Peroxisome Proliferator-activated Receptor γ Ligands Inhibit Transforming Growth Factor-β-induced, Hyaluronan-dependent, T Cell Adhesion to Orbital Fibroblasts

Guo, Naxin; Woeller, Collynn F.; Feldon, Steven E.; Phipps, Richard P.

doi:10.1074/jbc.m110.179317

Cited by 28 publications

(30 citation statements)

References 57 publications

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“…We think that the high PAI-1 concentration in the GO orbit acts toward increased matrix stability, which may contribute to matrix expansion. Enhanced HA synthesis was described in OFs cultured in serum-free medium with TGF-β (Wang et al 2005, Guo et al 2011. We found that under basic circumstances, HA production per cell did not show a cell density-dependent pattern but was highly dependent on the origin of fibroblasts (Fig.…”

Section: Discussionmentioning

confidence: 68%

“…HA is the major overproduced glycosaminoglycan in the GO orbit (Hufnagel et al 1984, Smith et al 1989, Bahn 2010. HA accumulation in the orbital connective tissue causes edematic swelling (Natt & Bahn 1997) and facilitates inflammatory cell infiltration (Guo et al 2011, Evanko et al 2012, thereby promoting disease progression. ECM remodeling requires proteolytic enzyme activity (Lu et al 2011).…”

Section: Discussionmentioning

confidence: 99%

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Cell density-dependent stimulation of PAI-1 and hyaluronan synthesis by TGF-β in orbital fibroblasts

Galgoczi

Jeney

Gazdag

et al. 2016

Journal of Endocrinology

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During the course of Graves’ orbitopathy (GO), orbital fibroblasts are exposed to factors that lead to proliferation and extracellular matrix (ECM) overproduction. Increased levels of tissue plasminogen activator inhibitor type 1 (PAI-1 (SERPINE1)) might promote the accumulation of ECM components. PAI-1 expression is regulated by cell density and various cytokines and growth factors including transforming growth factorβ(TGF-β). We examined the effects of increasing cell densities and TGF-β on orbital fibroblasts obtained from GO patients and controls. Responses were evaluated by the measurement of proliferation, PAI-1 expression, and ECM production. There was an inverse correlation between cell density and the per cell production of PAI-1. GO orbital, normal orbital, and dermal fibroblasts behaved similarly in this respect. Proliferation rate also declined with increasing cell densities. Hyaluronan (HA) production was constant throughout the cell densities tested in all cell lines. In both GO and normal orbital fibroblasts, but not in dermal fibroblasts, TGF-β stimulated PAI-1 production in a cell density-dependent manner, reaching up to a five-fold increase above baseline. This has been accompanied by increased HA secretion and pericellular HA levels at high cell densities. Increasing cell density is a negative regulator of proliferation and PAI-1 secretion both in normal and GO orbital fibroblasts; these negative regulatory effects are partially reversed in the presence of TGF-β. Cell density-dependent regulation of PAI-1 expression in the orbit, together with the local cytokine environment, may have a regulatory role in the turnover of the orbital ECM and may contribute to the expansion of orbital soft tissue in GO.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Cell density-dependent stimulation of PAI-1 and hyaluronan synthesis by TGF-β in orbital fibroblasts

Galgoczi

Jeney

Gazdag

et al. 2016

Journal of Endocrinology

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“…fibroblasts, which are key effector cells in the disease, both proliferate at a faster rate and more readily form myofibroblasts in response to TGF␤ than normal, non-TED fibroblasts (26,36). Therefore, TGF␤ signaling is paramount to the aberrant myofibroblast formation, collagen production, contraction, and ocular tissue remodeling underlying TED pathophysiology.…”

Section: Discussionmentioning

confidence: 99%

Salinomycin and Other Polyether Ionophores Are a New Class of Antiscarring Agent

Woeller¹,

O’Loughlin

Roztocil

et al. 2015

Journal of Biological Chemistry

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Background: Excessive scar formation is a debilitating complication underlying many diseases of the eye, lungs, and skin. Results: We identified salinomycin as an inhibitor of TGF␤-dependent cell signaling. Conclusion: Salinomycin and other polyether ionophores block TGF␤-driven fibroblast proliferation and myofibroblast formation. Significance: There are few effective therapies to combat excessive scarring, and salinomycin is a novel therapeutic candidate.

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“…IL-1β, leukoregulin, CD154, TGF-β1 and platelet-derived growth factor (PDGF) are all involved in stimulating HA synthesis, likely via receptor and ligand binding on the orbital fibroblast 26 34 35 58. Orbital fibroblast surface receptors for TSHR and insulin-like growth factor-1 receptor (IGF-1R) both appear to stimulate HA synthesis.…”

Section: Molecular Mechanisms Underlying Tomentioning

confidence: 99%

“…PDGFβ and TGF are growth factors that are significantly increased in TO orbital tissues. They induce orbital fibroblast proliferation and stimulate HAS1 and HAS2 expression in TO orbital fibroblasts 35 58. TGF-β acts via the Smad pathway 35.…”

Section: Molecular Mechanisms Underlying Tomentioning

confidence: 99%

Pathogenesis of thyroid eye disease: review and update on molecular mechanisms

et al. 2015

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Peroxisome Proliferator-activated Receptor γ Ligands Inhibit Transforming Growth Factor-β-induced, Hyaluronan-dependent, T Cell Adhesion to Orbital Fibroblasts

Cited by 28 publications

References 57 publications

Cell density-dependent stimulation of PAI-1 and hyaluronan synthesis by TGF-β in orbital fibroblasts

Cell density-dependent stimulation of PAI-1 and hyaluronan synthesis by TGF-β in orbital fibroblasts

Salinomycin and Other Polyether Ionophores Are a New Class of Antiscarring Agent

Pathogenesis of thyroid eye disease: review and update on molecular mechanisms

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