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Tofacitinib Inhibits STAT Phosphorylation and Matrix Metalloproteinase-3, -9 and -13 Production by C28/I2 Human

Jessica R Thorpe1, Rachel A Wilson2, Sam Mesiano2

  • 1Department of Medicine, Division of Rheumatic Diseases, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.

Open Access Rheumatology : Research and Reviews
|October 11, 2022
PubMed
Abstract

Insights

Tofacitinib, a Janus kinase inhibitor, effectively reduced interleukin-6 (IL-6)-induced STAT phosphorylation and matrix metalloproteinase (MMP) production in human chondrocytes. This suggests Tofacitinib

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Interleukin-6 (IL-6) plays a role in inflammatory processes.
  • Matrix metalloproteinases (MMPs) are involved in cartilage degradation.
  • Signal transducers and activators of transcription (STATs) mediate cellular responses to cytokines like IL-6.

Purpose of the Study:

  • To investigate the effect of Tofacitinib, a pan-Janus kinase (JAK) inhibitor, on IL-6-induced STAT phosphorylation.
  • To determine Tofacitinib's impact on MMP gene expression and production in human chondrocytes.
  • To elucidate the role of JAK-STAT signaling in MMP regulation within chondrocytes.

Main Methods:

  • In vitro study using C28/I2 human chondrocytes.
  • Treatment with recombinant human IL-6 (rhIL-6) and varying concentrations of Tofacitinib.
  • Analysis of STAT phosphorylation via quantitative Western blots.
  • Assessment of MMP gene expression using RT-PCR.
  • Evaluation of MMP production using immunohistochemistry.

Main Results:

  • rhIL-6 induced phosphorylation of STAT1, STAT3, and STAT5AB in chondrocytes.
  • Tofacitinib significantly inhibited rhIL-6-induced STAT phosphorylation.
  • Tofacitinib decreased the expression of MMP3 and MMP13, but not MMP9, MMP1, or MMP2.
  • Tofacitinib reduced the production of MMP3, MMP13, and MMP9 in rhIL-6-stimulated chondrocytes.

Conclusions:

  • Tofacitinib is a potent inhibitor of IL-6-induced STAT phosphorylation in human chondrocytes.
  • Tofacitinib effectively suppresses the production of MMP-3, MMP-9, and MMP-13.
  • The JAK-STAT pathway is crucial for IL-6-mediated MMP production in chondrocytes.
Keywords:
Janus kinasearthritiscytokinessignal transducers and activators of transcription

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