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

<b>Objectives:</b> To investigate the role of non-receptor tyrosine kinases (NRTKs) in inflammation-induced osteoclastogenesis. <b>Methods:</b> 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 <i>in vivo</i> therapeutic effect of A-419259 treatment on lipopolysaccharide (LPS)-induced inflammatory bone destruction was evaluated. <b>Results:</b> We confirmed that <i>Hck</i> 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 <i>Prdm1</i> and <i>Nfatc1</i>. Notably, LPS-induced inflammatory bone loss in murine calvarial bones was ameliorated by the administration of A-419259. <b>Conclusions:</b> 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.