Exploring the relationship between metabotype and the inflammatory phenotype of the osteoarthritis synovial fibroblast

Farah, Hussein (2023). Exploring the relationship between metabotype and the inflammatory phenotype of the osteoarthritis synovial fibroblast. University of Birmingham. Ph.D.

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Abstract

Osteoarthritis (OA) is a painful joint condition and a leading cause of disability worldwide. Unfortunately, there is currently no cure for the disease, and there are limited treatment options available. Importantly, despite historically being seen as a “wear and tear” disease of the cartilage there is now increasing evidence that inflammation of the synovial joint lining (synovitis) plays a key role in the disease pathology. Synovitis is pronounced in obese OA patients, with elevated levels of pro-inflammatory cytokines in the synovial fluid.
The aim of this study was therefore to characterise the metabolic profile of synovial joint fluid and synovial fibroblasts under both basal and inflammatory conditions in a cohort of obese and normal-weight OA patients. Furthermore, we sought to ascertain whether modulation of a metabolic pathway in OA synovial fibroblasts could alter their inflammatory activity.
1H NMR Metabolomics analysis of synovial fluid and synovial fibroblast conditioned media showed altered metabolism in obese OA patients compared to normal weight patients with increased enrichment of glycolytic metabolites. This was confirmed in vitro using metabolic flux analysis of isolated synovial fibroblasts. Obese OA synovial fibroblasts exhibited increased basal lactate secretion and glycolysis, compared to normal weight fibroblasts and could further increase oxidative phosphorylation upon inflammatory challenge.
Furthermore, metabolomic analysis of OA synovial fluid revealed enrichment of glutamine-glutamate metabolism in obese OA patients. Modulation of glutamine-glutamate metabolism through inhibition of glutaminase 1 (GLS1) reduced the expression and secretion of inflammatory cytokine IL6. Therefore, the synovial joint inflammation observed in obese OA patients is potentially underpinned by therapeutically targetable metabolic pathways. These differences in OA pathology suggest that lean and obese OA patients might benefit from different treatment strategies

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):