Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
The erosions of bone and cartilage are a cardinal feature of rheumatoid arthritis (RA) and associated with disease severity and poor functional outcome. 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). Bruton’s 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. 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.
In this study, we evaluated the effect of TAS5315, a novel BTK inhibitor, on the expression of inflammatory factors from macrophages and osteoclasts activation compared with BTK inhibitor CC-292, and bone erosion by time-dependent micro-CT analysis in mouse collagen-induced arthritis (CIA).
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, expression of inflammatory factors, osteoclast differentiation and bone resorptions compared with that of BTK inhibitor CC-292. TAS5315 were orally administrated once a day for 21 consecutive days in an established mouse CIA model. Disease severity was evaluated by clinical score of paw swelling. Changes in bone mineral density (BMD) and bone erosion by TAS5315 were assessed using time-dependent micro-CT analysis.
TAS5315 selectively inhibited the enzyme activity of BTK and had less off target inhibition against other kinases. TAS5315 dose-dependently suppressed the expression of inflammatory factors (TNFα and IL-8) in macrophages. TAS5315 showed more potent efficacy against phosphorylation of BTK, osteoclastogenesis and bone resorbing activity in osteoclasts compared with CC-292. In established mouse CIA model, TAS5315 significantly ameliorated paw swelling in a dose-dependent manner and showed the anti-inflammatory effects in pathological analysis at a dose of 0.1 mg/kg. Most importantly, TAS5315 also showed repair of bone erosion and improvements of BMD from joint destruction in the initial treatment by micro-CT analysis.
These data suggests that TAS5315 indicated more potent efficacy on joint damage as well as inflammation, and also improved bone erosion in murine model for RA through direct inhibitory effects against osteoclasts function.
Our study demonstrates that TAS5315 could be a promising RA therapeutic agent by improving bone erosion as well as inflammation.
To cite this abstract in AMA style:Yoshiga Y, Hosoi F, Iguchi S, Kaneko R, Nakachi Y, Akasaka D, Tanaka K, Yonekura K, Utsugi T, Sasaki E, Iwasawa Y. TAS5315, a Novel Bruton’s Tyrosine Kinase Inhibitor, Ameliorates Inflammation and Bone Erosion in Murine Model for Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/tas5315-a-novel-brutons-tyrosine-kinase-inhibitor-ameliorates-inflammation-and-bone-erosion-in-murine-model-for-rheumatoid-arthritis/. Accessed February 19, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tas5315-a-novel-brutons-tyrosine-kinase-inhibitor-ameliorates-inflammation-and-bone-erosion-in-murine-model-for-rheumatoid-arthritis/