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N. Guo, S. E. Feldon, C. W. O’Loughlin, X. Xi, R. P. Phipps; The Thiazolidinedione Class of PPAR Ligands Rosiglitazone and Pioglitazone Inhibit TGFβ Induced Hyaluronan Secretion by Orbital Fibroblasts Derived From Patients With Thyroid Eye Disease. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4370. doi: https://doi.org/.
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Thyroid Eye Dsease is characterized by infiltration of white blood cells and accumulation of nonsulfated glycosaminoglycan hyaluronan (HA) in orbital tissue. The inflamed orbital tissue can become full of scar and fat tissue. Transforming growth factor beta (TGFβ) acts as a key inducer of the fibrotic response by enhancing extracellular matrix production. Peroxisome proliferator-activated receptor gamma (PPARγ) ligands have anti-inflammatory and antifibrotic activities. In this study, we hypothesized that TGFβ would induce HA synthesis/secretion and that PPARγ ligands would inhibit this response in orbital fibroblasts.
Primary orbital fibroblasts were isolated from individual Graves’ patients undergoing orbital decompression surgery. The cells were grown in RPMI media containing 10%FBS. The amount of HA in the cell culture supernatant was measured by ELISA. HA synthase (HAS) mRNA expression was analyzed by real-time RT-PCR.
Treatment of human orbital fibroblasts with TGFβ leads to an increased HA level in conditioned medium by about 6 folds after 24 hours compared to the control value. TGFβ rapidly and strongly induced HAS1 mRNA expression, which increased about 250 folds, while HAS2 and HAS3 mRNA levels did not change significantly. Rosiglitazone or Pioglitazone alone did not change HA levels; however, both molecules down-regulated TGFβ-induced HA secretion and HAS1 mRNA expression in a dose-dependent manner. At 10 µM concentration, rosiglitazone and pioglitazone inhibited the TGFβ-induced HA secretion and HAS1 mRNA expression by 50%.
Our findings suggest that TGFβ plays an important role in human orbital fibroblast HA synthesis and secretion. Rosiglitazone and Pioglitazone have inhibitory effects on TGFβ induced HA secretion through blocking HAS1 mRNA expression. These findings may strongly implicate the PPARγ pathway as an important mediator for orbital fibroblast extracellular matrix production.
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