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Metabolic reprogramming in Rheumatoid Arthritis Synovial Fibroblasts: A hybrid modeling approach.

Sahar Aghakhani1,2, Sylvain Soliman2, Anna Niarakis1,2

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|December 12, 2022
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Summary

This study introduces a novel hybrid model to understand metabolic changes in Rheumatoid Arthritis Synovial Fibroblasts (RASFs). The model reveals how RASFs reprogram metabolism, potentially acting as "metabolic factories" in RA pathogenesis.

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Area of Science:

  • Systems Biology
  • Immunology
  • Metabolic Engineering

Background:

  • Rheumatoid Arthritis (RA) involves invasive pannus formation by Synovial Fibroblasts (RASFs), leading to joint destruction.
  • RASF activation is linked to metabolic alterations driven by dysregulated signaling and gene expression.
  • Understanding RASF metabolic reprogramming is crucial for RA pathogenesis and therapeutic development.

Purpose of the Study:

  • To develop the first hybrid model integrating a cell-specific regulatory network with a global metabolic network for RASFs.
  • To investigate the impact of regulatory outcomes on RASF metabolic flux distribution.
  • To explore potential metabolic reprogramming mechanisms, including the reverse Warburg effect, in RA.

Main Methods:

  • Developed an automated framework for hybrid modeling of RASFs.
  • Combined qualitative regulatory networks with quantitative metabolic networks.
  • Utilized regulatory network trap-spaces as constraints for flux balance analysis.

Main Results:

  • The hybrid RASF model successfully reproduced experimentally observed metabolic reprogramming.
  • Simulations demonstrated the impact of signaling and gene regulation on metabolic flux.
  • Hypotheses were generated regarding the reverse Warburg effect and RASFs as 'metabolic factories' driven by HIF1.

Conclusions:

  • The hybrid model provides a powerful tool for dissecting RASF metabolic complexity in RA.
  • Metabolic reprogramming of RASFs, potentially via the reverse Warburg effect, plays a significant role in RA pathogenesis.
  • Targeting RASF metabolic reprogramming may offer novel therapeutic strategies for Rheumatoid Arthritis.