ScholarWorks@경상국립대학교

초록

BackgroundRheumatoid arthritis (RA) is characterized by chronic inflammation and joint destructioncaused by dysregulated immune signaling. Despite the development of various protein kinaseinhibitors to treat inflammatory diseases such as RA, the results achieved are still notsatisfactory.PurposeThis study aimed to investigate the therapeutic potential and biological mechanisms of KMU-11361, an innovative multi-protein kinase inhibitor which modulates the inflammatorypathways involved in the pathophysiology of RA, using both in vitro and in vivo models ofarthritis.MethodsWe investigated the effects of KMU-11361 on lipopolysaccharide (LPS)-inducedinflammation, receptor activator of NF-kappa B ligand (RANKL)-induced osteoclast differentiation,and osteoblast differentiation, using various assays in human rheumatoid arthritis (RA)-fibroblast-like synoviocytes (RA-FLS), THP-1 cells, RAW264.7 cells, T cells, and MC-3T3-E1 cells. Furthermore, we evaluated the toxicity and efficacy of KMU-11361 in a zebrafishmodel and a K/BxN serum transfer-induced arthritis mouse model. In addition, we performedkinase profiling and conducted molecular docking simulations to examine whether KMU-11361 interacts with MAPK1 and TAK1 involved in TLR4 signaling.ResultsKinase profiling and molecular docking analyses revealed that KMU-11361 interacts with MAPK1 and TAK1, key regulators of TLR4 signaling. KMU-11361 markedly suppressedTLR4-mediated inflammatory signaling by reducing LPS-induced pro-inflammatory cytokineproduction, phosphorylation of TAK1 and MAPKs, NF-kappa B activation, and NLRP3 expressionin RA-FLS and THP-1 cells. Additionally, KMU-11361 inhibited RANKL-inducedosteoclastogenesis in RAW264.7 cells and attenuated T-cell activation-associated signalingpathways. Notably, KMU-11361 promoted osteoblastic differentiation in MC3T3-E1 cells. Inthe K/BxN serum transfer-induced arthritis mouse model, KMU-11361 significantly reducedankle swelling and IL-6 levels.ConclusionKMU-11361 exhibits potent anti-inflammatory and bone-protective properties by targeting keykinases involved in TLR4-mediated signaling and osteoclast differentiation. These findingsprovide mechanistic insight into its biological activity and highlight its therapeutic potential inboth in vitro and in vivo models of arthritis.

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