Suppression of hematopoietic cell kinase ameliorates the bone destruction associated with inflammation

Mod Rheumatol. 2020 Jan;30(1):85-92. doi: 10.1080/14397595.2018.1553266. Epub 2019 Jan 8.


Objectives: To investigate the role of non-receptor tyrosine kinases (NRTKs) in inflammation-induced osteoclastogenesis.Methods: Microarray analyses of global mRNA expression during receptor activator of NF-κB ligand (RANKL) and RANKL plus tumor necrosis factor (TNF)-α-induced osteoclast differentiation were performed. The inhibitory effect on TNF-α-induced osteoclast differentiation of A-419259, a potent inhibitor of hematopoietic cell kinase (Hck), was examined. The in vivo therapeutic effect of A-419259 treatment on lipopolysaccharide (LPS)-induced inflammatory bone destruction was evaluated.Results: We confirmed that Hck expression was selectively increased among the NRTKs during the osteoclast differentiation induced by RANKL and TNF-α, but not by RANKL alone. RANKL and TNF-α-induced osteoclast differentiation and they were dose-dependently inhibited by A-419259 treatment through inhibition of the expression of key regulators of osteoclastogenesis, including Prdm1 and Nfatc1. Notably, LPS-induced inflammatory bone loss in murine calvarial bones was ameliorated by the administration of A-419259.Conclusions: Our results demonstrate that the administration of A-419259 is effective for the inhibition of osteoclast differentiation induced by TNF-α in the presence of RANKL. Therefore, an inhibitor of Hck may be useful as a potent anti-osteoclastogenic agent for the treatment of inflammatory bone destruction.

Keywords: A-419259; Hck; RANKL; inflammatory bone destruction; osteoclast.

MeSH terms

  • Animals
  • Blotting, Western
  • Bone Resorption / drug therapy
  • Bone Resorption / genetics*
  • Bone Resorption / metabolism
  • Cell Differentiation
  • Cells, Cultured
  • Gene Expression Regulation*
  • Inflammation / genetics*
  • Inflammation / metabolism
  • Inflammation / pathology
  • Mice
  • Mice, Inbred BALB C
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism*
  • Osteoclasts / pathology
  • Osteogenesis / drug effects*
  • Proto-Oncogene Proteins c-hck / biosynthesis
  • Proto-Oncogene Proteins c-hck / genetics*
  • Pyrimidines / pharmacology*
  • Pyrroles / pharmacology*
  • RNA / genetics
  • src-Family Kinases


  • A 419259
  • Pyrimidines
  • Pyrroles
  • RNA
  • Proto-Oncogene Proteins c-hck
  • src-Family Kinases