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

Abstract

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
• inflammatory bone destruction
• osteoclast
• RANKL

Acknowledgements

We thank F. Sasaki, Y. Tsuchiya, M. Inoue, R. Denda, Y. Yamashita and Y. Ogiwara for technical support and for sharing knowledge with respect to this study. This work was supported in part by a grant for the Precursory Research for Embryonic Science and Technology (PRESTO) from the Japan Science and Technology Agency (JPMJPR13MC); AMED-CREST, AMED (JP17gm0810003); Grant-in-Aid for Challenging Exploratory Research, Specially Promoted Research, Young Scientists (A), Scientific Research (B) and Challenging Research (Exploratory) from the Japan Society for the Promotion of Science (JSPS); and grants from Mochida Memorial Foundation, Terumo Foundation, the Life Science Foundation of Japan, Uehara Memorial Foundation, Ichiro Kanehara Foundation, Naito Foundation, Nakatomi Foundation, Astellas Foundation for Research on Metabolic Disorders, The Sumitomo Foundation, The Asahi Glass Foundation, Mitsui Life Social Welfare Foundation, Daiichi Sankyo Foundation, Takeda Science Foundation, and Secom Science and Technology Foundation.

Conflict of interest

None.