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

Area of Science:

• Immunology
• Metabolic disease
• Cell biology

Background:

• Rheumatoid arthritis (RA) involves synovial inflammation and joint destruction, partly driven by synovial fibroblasts (SFs).
• Metabolic dysfunction in SFs is increasingly implicated in RA pathogenesis.
• Studying autoantibody-positive, RA-risk individuals offers insight into early disease mechanisms.

Purpose of the Study:

• To investigate early metabolic shifts in SFs from RA-risk individuals.
• To compare lipid metabolism and transcriptomic profiles in SFs across different disease stages.
• To determine if observed metabolic alterations precede clinical RA diagnosis.

Main Methods:

• Compared transcriptomic profiles and lipid metabolism in SFs from RA-risk individuals, RA patients, osteoarthritis (OA) patients, and controls.
• Analyzed lipid droplet content and lipolysis in SFs.
• Investigated the role of G0S2 expression and adipose triglyceride lipase.

Main Results:

• RA and RA-risk SFs exhibited distinct transcriptional signatures, including dysregulated lipid metabolism, compared to controls.
• Despite normal adipogenic potential, RA, RA-risk, and OA SFs showed reduced lipid droplet content.
• Reduced lipid droplets in RA and RA-risk SFs were linked to enhanced lipolysis and potentially decreased G0S2 expression, reversible by inhibiting adipose triglyceride lipase.

Conclusions:

• Early alterations in SF lipid metabolism precede clinical RA development.
• These metabolic shifts in SFs are associated with cellular functional changes.
• Further research into lipid metabolism's role in RA progression is warranted.