From Fat to Flame: How Adipose Tissue Stokes the Fires of Osteoarthritis

To investigate the inflammatory profiles of adipose tissues from patients with osteoarthritis (OA), comparing the joint-associated adipose tissues, infrapatellar fat pad (IFP) and sub-synovial (SSAT)with subcutaneous adipose tissue (SCAT), and to explore adipose-joint cell crosstalk. RNA sequencing was performed on autologous IFP, SSAT, and SCAT from six patients. The adipose tissue secretome was profiled using targeted proteomics. Primary joint cells (synovial fibroblasts, osteoblasts, and chondrocytes) were treated with adipose-conditioned media for 24 hours, followed by RNA sequencing (N=6 per treatment). Key findings were validated using qPCR, ELISA, and recombinant protein treatments. IFP and SSAT exhibited distinct transcriptomic profiles, with 649 and 1263 differentially expressed genes (DEGs), respectively (FDR<0.1). Both IFP and SSAT showed enrichment in inflammation-related pathways, with IFP linked to innate immunity and neuroinflammation, whilst SSAT was associated with metabolism of cholesterol (p<0.05). Proteomic analysis identified 33 elevated biomarkers secreted by IFP and SSAT (p<0.05). Treatment with adipose conditioned media revealed adipose-derived signals modulated joint cell behaviour. Upstream regulator analysis identified common inflammatory and metabolic regulators across adipose conditioned media treated cells, 12 of which were detected in IFP and SSAT secretome. Further validation confirmed that transcriptional signatures identified in joint cells were driven by these shared regulators. Our findings demonstrate that joint adipose tissues contribute to inflammatory and metabolic dysfunction in OA joints. These interactions offer insight into disease pathophysiology and may help identify candidate therapeutic targets, although further in vivo studies are needed to confirm their functional relevance.