Enhanced lipolysis in synovial fibroblasts mark early pathogenic changes in RA-risk individuals

Rheumatoid arthritis (RA) is a chronic autoimmune disease marked by synovial inflammation and progressive joint destruction, driven in part by the aggressive behaviour of synovial fibroblasts (SFs). Emerging evidence suggests that metabolic dysfunction in SFs contributes to RA pathogenesis. Studying autoantibody-positive at-risk individuals who have not yet developed clinical arthritis (RA-risk) offers a unique opportunity to investigate early disease mechanisms. Our previous work identified a transcriptional downregulation of genes involved in lipid and fatty acid metabolism in synovium samples of RA-risk individuals who later developed RA, even in the absence of overt immune cell infiltration. Here, we hypothesised that these alterations reflect an early metabolic shift in SFs.

To investigate this, we compared transcriptomic profiles and lipid metabolism in SFs from RA-risk individuals, patients with RA and osteoarthritis (OA), and age-matched noninflammatory orthopaedic injury controls. RA and RA-risk SFs displayed distinct transcriptional signatures compared with controls, including dysregulation of lipid metabolism.

Despite retained adipogenic differentiation potential, RA, RA-risk, and OA SFs showed reduced baseline lipid droplet (LD) content compared with controls. In RA and RA-risk SFs, this reduction was a result of enhanced LD lipolysis, plausibly as a result of decreased G0S2 expression, and could be reversed by adipose triglyceride lipase inhibition. Furthermore, stimulating G0S2 expression coincided with a reduced myeloid-supporting SF phenotype.

Overall, these findings suggest that early lipid metabolic alterations in SFs represent important shifts in cellular function that precedes clinical disease and highlight the need to further interrogate the role of lipid metabolism in RA progression.