiroaki Omae, Takashi Ito, Yukio YonedaAbstract:ITZ-1 is a Chondroprotective Agent that inhibits interleukin-1beta-induced matrix metalloproteinase-13 (MMP-13) production and suppresses nitric oxide-induced chondrocyte death. Here we describe its mechanisms of action. Heat shock protein 90 (Hsp90) was identified as a specific ITZ-1-binding protein. Almost all known Hsp90 inhibitors have been reported to bind to the Hsp90 N-terminal ATP-binding site and to simultaneously induce degradation and activation of its multiple client proteins. However, within the Hsp90 client proteins, ITZ-1 strongly induces heat shock factor-1 (HSF1) activation and causes mild Raf-1 degradation, but scarcely induces degradation of a broad range of Hsp90 client proteins by binding to the Hsp90 C terminus. These results may explain ITZ-1's inhibition of MMP-13 production, its cytoprotective effect, and its lower cytotoxicity. These results suggest that ITZ-1 is a client-selective Hsp90 inhibitor.
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The Chondroprotective Agent ITZ-1 Inhibits Interleukin-1β–Induced Matrix Metalloproteinase–13 Production and Suppresses Nitric Oxide–Induced Chondrocyte Death
Journal of pharmacological sciences, 2009Co-Authors: Haruhide Kimura, Hiroshi Yukitake, Yasukazu Tajima, Hirobumi Suzuki, Shinji Morimoto, Yasunori Funabashi, Koyo Gomaibashi, Kiyofumi Yamada, Masayuki TakizawaAbstract:Abstract. 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.
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the Chondroprotective Agent itz 1 inhibits interleukin 1β induced matrix metalloproteinase 13 production and suppresses nitric oxide induced chondrocyte death
Journal of Pharmacological Sciences, 2009Co-Authors: Haruhide Kimura, Hiroshi Yukitake, Yasukazu Tajima, Hirobumi Suzuki, Shinji Morimoto, Yasunori Funabashi, Koyo Gomaibashi, Kiyofumi Yamada, Masayuki TakizawaAbstract:Abstract. 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.
T L Vincent - One of the best experts on this subject based on the ideXlab platform.
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fibroblast growth factor 2 is an intrinsic Chondroprotective Agent that suppresses adamts 5 and delays cartilage degradation in murine osteoarthritis
Arthritis & Rheumatism, 2009Co-Authors: Shilu Chia, Y Sawaji, A Burleigh, Celia Mclean, Julia J Inglis, Jeremy Saklatvala, T L VincentAbstract:Objective We have previously identified in articular cartilage an abundant pool of the heparin-binding growth factor, fibroblast growth factor 2 (FGF-2), which is bound to the pericellular matrix heparan sulfate proteoglycan, perlecan. This pool of FGF-2 activates chondrocytes upon tissue loading and is released following mechanical injury. In vitro, FGF-2 suppresses interleukin-1–driven aggrecanase activity in human cartilage explants, suggesting a Chondroprotective role in vivo. We undertook this study to investigate the in vivo role of FGF-2 in murine cartilage. Methods Basal characteristics of the articular cartilage of Fgf2−/− and Fgf2+/+ mice were determined by histomorphometry, nanoindentation, and quantitative reverse transcriptase–polymerase chain reaction. The articular cartilage was graded histologically in aged mice as well as in mice in which osteoarthritis (OA) had been induced by surgical destabilization of the medial meniscus. RNA was extracted from the joints of Fgf2−/− and Fgf2+/+ mice following surgery and quantitatively assessed for key regulatory molecules. The effect of subcutaneous administration of recombinant FGF-2 on OA progression was assessed in Fgf2−/− mice. Results Fgf2−/− mice were morphologically indistinguishable from wild-type (WT) animals up to age 12 weeks; the cartilage thickness and proteoglycan staining were equivalent, as was the mechanical integrity of the matrix. However, Fgf2−/− mice exhibited accelerated spontaneous and surgically induced OA. Surgically induced OA in Fgf2−/− mice was suppressed to levels in WT mice by subcutaneous administration of recombinant FGF-2. Increased disease in Fgf2−/− mice was associated with increased expression of messenger RNA of Adamts5, the key murine aggrecanase. Conclusion These data identify FGF-2 as a novel endogenous Chondroprotective Agent in articular cartilage.
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Fibroblast growth factor 2 is an intrinsic Chondroprotective Agent that suppresses ADAMTS‐5 and delays cartilage degradation in murine osteoarthritis
Arthritis and rheumatism, 2009Co-Authors: Shilu Chia, Y Sawaji, A Burleigh, Celia Mclean, Julia J Inglis, Jeremy Saklatvala, T L VincentAbstract:Objective We have previously identified in articular cartilage an abundant pool of the heparin-binding growth factor, fibroblast growth factor 2 (FGF-2), which is bound to the pericellular matrix heparan sulfate proteoglycan, perlecan. This pool of FGF-2 activates chondrocytes upon tissue loading and is released following mechanical injury. In vitro, FGF-2 suppresses interleukin-1–driven aggrecanase activity in human cartilage explants, suggesting a Chondroprotective role in vivo. We undertook this study to investigate the in vivo role of FGF-2 in murine cartilage. Methods Basal characteristics of the articular cartilage of Fgf2−/− and Fgf2+/+ mice were determined by histomorphometry, nanoindentation, and quantitative reverse transcriptase–polymerase chain reaction. The articular cartilage was graded histologically in aged mice as well as in mice in which osteoarthritis (OA) had been induced by surgical destabilization of the medial meniscus. RNA was extracted from the joints of Fgf2−/− and Fgf2+/+ mice following surgery and quantitatively assessed for key regulatory molecules. The effect of subcutaneous administration of recombinant FGF-2 on OA progression was assessed in Fgf2−/− mice. Results Fgf2−/− mice were morphologically indistinguishable from wild-type (WT) animals up to age 12 weeks; the cartilage thickness and proteoglycan staining were equivalent, as was the mechanical integrity of the matrix. However, Fgf2−/− mice exhibited accelerated spontaneous and surgically induced OA. Surgically induced OA in Fgf2−/− mice was suppressed to levels in WT mice by subcutaneous administration of recombinant FGF-2. Increased disease in Fgf2−/− mice was associated with increased expression of messenger RNA of Adamts5, the key murine aggrecanase. Conclusion These data identify FGF-2 as a novel endogenous Chondroprotective Agent in articular cartilage.
Yasunori Funabashi - One of the best experts on this subject based on the ideXlab platform.
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ITZ-1, a Client-Selective Hsp90 Inhibitor, Efficiently Induces Heat Shock Factor 1 Activation
Chemistry & biology, 2010Co-Authors: Haruhide Kimura, Hiroshi Yukitake, Yasukazu Tajima, Hirobumi Suzuki, Tomoko Chikatsu, Shinji Morimoto, Yasunori Funabashi, Hiroaki Omae, Takashi Ito, Yukio YonedaAbstract:ITZ-1 is a Chondroprotective Agent that inhibits interleukin-1beta-induced matrix metalloproteinase-13 (MMP-13) production and suppresses nitric oxide-induced chondrocyte death. Here we describe its mechanisms of action. Heat shock protein 90 (Hsp90) was identified as a specific ITZ-1-binding protein. Almost all known Hsp90 inhibitors have been reported to bind to the Hsp90 N-terminal ATP-binding site and to simultaneously induce degradation and activation of its multiple client proteins. However, within the Hsp90 client proteins, ITZ-1 strongly induces heat shock factor-1 (HSF1) activation and causes mild Raf-1 degradation, but scarcely induces degradation of a broad range of Hsp90 client proteins by binding to the Hsp90 C terminus. These results may explain ITZ-1's inhibition of MMP-13 production, its cytoprotective effect, and its lower cytotoxicity. These results suggest that ITZ-1 is a client-selective Hsp90 inhibitor.
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The Chondroprotective Agent ITZ-1 Inhibits Interleukin-1β–Induced Matrix Metalloproteinase–13 Production and Suppresses Nitric Oxide–Induced Chondrocyte Death
Journal of pharmacological sciences, 2009Co-Authors: Haruhide Kimura, Hiroshi Yukitake, Yasukazu Tajima, Hirobumi Suzuki, Shinji Morimoto, Yasunori Funabashi, Koyo Gomaibashi, Kiyofumi Yamada, Masayuki TakizawaAbstract:Abstract. 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.
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the Chondroprotective Agent itz 1 inhibits interleukin 1β induced matrix metalloproteinase 13 production and suppresses nitric oxide induced chondrocyte death
Journal of Pharmacological Sciences, 2009Co-Authors: Haruhide Kimura, Hiroshi Yukitake, Yasukazu Tajima, Hirobumi Suzuki, Shinji Morimoto, Yasunori Funabashi, Koyo Gomaibashi, Kiyofumi Yamada, Masayuki TakizawaAbstract:Abstract. 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.
Hirobumi Suzuki - One of the best experts on this subject based on the ideXlab platform.
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ITZ-1, a Client-Selective Hsp90 Inhibitor, Efficiently Induces Heat Shock Factor 1 Activation
Chemistry & biology, 2010Co-Authors: Haruhide Kimura, Hiroshi Yukitake, Yasukazu Tajima, Hirobumi Suzuki, Tomoko Chikatsu, Shinji Morimoto, Yasunori Funabashi, Hiroaki Omae, Takashi Ito, Yukio YonedaAbstract:ITZ-1 is a Chondroprotective Agent that inhibits interleukin-1beta-induced matrix metalloproteinase-13 (MMP-13) production and suppresses nitric oxide-induced chondrocyte death. Here we describe its mechanisms of action. Heat shock protein 90 (Hsp90) was identified as a specific ITZ-1-binding protein. Almost all known Hsp90 inhibitors have been reported to bind to the Hsp90 N-terminal ATP-binding site and to simultaneously induce degradation and activation of its multiple client proteins. However, within the Hsp90 client proteins, ITZ-1 strongly induces heat shock factor-1 (HSF1) activation and causes mild Raf-1 degradation, but scarcely induces degradation of a broad range of Hsp90 client proteins by binding to the Hsp90 C terminus. These results may explain ITZ-1's inhibition of MMP-13 production, its cytoprotective effect, and its lower cytotoxicity. These results suggest that ITZ-1 is a client-selective Hsp90 inhibitor.
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The Chondroprotective Agent ITZ-1 Inhibits Interleukin-1β–Induced Matrix Metalloproteinase–13 Production and Suppresses Nitric Oxide–Induced Chondrocyte Death
Journal of pharmacological sciences, 2009Co-Authors: Haruhide Kimura, Hiroshi Yukitake, Yasukazu Tajima, Hirobumi Suzuki, Shinji Morimoto, Yasunori Funabashi, Koyo Gomaibashi, Kiyofumi Yamada, Masayuki TakizawaAbstract:Abstract. 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.
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the Chondroprotective Agent itz 1 inhibits interleukin 1β induced matrix metalloproteinase 13 production and suppresses nitric oxide induced chondrocyte death
Journal of Pharmacological Sciences, 2009Co-Authors: Haruhide Kimura, Hiroshi Yukitake, Yasukazu Tajima, Hirobumi Suzuki, Shinji Morimoto, Yasunori Funabashi, Koyo Gomaibashi, Kiyofumi Yamada, Masayuki TakizawaAbstract:Abstract. 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.