FRI0079 TAS5315, a novel bruton's tyrosine kinase inhibitor, improve bone mineral density (BMD) and bone erosion via inhibition of osteoclast activation in murine model for rheumatoid arthritis
Authors: Y Yoshiga, F Hosoi, S Iguchi, R Kaneko, Y Nakachi, D Akasaka, K Tanaka, K Yonekura, T Utsugi, E Sasaki, Y Iwasawa
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The erosions of bone and cartilage are a cardinal feature of rheumatoid arthritis (RA) and associated with disease severity and poor functional outcome<sup>1</sup>. Although several anti-inflammatory drugs improve symptoms of articular inflammation, they are less effective against bone erosion. The bone erosions in RA are associated with aberrant activations of osteoclasts induced by pro-inflammatory cytokines and receptor activator of nuclear factor κB ligand (RANKL)<sup>2</sup>. Bruton9s tyrosine kinase (BTK), which is expressed in immune cells and mature osteoclast, is reported to be a key molecule in inflammatory response and bone resorption<sup>3,4</sup>. Thus, targeting BTK may be efficacious against not only inflammation but also bone erosion through direct regulation of activation of effector cells such as B cells, macrophages and osteoclasts in RA. <h3>Objectives</h3> In this study, we evaluated the effect of TAS5315, a novel BTK inhibitor, on <i>in vitro</i> osteoclasts activation and bone erosion in mouse collagen-induced arthritis. <h3>Methods</h3> Kinase selectivity of TAS5315 was assessed by available kinase assay panels. The effects of TAS5315 on macrophages and osteoclasts were assessed by examining phosphorylation of BTK, cytokine productions, osteoclast differentiation and bone resorptions. The effects of TAS5315 were investigated in mouse collagen-induced arthritis (CIA). Disease severity was evaluated by clinical score of paw swelling. Changes in bone mineral density (BMD) and bone erosion were assessed using microCT. TNF blocker was used as a control drug. <h3>Results</h3> TAS5315 selectively inhibited the enzyme activity of BTK and had less off target inhibition against other kinases. TAS5315 dose-dependently inhibited cytokine productions by macrophages, phosphorylation of BTK, osteoclastogenesis and bone resorbing activity in osteoclasts. In established mouse CIA, TAS5315 significantly ameliorated paw swelling in a dose dependent manner and the anti-inflammatory effect of TAS5315 (0.3 mg/kg, once daily) was comparable to that of TNF blocker. Most importantly, improvement of BMD and bone erosion were observed in TAS5315 treated mice at a doses of higher than 0.1 mg/kg within 13 days from treatment initiation, but not in TNF blocker-treated mice. The onset of action of TAS5315 on BMD and bone erosion was earlier and stronger compared with that of TNF blocker. These data suggest that TAS5315 had direct effect against osteoclasts function and led to improvement of bone erosion in murine model for RA. <h3>Conclusions</h3> Our study demonstrates that TAS5315, a novel BTK inhibitor, would be an ideal RA therapeutic agent that could inhibit bone destruction as well as inflammation. <h3>References</h3> Nat Rev Rheumatol. 2012;8,656–64. Nat Rev Rheumatol. 2015;11,189–94. Cell. 2008;132,794–806. Drug Discov Today. 2014;19,1200–4. <h3>Disclosure of Interest</h3> None declared