Anti-inflammatory and anti-osteoarthritis effects of Cm-02 and Ck-02

Yi Jung Ho, Jeng Wei Lu, Ling Jun Ho, Jenn Haung Lai, Hsu Shan Huang, Chia Chung Lee, Te Yu Lin, Shiu Bii Lien, Leou Chyr Lin, Liv Weichien Chen, Zhiyuan Gong, Min Chung Shen, Feng Cheng Liu

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Osteoarthritis (OA) is a common degenerative joint disease characterized by progressive deterioration of articular cartilage. There have been reports that small molecule inhibitors have anti-osteoarthritis effects; however, the effects of 3-(4-chloro-2-fluorophenyl)-6-(2,4-difluorophenyl)-2H-benzo[e] [1,3]oxazine-2,4(3H)-dione (Cm-02) and 6-(2,4-difluorophenyl)-3-(3,4-difluorophenyl)-2H-benzo[e] [1,3]oxazine-2,4(3H)-dione (Ck-02), small molecule inhibitors which share many structural similarities with quercetin (a potent anti-inflammatory flavonoid), remain unclear. In this study, TNF-α-stimulated porcine and human chondrocyte models were used to investigate the inhibitory effects of Cm-02 and Ck-02 on the molecular mechanisms underlying the anti-OA effects. TNF-α was used to stimulate porcine and human chondrocytes to mimic immunomodulatory potency in-vitro. Anti-osteoarthritic effects were characterized in terms of protein and mRNA levels associated with the pathogenesis of OA. We also examined (1) the inducible nitric oxide synthase (iNOS)-nitric oxide (NO) system in cultured chondrocytes, (2) matrix metalloproteinases (MMPs) in cultured chondrocytes, and (3) aggrecan degradation in cartilage explants. Finally, we tested the activation of nuclear factor-kappaB (NF-κB), interferon regulatory factor-1 (IRF-1), and activate the protein-1 (AP-1), and we tested the signal transduction and activation of transcription-3 (STAT-3). Our results indicate that, in chondrocytes, Cm-02 and Ck-02 inhibit TNF-α induced NO production, iNOS, MMP, the expression of disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), and the enzyme activity of MMP-13. Furthermore, both Cm-02 and Ck-02 were found to stimulate TNF-α, which has been shown to suppress the activation of several transcription factors, including NF-κB, STAT-3, and IRF-1 in porcine and human chondrocytes. Cm-02 and Ck-02 were also found to help prevent the release of proteoglycans from cartilage explants. Our findings demonstrate that both Cm-02 and Ck-02 have potent anti-inflammatory activities and the ability to protect cartilage in an OA cell model. These findings indicate that Cm-02 and Ck-02 have the potential to be further developed for the therapeutic treatment of OA.

Original languageEnglish
Pages (from-to)155-163
Number of pages9
JournalBiochemical and Biophysical Research Communications
Volume517
Issue number1
DOIs
Publication statusPublished - Sep 10 2019

Fingerprint

Cartilage
Osteoarthritis
Chondrocytes
Anti-Inflammatory Agents
Chemical activation
Oxazines
Interferon Regulatory Factor-1
Signal transduction
Nitric Oxide Synthase Type II
Transcription
Nitric Oxide
Matrix Metalloproteinase 13
Swine
Thrombospondins
Disintegrins
Aggrecans
Molecules
Matrix Metalloproteinase 2
Quercetin
Enzyme activity

Keywords

  • Ck-02
  • Cm-02
  • Inflammation
  • Osteoarthritis
  • Small molecule inhibitor
  • TNF-α

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Anti-inflammatory and anti-osteoarthritis effects of Cm-02 and Ck-02. / Ho, Yi Jung; Lu, Jeng Wei; Ho, Ling Jun; Lai, Jenn Haung; Huang, Hsu Shan; Lee, Chia Chung; Lin, Te Yu; Lien, Shiu Bii; Lin, Leou Chyr; Chen, Liv Weichien; Gong, Zhiyuan; Shen, Min Chung; Liu, Feng Cheng.

In: Biochemical and Biophysical Research Communications, Vol. 517, No. 1, 10.09.2019, p. 155-163.

Research output: Contribution to journalArticle

Ho, YJ, Lu, JW, Ho, LJ, Lai, JH, Huang, HS, Lee, CC, Lin, TY, Lien, SB, Lin, LC, Chen, LW, Gong, Z, Shen, MC & Liu, FC 2019, 'Anti-inflammatory and anti-osteoarthritis effects of Cm-02 and Ck-02', Biochemical and Biophysical Research Communications, vol. 517, no. 1, pp. 155-163. https://doi.org/10.1016/j.bbrc.2019.07.036
Ho, Yi Jung ; Lu, Jeng Wei ; Ho, Ling Jun ; Lai, Jenn Haung ; Huang, Hsu Shan ; Lee, Chia Chung ; Lin, Te Yu ; Lien, Shiu Bii ; Lin, Leou Chyr ; Chen, Liv Weichien ; Gong, Zhiyuan ; Shen, Min Chung ; Liu, Feng Cheng. / Anti-inflammatory and anti-osteoarthritis effects of Cm-02 and Ck-02. In: Biochemical and Biophysical Research Communications. 2019 ; Vol. 517, No. 1. pp. 155-163.
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AU - Ho, Yi Jung

AU - Lu, Jeng Wei

AU - Ho, Ling Jun

AU - Lai, Jenn Haung

AU - Huang, Hsu Shan

AU - Lee, Chia Chung

AU - Lin, Te Yu

AU - Lien, Shiu Bii

AU - Lin, Leou Chyr

AU - Chen, Liv Weichien

AU - Gong, Zhiyuan

AU - Shen, Min Chung

AU - Liu, Feng Cheng

PY - 2019/9/10

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N2 - Osteoarthritis (OA) is a common degenerative joint disease characterized by progressive deterioration of articular cartilage. There have been reports that small molecule inhibitors have anti-osteoarthritis effects; however, the effects of 3-(4-chloro-2-fluorophenyl)-6-(2,4-difluorophenyl)-2H-benzo[e] [1,3]oxazine-2,4(3H)-dione (Cm-02) and 6-(2,4-difluorophenyl)-3-(3,4-difluorophenyl)-2H-benzo[e] [1,3]oxazine-2,4(3H)-dione (Ck-02), small molecule inhibitors which share many structural similarities with quercetin (a potent anti-inflammatory flavonoid), remain unclear. In this study, TNF-α-stimulated porcine and human chondrocyte models were used to investigate the inhibitory effects of Cm-02 and Ck-02 on the molecular mechanisms underlying the anti-OA effects. TNF-α was used to stimulate porcine and human chondrocytes to mimic immunomodulatory potency in-vitro. Anti-osteoarthritic effects were characterized in terms of protein and mRNA levels associated with the pathogenesis of OA. We also examined (1) the inducible nitric oxide synthase (iNOS)-nitric oxide (NO) system in cultured chondrocytes, (2) matrix metalloproteinases (MMPs) in cultured chondrocytes, and (3) aggrecan degradation in cartilage explants. Finally, we tested the activation of nuclear factor-kappaB (NF-κB), interferon regulatory factor-1 (IRF-1), and activate the protein-1 (AP-1), and we tested the signal transduction and activation of transcription-3 (STAT-3). Our results indicate that, in chondrocytes, Cm-02 and Ck-02 inhibit TNF-α induced NO production, iNOS, MMP, the expression of disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), and the enzyme activity of MMP-13. Furthermore, both Cm-02 and Ck-02 were found to stimulate TNF-α, which has been shown to suppress the activation of several transcription factors, including NF-κB, STAT-3, and IRF-1 in porcine and human chondrocytes. Cm-02 and Ck-02 were also found to help prevent the release of proteoglycans from cartilage explants. Our findings demonstrate that both Cm-02 and Ck-02 have potent anti-inflammatory activities and the ability to protect cartilage in an OA cell model. These findings indicate that Cm-02 and Ck-02 have the potential to be further developed for the therapeutic treatment of OA.

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KW - Cm-02

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KW - Osteoarthritis

KW - Small molecule inhibitor

KW - TNF-α

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