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Novel Bruton's tyrosine kinase inhibitor TAS5315 suppresses the progression of inflammation and joint destruction in rodent collagen-induced arthritis.

ABSTRACT: Rheumatoid arthritis is an inflammatory autoimmune disease, characterized by autoantibody production, synovial inflammation, and joint destruction. Its pathogenesis is due to environmental factors and genetic backgrounds. Bruton's tyrosine kinase is a cytoplasmic non-receptor tyrosine kinase, expressed in most hematopoietic cell lineages, except T cells and plasma cells, and regulates various immune-related signaling pathways, thereby playing a crucial role in pathogenesis. Thus, inhibiting Bruton's tyrosine kinase may prove beneficial in treating autoimmune diseases. In the present study, we characterized Bruton's tyrosine kinase inhibitor, TAS5315, in vitro and evaluated its therapeutic effects in experimental arthritis models. TAS5315 markedly inhibited Bruton's tyrosine kinase enzyme activity and suppressed the B-cell receptor signaling pathway in Ramos cells. Moreover, it suppressed the expression of CD69, CD86, and MHC class II in mouse B lymphocytes and the production of TNF-α and MIP-1α in mouse macrophages and decreased bone resorption activity in mouse osteoclasts. Furthermore, it ameliorated the pathological changes in two rodent models of collagen-induced arthritis in vivo. TAS5315 improved bone mineral density and bone intensity. Thus, these results suggest that TAS5315 could be a promising therapeutic option for the treatment of rheumatoid arthritis.

SUBMITTER: Akasaka D

PROVIDER: S-EPMC9949657 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Novel Bruton's tyrosine kinase inhibitor TAS5315 suppresses the progression of inflammation and joint destruction in rodent collagen-induced arthritis.

Akasaka Daichi D Iguchi Satoru S Kaneko Ryusuke R Yoshiga Yohei Y Kajiwara Daisuke D Nakachi Yoshinori Y Noma Naruto N Tanaka Kenji K Shimizu Atsushi A Hosoi Fumihito F

PloS one 20230223 2

Rheumatoid arthritis is an inflammatory autoimmune disease, characterized by autoantibody production, synovial inflammation, and joint destruction. Its pathogenesis is due to environmental factors and genetic backgrounds. Bruton's tyrosine kinase is a cytoplasmic non-receptor tyrosine kinase, expressed in most hematopoietic cell lineages, except T cells and plasma cells, and regulates various immune-related signaling pathways, thereby playing a crucial role in pathogenesis. Thus, inhibiting Brut ...[more]

PMID: 36821545

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Project description:IntroductionProgression of joint destruction in rheumatoid arthritis (RA) is partly heritably; 45 to 58% of the variance in joint destruction is estimated to be explained by genetic factors. The binding of RANKL (Receptor Activator for Nuclear Factor κ B Ligand) to RANK results in the activation of TRAF6 (tumor necrosis factor (TNF) receptor associated factor-6), and osteoclast formation ultimately leading to enhanced bone resorption. This bone resorption is inhibited by osteoprotegerin (OPG) which prevents RANKL-RANK interactions. The OPG/RANK/RANKL/TRAF6 pathway plays an important role in bone remodeling. Therefore, we investigated whether genetic variants in OPG, RANK, RANKL and TRAF6 are associated with the rate of joint destruction in RA.Methods1,418 patients with 4,885 X-rays of hands and feet derived from four independent data-sets were studied. In each data-set the relative increase of the progression rate per year in the presence of a genotype was assessed. First, explorative analyses were performed on 600 RA-patients from Leiden. 109 SNPs, tagging OPG, RANK, RANKL and TRAF6, were tested. Single nucleotide polymorphisms (SNPs) significantly associated in phase-1 were genotyped in data-sets from Groningen (Netherlands), Sheffield (United Kingdom) and Lund (Switzerland). Data were summarized in an inverse weighted variance meta-analysis. Bonferonni correction for multiple testing was applied.ResultsWe found that 33 SNPs were significantly associated with the rate of joint destruction in phase-1. In phase-2, six SNPs in OPG and four SNPs in RANK were associated with progression of joint destruction with P-value <0.05. In the meta-analyses of all four data-sets, RA-patients with the minor allele of OPG-rs1485305 expressed higher rates of joint destruction compared to patients without these risk variants (P = 2.35x10-4). This variant was also significant after Bonferroni correction.ConclusionsThese results indicate that a genetic variant in OPG is associated with a more severe rate of joint destruction in RA.

Dataset Information

Novel Bruton's tyrosine kinase inhibitor TAS5315 suppresses the progression of inflammation and joint destruction in rodent collagen-induced arthritis.

Publications

Novel Bruton's tyrosine kinase inhibitor TAS5315 suppresses the progression of inflammation and joint destruction in rodent collagen-induced arthritis.

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