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Inflammation Research

, Volume 66, Issue 11, pp 999–1009 | Cite as

Inhibitory effect of JAK inhibitor on mechanical stress-induced protease expression by human articular chondrocytes

  • Takahiro Machida
  • Keiichiro Nishida
  • Yoshihisa Nasu
  • Ryuichi Nakahara
  • Masatsugu Ozawa
  • Ryozo Harada
  • Masahiro Horita
  • Ayumu Takeshita
  • Daisuke Kaneda
  • Aki Yoshida
  • Toshifumi Ozaki
Original Research Paper

Abstract

Objective

To investigate whether janus kinase (JAK) inhibitor exhibits a chondro-protective effect against mechanical stress-induced expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) and matrix metalloproteinase (MMPs) in human chondrocytes.

Materials and methods

Normal human articular chondrocytes were seeded onto stretch chambers and incubated with or without tofacitinib (1000 nM) for 12 h before mechanical stimulation or cytokine stimulation. Uni-axial cyclic tensile strain (CTS) (0.5 Hz, 10% elongation, 30 min) was applied and the gene expression levels of type II collagen α1 chain (COL2A1), aggrecan (ACAN), ADAMTS4, ADAMTS5, MMP13, and runt-related transcription factor 2 (RUNX-2) were examined by real-time polymerase chain reaction. Nuclear translocation of RUNX-2 and nuclear factor-κB (NF-κB) was examined by immunocytochemistry, and phosphorylation of mitogen-activated protein kinase (MAPK) and signaling transducer and activator of transcription (STAT) 3 was examined by western blotting. The concentration of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in the supernatant was examined by enzyme-linked immunosorbent assay.

Results

COL2A1 and ACAN gene expression levels were decreased by CTS, but these catabolic effects were canceled by tofacitinib. Tofacitinib significantly down-regulated CTS-induced expression of ADAMTS4, ADAMTS5, MMP13, and RUNX2, and the release of IL-6 in supernatant by chondrocytes. Tofacitinib also reduced CTS-induced nuclear translocation of RUNX-2 and NF-κB, and phosphorylation of MAPK and STAT3.

Conclusion

Tofacitinib suppressed mechanical stress-induced expression of ADAMTS4, ADAMTS5, and MMP13 by human chondrocytes through inhibition of the JAK/STAT and MAPK cascades.

Keywords

Janus kinase Chondrocyte Mechanical stress Tofacitinib Rheumatoid arthritis 

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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Takahiro Machida
    • 1
  • Keiichiro Nishida
    • 1
  • Yoshihisa Nasu
    • 2
  • Ryuichi Nakahara
    • 3
  • Masatsugu Ozawa
    • 4
  • Ryozo Harada
    • 1
  • Masahiro Horita
    • 1
  • Ayumu Takeshita
    • 1
  • Daisuke Kaneda
    • 1
  • Aki Yoshida
    • 1
  • Toshifumi Ozaki
    • 1
  1. 1.Department of Orthopaedic SurgeryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
  2. 2.Department of Medical Materials for Musculoskeletal ReconstructionOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
  3. 3.Department of Musculoskeletal TraumatologyOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
  4. 4.Department of Orthopaedic SurgeryOkayama City HospitalOkayamaJapan

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