Salt Inducible Kinase 2 regulates fibrosis during bleomycin-induced lung injury

Manuel van Gijsel-Bonnello, Nicola J Darling, Takashi Tanaka, Samuele Di Carmine, Francesco Marchesi, Sarah Thomson, Kristopher Clark, Mariola Kurowska-Stolarska, Henry J. McSorley, Philip Cohen, J. Simon C. Arthur (Lead / Corresponding author)

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Idiopathic pulmonary fibrosis is a progressive and normally fatal disease with limited treatment options. The tyrosine kinase inhibitor nintedanib has recently been approved for the treatment of idiopathic pulmonary fibrosis, and its effectiveness has been linked to its ability to inhibit a number of receptor tyrosine kinases including the platelet-derived growth factor, vascular endothelial growth factor, and fibroblast growth factor receptors. We show here that nintedanib also inhibits salt-inducible kinase 2 (SIK2), with a similar IC 50 to its reported tyrosine kinase targets. Nintedanib also inhibited the related kinases SIK1 and SIK3, although with 12-fold and 72-fold higher IC 50s, respectively. To investigate if the inhibition of SIK2 may contribute to the effectiveness of nintedanib in treating lung fibrosis, mice with kinase-inactive knockin mutations were tested using a model of bleomycin-induced lung fibrosis. We found that loss of SIK2 activity protects against bleomycin-induced fibrosis, as judged by collagen deposition and histological scoring. Loss of both SIK1 and SIK2 activity had a similar effect to loss of SIK2 activity. Total SIK3 knockout mice have a developmental phenotype making them unsuitable for analysis in this model; however, we determined that conditional knockout of SIK3 in the immune system did not affect bleomycin-induced lung fibrosis. Together, these results suggest that SIK2 is a potential drug target for the treatment of lung fibrosis.

Original languageEnglish
Article number102644
Number of pages15
JournalJournal of Biological Chemistry
Issue number12
Early online date26 Oct 2022
Publication statusPublished - Dec 2022


  • SIK1
  • SIK2
  • SIK3
  • kinase inhibitor
  • nintedanib
  • pulmonary fibrosis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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