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

Abstract

Rheumatoid Arthritis (RA) is an autoimmune disease characterized by a highly invasive pannus formation consisting mainly of Synovial Fibroblasts (RASFs). This pannus leads to cartilage, bone, and soft tissue destruction in the affected joint. RASFs' activation is associated with metabolic alterations resulting from dysregulation of extracellular signals' transduction and gene regulation. Deciphering the intricate mechanisms at the origin of this metabolic reprogramming may provide significant insight into RASFs' involvement in RA's pathogenesis and offer new therapeutic strategies. Qualitative and quantitative dynamic modeling can address some of these features, but hybrid models represent a real asset in their ability to span multiple layers of biological machinery. This work presents the first hybrid RASF model: the combination of a cell-specific qualitative regulatory network with a global metabolic network. The automated framework for hybrid modeling exploits the regulatory network's trap-spaces as additional constraints on the metabolic network. Subsequent flux balance analysis allows assessment of RASFs' regulatory outcomes' impact on their metabolic flux distribution. The hybrid RASF model reproduces the experimentally observed metabolic reprogramming induced by signaling and gene regulation in RASFs. Simulations also enable further hypotheses on the potential reverse Warburg effect in RA. RASFs may undergo metabolic reprogramming to turn into "metabolic factories", producing high levels of energy-rich fuels and nutrients for neighboring demanding cells through the crucial role of HIF1.

Fig 1. General architecture of the hybrid modeling framework.

Fig 2

Statistical analysis of the RASF model. (A) Distribution of the RASF model’s cellular specificity. (B) Distribution of the RASF model’s cellular specificity when only exclusive components are considered. (C) Annotation score’s distribution among the RASF model’s components.

Fig 3. Simulation of the RASF model under RASF-specific initial conditions performed on the Cell Collective platform.

The different curves depict the state of the phenotype components.

Fig 4

Summary of the major active pathways of central metabolism according to Flux Balance Analysis in control (A) and RASF-specific conditions (B) with maximum cellular ATP production as objective function.