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JAK inhibition with tofacitinib suppresses arthritic joint structural damage through decreased RANKL production

Timothy P LaBranche1, Michael I Jesson, Zaher A Radi

  • 1Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA. timothy.labranche@pfizer.com

Arthritis and Rheumatism
|August 18, 2012
PubMed
Abstract

Insights

The Janus kinase (JAK) inhibitor tofacitinib significantly reduces joint structural damage in rheumatoid arthritis by decreasing osteoclast activity. This occurs through reduced T lymphocyte production of RANKL, a key factor in bone resorption.

Area of Science:

  • Immunology
  • Rheumatology
  • Pharmacology

Background:

  • Rheumatoid arthritis (RA) involves significant joint structural damage, with Janus kinase (JAK) signaling implicated but not fully understood.
  • Osteoclast-mediated bone resorption is a critical component of RA joint destruction.
  • Targeting JAK signaling is a therapeutic strategy for RA, but its precise impact on bone resorption requires elucidation.

Purpose of the Study:

  • To investigate the effect of the JAK inhibitor tofacitinib on osteoclast-mediated bone resorption in a rat adjuvant-induced arthritis (AIA) model.
  • To assess tofacitinib's impact on human T lymphocyte RANKL production.
  • To evaluate tofacitinib's effects on human osteoclast differentiation and function.

Main Methods:

  • Assessment of hind paw edema, inflammation, and bone resorption in rat AIA using plethysmography, histopathology, and immunohistochemistry.
  • Measurement of cytokine and chemokine levels, including RANKL, in rat plasma and paw tissue.
  • In vitro evaluation of human T lymphocyte RANKL production and human osteoclast differentiation/function.

Main Results:

  • Tofacitinib treatment dramatically reduced edema, inflammation, and osteoclast-mediated bone resorption in the AIA rat model.
  • Reduced CD68/ED-1+, CD3+, and RANKL+ cell counts correlated with tofacitinib treatment.
  • While tofacitinib did not affect human osteoclast differentiation or function, it dose-dependently reduced human T lymphocyte RANKL production.

Conclusions:

  • The JAK inhibitor tofacitinib effectively suppresses osteoclast-mediated structural damage in arthritic joints.
  • This suppression is primarily attributed to a decrease in RANKL production by T lymphocytes.
  • Tofacitinib represents a potential therapeutic agent for mitigating joint destruction in RA by targeting JAK-mediated RANKL pathways.

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