Session Type: ACR Poster Session A
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 for treatment of RA improve symptoms of articular inflammation and bone erosion, unfortunately they do not have a powerful potency against repair of existing bone erosion. Bruton’s tyrosine kinase (BTK), which is expressed in immune cells and mature osteoclasts, 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.
Previously, we evaluated the effect of TAS5315, a novel BTK inhibitor, on bone damage in an established mouse collagen-induced arthritis (CIA) by micro-CT analysis, and revealed that TAS5315 improves bone erosion in a mouse CIA. However, it remained uncertain whether TAS5315 improves the bone quality.
In this study, we assessed mechanical bone strength of the tibia in a mouse CIA for the purpose of examining whether TAS5315 improves bone quality as well as bone erosion.
Kinase selectivity of TAS5315 was assessed by available kinase assay panels. The BioMAP Diversity PLUS panels were used to determine the profile of TAS5315 in primary human cell systems. The effects of TAS5315 on osteoclasts were assessed by examining phosphorylation of BTK, osteoclast differentiation and bone resorptions. TAS5315 were orally administrated once a day for 14 or 21 consecutive days in an established mouse CIA model. Bone mineral density (BMD) and bone erosion were assessed using micro-CT analysis. The mechanical strength of the tibia was evaluated by a three-point bending test of the tibial diaphysis and a compression test of proximal metaphysis using a material-testing machine.
TAS5315 selectively inhibited the enzyme activity of BTK and had less off target inhibition against other kinases. In BioMAP Systems, TAS5315 decreased the production of IgG and the expression of cytokines (TNFα, IL-8, IL-17A, IL-6, IL-17F and IL-2) and increased the expression of IL-10. TAS5315 also inhibited RANKL and M-CFS-induced phosphorylation of BTK, and bone resorbing activity in osteoclasts.
In an established mouse CIA model, TAS5315 significantly ameliorated paw swelling and pathological features at a dose of 0.1 mg/kg. TAS5315 also showed repair of BMD by time-dependent micro-CT analysis. The mechanical strength tests of tibia were performed in an established mouse CIA model. Whereas the mechanical strength of tibia was decreased in CIA model mice compared to normal mice, TAS5315 led to recovery of the decreased parameters of mechanical strength of tibia.
These data suggests that TAS5315 indicated more potent efficacy on joint damage as well as inflammation, and improved bone quality as well as bone erosion in mouse model for RA through direct inhibitory effects against osteoclasts function.
Our study demonstrates that TAS5315 would be an ideal RA therapeutic agent that could improve bone destruction as well as inflammation.
To cite this abstract in AMA style:Kaneko R, Hosoi F, Iguchi S, Hayashi H, Yoshiga Y, Nakachi Y, Akasaka D, Tanaka K, Utsugi T, Sasaki E, Iwasawa Y. TAS5315, a Novel Bruton’s Tyrosine Kinase Inhibitor, Improves Bone Strength in Mouse Model for Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/tas5315-a-novel-brutons-tyrosine-kinase-inhibitor-improves-bone-strength-in-mouse-model-for-rheumatoid-arthritis/. Accessed April 7, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tas5315-a-novel-brutons-tyrosine-kinase-inhibitor-improves-bone-strength-in-mouse-model-for-rheumatoid-arthritis/