The small molecule NSM00191 specifically represses the TNF-α/NF-кB axis in foot and ankle rheumatoid arthritis

Area of Science:

• Immunology
• Molecular Biology
• Rheumatology

Background:

• Tumor necrosis factor-alpha (TNF-α)/nuclear factor-kappa B (NF-κB) signaling regulates critical cellular processes and is implicated in diseases like cancer and inflammation.
• This signaling pathway is known to be dysregulated in various inflammatory conditions.

Purpose of the Study:

• To investigate the role of TNF-α/NF-κB signaling in foot and ankle rheumatoid arthritis (RA).
• To identify novel therapeutic targets and agents for RA treatment by exploring the molecular mechanisms of TNF-α/NF-κB activation.

Main Methods:

• Microarray analysis of human synovial sarcoma (SW982) and fibroblast-like synoviocyte (HFLS-RA) cell lines, including p65 knockdown and overexpression models.
• MicroRNA-specific microarray analysis of patient samples.
• In vitro screening for small molecules inhibiting the TRADD-TNFR2 interaction.
• In vivo validation of therapeutic efficacy and molecular target engagement.

Main Results:

• TNF-α/NF-κB signaling was found to be activated in blood samples from RA patients.
• Numerous p65 targets, including cytokines (TNF-α, IL-6), chemokines (MCP-1, PANTES), receptors (CD-40, MHC-1), and enzymes (COX2), were identified.
• MicroRNA miR-7-5p was found to negatively regulate p65 expression.
• The small molecule NSM00191 effectively inhibited TNF-α/NF-κB signaling in vitro and in vivo, reducing NF-κB target expression and decreasing arthritis scores.

Conclusions:

• The TNF-α/NF-κB signaling axis is a key player in the pathogenesis of rheumatoid arthritis.
• miR-7-5p acts as a negative regulator of p65, suggesting its potential role in RA.
• NSM00191 demonstrates therapeutic potential for RA by inhibiting TNF-α/NF-κB activation and alleviating disease symptoms.