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 machinery. 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 cellspecific 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 networks. Subsequent flux balance analysis allows assessment of RASFs' regulatory outcomes' impact on their metabolic flux distribution. The hybrid RASF model simulates 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.

Hypoxia-inducible factor in breast cancer: role and target for breast cancer treatment

“…CAFs, mainly normal interstitial fibroblasts (NFs), are the most abundant cell type in the stroma of breast cancer (153,154). In breast cancer tumors, only a small fraction of fibroblasts are quiescent; these fibroblasts are responsible for the structural integrity of the extracellular matrix (ECM) and its nutrient supply and contribute to wound healing (155). However, most fibroblasts exhibit an activated phenotype characterized by producing various extracellular matrix components and paracrine mediators (156).…”

High-quality Reconstruction of Disease Mechanisms: Planning, Development and Maintenance

“…• creating computational models based on disease maps, for example for rheumatoid arthritis [16,17] and atherosclerosis [15]; • creating causal-interaction networks based on a disease map [68];…”

A large-scale Boolean model of the Rheumatoid Arthritis Fibroblast-Like Synoviocytes predicts drug synergies in the arthritic joint

“…Nevertheless, the need for kinetic parameters limits its use for large-scale molecular interaction networks. Lastly, a large-scale hybrid model covering signalling, gene regulation, and metabolism in RA-FLS was published (Aghakhani et al , 2022). The model focuses on the metabolic reprogramming of fibroblasts under hypoxic conditions in the arthritic joint and suggests a reverse Warburg effect as the origin of the observed metabolic switch.…”