Rheumatoid arthritis (RA) is associated with a loss of lean mass and a corresponding increase in fat mass. How fat accumulation in RA is linked to synovial inflammation is unknown. Wnts comprise a family of secreted glycoproteins that are crucial in regulating adipocyte proliferation, apoptosis and differentiation. Recently we demonstrated that endogenously generated glucocorticoids (GCs) alter the pattern of wnt secretion by synovial fibroblasts (SFs), favouring production of wnt inhibitors. Inhibition of wnt signalling in adipocytes promotes their differentiation through inhibition of PPARγ. In this study we have investigated whether wnt production by SFs could influence adipocyte differentiation and thus contribute to the increased fat accumulation seen in RA.
Media conditioned for 24 h (CM) was collected from primary human SFs following 24 h pre-treatment with vehicle, TNFα or dexamethasone. 200 μl of CM was co-cultured with Chub-S7 human pre-adipocytes for 10 days +/− differentiation media. Differentiation was assessed by Nile red staining followed by FACS analysis and expression of adipocyte differentiation genes G6PDH, 11β-HSD1, lipoprotein lipase (LPL) and leptin by real time RT-PCR in three separate experiments.
Co-culture with un-stimulated CM did not induce adipocyte differentiation, as measured by lipid accumulation or gene expression. Significant increases in all markers of adipocyte differentiation were observed in response to TNFα treated CM (11β-HSD1, 3.6-fold; G6PDH, 18-fold; LPL, 30-fold; leptin, 15-fold; P<0.05). Similarly treatment with CM from SFs exposed to Dex significantly increased expression of adipocyte differentiation genes (G6PDH, 156-fold; LPL, 37-fold; Leptin, 5.4-fold; P<0.05). CM from cells previously exposed to TNFα or Dex resulted in increased lipid accumulation (3%±0.13; 2.8%±0.11 respectively; P<0.05) determined by FACS.
These data suggest that when exposed to pro-inflammatory cytokines or GCs, SFs produce secreted factors, likely of the wnt family, that enhance adipocyte differentiation. These data provide a direct link between joint inflammation and abnormal fat accumulation.