Anti-TNF effects on destructive fibroblasts depend on mechanical stress

Area of Science:

• Rheumatology
• Molecular Biology
• Immunology

Background:

• Rheumatoid arthritis (RA) involves joint destruction initiated at mechanically stressed synovial membrane sites.
• Tumour necrosis factor (TNF) antagonists are effective in reducing joint destruction in RA therapy.

Purpose of the Study:

• To investigate and profile genes affected by the interplay of mechanical stress and anti-TNF therapy in an in vitro RA model.
• To identify transcriptional events modulated by mechanical forces and anti-TNF treatment in synovial fibroblasts.

Main Methods:

• Murine LS48 cells (RA synovial fibroblast model) were subjected to mechanical stretching and/or anti-TNF-alpha antibody treatment.
• Gene expression profiling was performed using Affymetrix GeneChips, with key findings validated by polymerase chain reaction (PCR).

Main Results:

• 170 differentially regulated genes were identified, with 44 of particular interest, falling into functional groups relevant to RA pathogenesis.
• Mechanical stretching modulated gene expression and cellular response to anti-TNF therapy, with significant regulation of structural and functional genes observed.
• The interleukin-18 system's role in joint destruction was confirmed.

Conclusions:

• Mechanical exertion significantly influences gene expression and cellular response to anti-TNF therapy in the context of rheumatoid arthritis.
• The study provides insights into the molecular mechanisms underlying joint destruction in RA and the efficacy of anti-TNF agents.
• The findings underscore the importance of considering mechanical factors in RA pathogenesis and treatment.