The Fibroblast Is the Target Cell in the Connective Tissue Manifestations of Graves' Disease

Bahn, Rebecca S.

doi:10.1159/000236845

Cited by 27 publications

(12 citation statements)

References 31 publications

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“…In the absence of an accepted animal model, we used the human model of TAO, which involves culturing OFs taken from patients undergoing surgery (14,24). This model has certain limitations.…”

Section: Discussionmentioning

confidence: 99%

The effects of tumour necrosis factor-α and interleukin1 on an in vitro model of thyroid-associated ophthalmopathy; contrasting effects on adipogenesis

Cawood

Moriarty²,

O’Farrelly³

et al. 2006

eur j endocrinol

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Objective: Cytokines are likely to play a key pathogenic role in thyroid-associated ophthalmopathy (TAO). Anti-cytokine therapy has been proposed to be a possible treatment for active TAO. We aimed to establish the effects of selected cytokines on intercellular adhesion molecule 1 (ICAM1) expression, glycosaminoglycan (GAG) production and adipogenesis in orbital fibroblasts (OFs) from patients with TAO. Methods: Orbital tissue was taken during surgery from eight patients with TAO and five control subjects. OFs were cultured and ICAM1 expression measured by flow cytometry. GAG production was measured by hyaluronic acid ELISA. OFs were grown in adipogenic media and the degree of adipogenesis quantified. Results: Responses were similar in OFs from patients with and without TAO. Tumour necrosis factor-a (TNFa) and interleukin1 (IL1) (0.1 ng/ml) stimulated ICAM1 expression by eight-to ten-fold. Anticytokine agents inhibited the cytokine-upregulated ICAM1 expression by 90-99% (P!0.01). TNFa and IL1 (0.1 ng/ml) increased hyaluronic acid production by 44 and 95% (P!0.01) respectively. Anti-cytokine agents inhibited these responses by 79-138% (P!0.04). TNFa (0.1 ng/ml) inhibited adipogenesis (K0.013 AU and K1.0; P!0.03) whilst IL1 (0.1 ng/ml) stimulated adipogenesis (C0.05 AU and C5.7; P!0.02) measured by oil-red-O extraction and visual assessment respectively. The anti-IL1 agent inhibited IL1-mediated adipogenesis by 69-106% (P!0.04). Conclusion: TNFa and IL1 stimulate ICAM1 expression and GAG production, but have opposite effects on adipogenesis in OFs in vitro. IL1 promotes adipogenesis and its effects can be blocked by anti-IL1 agents in vitro. These agents may be the anti-cytokine treatment of choice for clinical trials in active TAO. European Journal of Endocrinology 155 395-403

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Section: Discussionmentioning

confidence: 99%

The effects of tumour necrosis factor-α and interleukin1 on an in vitro model of thyroid-associated ophthalmopathy; contrasting effects on adipogenesis

Cawood

Moriarty²,

O’Farrelly³

et al. 2006

eur j endocrinol

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“…Thus, present investigations focus on sites with obvious clinical disease (orbit and lower extremity) with the intuitive assumption that such localization of disease must involve cellular and/or biochemical differences between different regions of the body. However, previous studies have raised the possibility that Graves' disease may have a systemic, connective tissue systemic component (27)(28)(29)(30)(31)(32)(33). Perhaps the strongest evidence for this notion is increased urinary excretion of mucopolysaccharides or glycosaminoglycans in Graves' patients with, as opposed to without, GO (28,32).…”

Section: Discussionmentioning

confidence: 99%

Elephantiasic Pretibial Myxedema: Insight into and a Hypothesis Regarding the Pathogenesis of the Extrathyroidal Manifestations of Graves' Disease

Rapoport

Alsabeh

Aftergood

et al. 2000

Thyroid

110

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The basis for the extrathyroidal manifestations of Graves' ophthalmopathy (GO) and dermopathy are not well understood. We describe immunohistochemical studies on the skin of a patient with an extreme, elephantiasic form of Graves' dermopathy that developed after periods of prolonged standing with dependent edema. Excision of part of the lesion with subsequent skin grafting from a normal donor site resulted in recurrence of the disease at the original site as well as in development of disease at the donor site. A murine monoclonal antibody reacted with the thyrotropin receptor (TSHR) or a cross-reacting protein in fibroblast-like cells in the patient's upper dermis and, surprisingly, with dermal cells from unaffected individuals. The patient's dermis containing lymphoid follicles comprising B cells and CD3+, CD4+ T cells, with few CD8+ T cells. CD21+ cells (most likely follicular dendritic cells) were also present in the dermis. Based on past and present observations, we raise an unifying hypothesis to explain the diverse extrathyroidal manifestations of Graves' disease and their apparent lack of association with TSHR autoantibodies. As opposed to the present concept that these phenomena relate to site-specific properties on preadipocytes or fibroblasts, we suggest that clinically evidence GO and dermopathy are primarily caused by local factors (particularly in the orbit) superimposed on a systemic, low-grade connective tissue inflammation.

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“…Fatty orbital adipose tissue in GO has been the subject of much research in recent years (3)(4)(5)(6)(7). The development of adipose tissue requires adipocytic differentiation of fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor-γ Gene Expression in Orbital Adipose/Connective Tissues is Increased During the Active Stage of Graves' Ophthalmopathy

Mimura¹,

Villares²,

Monteiro³

et al. 2003

Thyroid

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The mechanisms involved in the increase of orbital retro-ocular adipose tissue that occurs in Graves' ophthalmopathy (GO) are still unclear. In this condition, the orbital tissue shows glycosaminoglycans deposition produced by activated fibroblasts capable of undergoing adipocytic differentiation. Many genes are involved in adipogenic mechanisms including the transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma). We evaluated the level of expression of the PPAR-gamma gene in normal and GO orbital adipose/connective tissue specimens using a quantitative and sensitive reverse transcription (RT) competitive polymerase chain reaction (PCR) assay. Our results show that the expression of PPAR-gamma was significantly greater in adipose/connective tissue from patients in the active stage of GO than in controls (150.8 +/- 103.9 and 24.0 +/- 4.9 amol/micro g of total RNA respectively, p < 0.05), while there was no significant difference between patients with inactive GO (58.8 +/- 40.6 aM/microg total RNA) and controls. These results suggest that increased PPAR-gamma gene expression in the active stage of GO may be dependent on the inflammatory process in this disease. We speculate that the increased orbital fat tissue observed in GO may be a consequence of the anti-inflammatory PPAR-gamma action.

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The Fibroblast Is the Target Cell in the Connective Tissue Manifestations of Graves' Disease

Cited by 27 publications

References 31 publications

The effects of tumour necrosis factor-α and interleukin1 on an in vitro model of thyroid-associated ophthalmopathy; contrasting effects on adipogenesis

The effects of tumour necrosis factor-α and interleukin1 on an in vitro model of thyroid-associated ophthalmopathy; contrasting effects on adipogenesis

Elephantiasic Pretibial Myxedema: Insight into and a Hypothesis Regarding the Pathogenesis of the Extrathyroidal Manifestations of Graves' Disease

Peroxisome Proliferator-Activated Receptor-γ Gene Expression in Orbital Adipose/Connective Tissues is Increased During the Active Stage of Graves' Ophthalmopathy

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