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

Takahiro Machida, Keiichiro Nishida, Yoshihisa Nasu, Ryuuichi Nakahara, Masatsugu Ozawa, Ryozo Harada, Masahiro Horita, Ayumu Takeshita, Daisuke Kaneda, Aki Yoshida, Toshihumi Ozaki

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4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1-11
Number of pages11
JournalInflammation Research
DOIs
Publication statusAccepted/In press - Jul 27 2017

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Keywords

  • Chondrocyte
  • Janus kinase
  • Mechanical stress
  • Rheumatoid arthritis
  • Tofacitinib

ASJC Scopus subject areas

  • Immunology
  • Pharmacology

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