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Impact of Janus Kinase Inhibition with Tofacitinib on Fundamental Processes of Bone Healing

Timo Gaber1,2, Antonia Clara Katharina Brinkman1,2, Justyna Pienczikowski1,2

  • 1Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Rheumatology and Clinical Immunology, 10117 Berlin, Germany.

International Journal of Molecular Sciences
|February 5, 2020
PubMed

Insights

Tofacitinib promotes human mesenchymal stromal cell recruitment in hypoxic fracture environments and enhances bone formation while reducing resorption. This suggests tofacitinib may aid fracture healing and potentially benefit osteoporosis patients.

Area of Science:

  • Biomedical Engineering
  • Cell Biology
  • Orthopedics

Background:

  • Rheumatoid arthritis (RA) and its treatments negatively impact bone metabolism and fracture healing.
  • The effect of Janus kinase (JAK) inhibition with tofacitinib on bone regeneration is controversial.
  • Understanding tofacitinib's role in bone healing is crucial for RA patients with fractures.

Purpose of the Study:

  • To investigate tofacitinib's effects on human mesenchymal stromal cell (hMSC) recruitment, chondrogenesis, osteogenesis, and osteoclastogenesis in a simulated fracture microenvironment.
  • To evaluate tofacitinib's impact under hypoxic conditions mimicking in vivo fracture sites.

Main Methods:

  • In vitro analysis of hMSC recruitment, chondrogenic, and osteogenic differentiation under hypoxic and normoxic conditions.
  • Assessment of osteoclast differentiation and activity.
  • Dose-dependent evaluation of tofacitinib at therapeutically relevant concentrations (10-100 nM).

Main Results:

  • Tofacitinib dose-dependently promoted hMSC recruitment under hypoxia but inhibited it under normoxia.
  • Tofacitinib did not inhibit hMSC survival at therapeutic doses.
  • Tofacitinib enhanced osteogenic differentiation and reduced osteoclast differentiation and activity.
  • Tofacitinib did not interfere with the cartilaginous phase of fracture healing.

Conclusions:

  • Tofacitinib may enhance bone healing by promoting hMSC recruitment in hypoxic fracture gaps and stimulating bone formation while suppressing bone resorption.
  • These findings suggest tofacitinib might not require discontinuation during fracture events and could offer benefits for osteoporosis.
  • Tofacitinib's positive effects on bone erosions in RA may be partly explained by its impact on bone metabolism.
Keywords:
bone healingchondrogenic differentiationhMSC-migrationosteoclast differentiationosteogenic differentiationtofacitinib

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