Abstract
Orbital fibrosis, a hallmark of tissue remodeling in Graves’ ophthalmopathy (GO), is a chronic, progressive orbitopathy with few effective treatments. Orbital fibroblasts are effector cells, and transforming growth factor β1 (TGF-β1) acts as a critical inducer to promote myofibroblast differentiation and subsequent tissue fibrosis. Curcumin is a natural compound with anti-fibrotic activity. This study aims to investigate the effects of curcumin on TGF-β1-induced myofibroblast differentiation and on the pro-angiogenic activities of orbital fibroblasts. Orbital fibroblasts from one healthy donor and three patients with GO were collected for primary cell culture and subjected to myofibroblast differentiation under the administration of 1 or 5 ng/mL TGF-β1 for 24 h. The effects of curcumin on TGF-β1-induced orbital fibroblasts were assessed by measuring the cellular viability and detecting the expression of myofibroblast differentiation markers, including connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA). The pro-angiogenic potential of curcumin-treated orbital fibroblasts was evaluated by examining the transwell migration and tube-forming capacities of fibroblast-conditioned EA.hy926 and HMEC-1 endothelial cells. Treatment of orbital fibroblasts with curcumin inhibited the TGF-β1 signaling pathway and attenuated the expression of CTGF and α-SMA induced by TGF-β1. Curcumin, at the concentration of 5 μg/mL, suppressed 5 ng/mL TGF-β1-induced pro-angiogenic activities of orbital fibroblast-conditioned EA hy926 and HMEC-1 endothelial cells. Our findings suggest that curcumin reduces the TGF-β1-induced myofibroblast differentiation and pro-angiogenic activity in orbital fibroblasts. The results support the potential application of curcumin for the treatment of GO.
Highlights
Previous studies have demonstrated the role of transforming growth factor β1 (TGF-β1) as an important mediator in fibrosis induced by oxidative stress in orbital fibroblasts from patients with Graves’ ophthalmopathy (GO) [11,21]
In an attempt to establish a fibrosis model to identify the anti-fibrotic effects of natural compounds, we isolated and cultured orbital fibroblasts from two donors in the presence of transforming growth factor β1 (TGF-β1) as the TGF-β1/connective tissue growth factor (CTGF)
The expression of CTGF and α-smooth muscle actin (α-SMA) increased in a dose-dependent manner upon TGF-β1 treatment (Figure 1C, D) in two culture conditions, suggesting a successful induction of the myofibroblast differentiation in the primary culture of orbital fibroblasts
Summary
A hallmark of tissue remodeling in Graves’ ophthalmopathy (GO), is an appearance-destructing and vision-threatening condition that is mostly associated with Graves’ disease (GD). The mechanism underlying the thyroid endocrine dysfunction in GD is relatively better elucidated, the pathophysiology of GO is incompletely understood [1]. The clinical manifestations of GO are associated with inflammatory enlargement of orbital soft tissues characterized by mononuclear cell infiltration, adipogenesis, and orbital fibrosis [3,4]. Orbital fibrosis in advanced GO may result in severe morbidities, including exophthalmos, exposure keratitis, diplopia, and dysthyroid optic neuropathy, which are often unresponsive to drug treatment and require surgical intervention [5]. Investigating the molecular mechanisms modulating the myofibroblast differentiation in GO is pivotal to the development of novel therapeutic strategies for blocking orbital fibrosis
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