Orbit-Infiltrating Mast Cells, Monocytes, and Macrophages Produce PDGF Isoforms that Orchestrate Orbital Fibroblast Activation in Graves' Ophthalmopathy

Steensel, Leendert van; Paridaens, Dion; Meurs, Marjan van; Hagen, P. Martin van; Bosch, W A van den; Kuijpers, R. W. A. M.; Drexhage, Hemmo A.; Hooijkaas, Herbert; Dik, Willem A.

doi:10.1210/jc.2011-2697

Cited by 71 publications

(58 citation statements)

References 40 publications

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“…Orbital fibroblasts are considered to be the primary targets of the autoimmune process in GO, activated by cytokines released by immune cells infiltrating the orbital connective tissue (Bahn 2010, van Steensel et al 2012. Stimulated OFs deposit ECM components and proliferate in an unregulated manner (Wang & Smith 2014).…”

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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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: 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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“…Although trials with first-generation inhibitors, such as wortmannin, LY294002, or rapamycin and its derivatives, have been stopped because of significant untoward effects, second-generation inhibitors are currently being used in clinical trials on patients with refractory cancers (93), but to date, no trials have been planned in autoimmune thyroid disease. A PDGF-BB isoform of the PDGF receptor has recently been found expressed and increased in the orbital tissue of GO patients (94,95,96,97). Its signaling on orbital fibroblast can be blocked by tyrosine kinase inhibitors, such as imatinib mesylate, nilotinib ,and dasatinib, which has been shown to decrease in vitro the mRNA expression of hyaluronic synthetase 2 and IL-6 and IL-8 cytokines in orbital tissue from active GO (96) (Fig.…”

Section: Modifiers Of Orbital Tissue Remodelingmentioning

confidence: 97%

THERAPY OF ENDOCRINE DISEASE: Endocrine dilemma: management of Graves’ orbitopathy

Campi

Vannucchi

Salvi

2016

European Journal of Endocrinology

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Management of Graves' orbitopathy (GO) must be based on the correct assessment of activity and severity of the disease. Activity is usually assessed with the Clinical Activity Score, whereas severity is classified according to a European Group On Graves' Orbitopathy (EUGOGO) consensus statement as mild, moderate-to-severe, and sight-threatening. Myopathic and chronic congestive forms are uncommon clinical presentations of GO. Restoration and maintenance of stable euthyroidism are recommended in the presence of GO. In moderate-to-severe disease, steroids have been widely employed and have shown to possess an anti-inflammatory activity, but about 20 -30% of patients are not responsive and present recurrence. Some novel immunosuppressors have already been employed in clinical studies and have shown interesting results, although the lack of randomized and controlled trials suggests caution for their use in clinical practice. Potential targets for therapy in GO are the thyroid-stimulating hormone and the insulin-like growth factor 1 receptor on the fibroblasts, inflammatory cytokines, B and T cells, and the PIK3/mTORC1 signaling cascades for adipogenesis. A recent open study has shown that tocilizumab, an anti-sIL-6R antibody, inactivates GO. Consistent reports on the efficacy of rituximab have recently been challenged by randomized controlled trials. As the main goal of treatment is the well-being of the patient, the therapeutic strategy should be addressed to better suit the patient needs, more than improving one or more biological parameters. The increasing availability of new therapies will expand the therapeutic options for GO patients and allow the clinician to really personalize the treatment to better suit the patients' personal needs.

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“…It was found that orbital fibroblasts are the main target of the autoagression process [16]. Activation of fibroblasts leads to their proliferation and differentiation into myofibroblasts and adipocytes and secondary production of glycosaminoglycans, chemokines and cytokines, which enhance inflammatory reaction in the orbital tissues [17,18]. Activated orbital fibroblasts in patients with TAO show increased response to proinflammatory cytokines in comparison with healthy adults.…”

Section: Pathogenesis Of Thyroid-associated Ophthalmopathymentioning

confidence: 99%

An update on thyroid-associated ophthalmopathy in children and adolescents

Szczapa-Jagustyn¹,

Gotz‐Więckowska²,

Kocięcki³

2016

Journal of Pediatric Endocrinology and Metabolism

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Orbit-Infiltrating Mast Cells, Monocytes, and Macrophages Produce PDGF Isoforms that Orchestrate Orbital Fibroblast Activation in Graves' Ophthalmopathy

Cited by 71 publications

References 40 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

THERAPY OF ENDOCRINE DISEASE: Endocrine dilemma: management of Graves’ orbitopathy

An update on thyroid-associated ophthalmopathy in children and adolescents

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