Detection of TSH Receptor RNA in Cultured Fibroblasts from Patients with Graves' Ophthalmopathy and Pretibial Dermopathy

Heufelder, Armin E.; Dutton, Charyl M.; Sarkar, Gobinda; Donovan, Kathleen A.; Bahn, Rebecca S.

doi:10.1089/thy.1993.3.297

Cited by 163 publications

(67 citation statements)

References 17 publications

(20 reference statements)

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“…Since TSHR was first cloned in 1989, it has been believed to be responsible solely for the control of thyroid follicular cell growth and thyroid hormone synthesis (Nagayama et al 1989, Laugwitz et al 1996. However, it is becoming increasingly clear that expression of TSHR is not confined to the thyroid gland, but is widely expressed in a variety of tissues (Francis et al 1991, Endo et al 1993, Feliciello et al 1993, Heufelder et al 1993. TSHR protein expression has been reported in fibroblasts and adipose tissue from the retro-orbital space of Graves' patients, where it may play a role in thyroid-associated ophthalmopathy (Bahn et al 1998a,b, Starkey et al 2003, Bahn 2004.…”

Section: Discussionmentioning

confidence: 99%

TSH stimulates adipogenesis in mouse embryonic stem cells

Lü¹,

Lin²

2007

Journal of Endocrinology

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Although TSH is the main regulator of thyroid growth and function, TSH binding activity in fat has long been reported. Since the TSH receptor (TSHR) has been detected in both preadipocytes and adipocytes, we hypothesized that it may play a role in adipose differentiation. Here, we use an in vitro model of adipogenesis from mouse embryonic stem (ES) cells to define TSH function. Directed differentiation of ES cells into the adipose lineage can be achieved over a 3-week period. Although adipocyte differentiation is initiated early in the development of cultured ES cells, TSHR up-regulation is precisely correlated with terminal differentiation of those adipocytes. The adipocytes express TSHR on the cell surface and respond to TSH with increased intracellular cAMP production, suggesting the activation of the protein kinase A signaling pathway. To determine whether TSH impacts adipogenesis, we examined how adipocytes responded to TSH at various points during their differentiation from cultured ES cells. We found that TSH greatly increases adipogenesis when added in the presence of adipogenic factors. More importantly, our data suggest that TSH also stimulates adipogenesis in cultured ES cells even in the absence of adipogenic factors. This finding provides the first evidence of TSH being a pro-adipogenic factor that converts ES cells into adipocytes. It further highlights the potential of ES cells as a model system for use in the study of TSH's role in the regulation of physiologically relevant adipose tissue.

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Section: Discussionmentioning

confidence: 99%

TSH stimulates adipogenesis in mouse embryonic stem cells

Lü¹,

Lin²

2007

Journal of Endocrinology

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“…Numerous results from several laboratories now suggest that the TSHr is expressed in various human extrathyroidal tissues (29,30,31). The presence of the TSHr in human orbital tissue and orbital fibroblasts was demonstrated by using RT-PCR in 1993 (8,9), but the possibility of an illegitimate transcription was raised (32,33,34). In a previous report, we demonstrated by using a very sensitive and quantitative method such as real-time PCR that the levels of TSHr mRNA expressed in orbital tissues from TAO patients were similar to those obtained from tissues of patients not affected by thyroid diseases (12).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, there is no general agreement regarding the presence of the TSHr or its transcript in eye orbit structures. Some have found transcripts in retro-ocular fibroblasts (8) or inferred their presence in fat (9); others have failed to find a TSHr transcript in retro-ocular muscle also containing fibroblasts (10). A TSHr variant transcript comprising essentially exons 1 -8 was also described in many locations, including ocular muscle, fat, lymphocytes and fibroblasts (11).…”

Section: Introductionmentioning

confidence: 99%

Evidence for protein and mRNA TSHr expression in fibroblasts from patients with thyroid-associated ophthalmopathy (TAO) after adipocytic differentiation

et al. 2005

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Objective: Thyroid-associated ophthalmopathy (TAO) is a chronic autoimmune disorder characterized by an increased volume of adipose/connective tissue in the human orbit. Design: The aim of this study was to investigate the thyrotropin receptor (TSHr) expression in orbital fibroblasts from TAO patients undergoing adipocytic differentiation. Methods: Retro-ocular tissue and skin were obtained from five patients undergoing orbital decompression surgery for TAO and placed in culture. Proliferating fibroblasts were subjected to adipocytic differentiation for 10 days. Total RNA was isolated from fibroblasts and was reverse transcribed. TSHr mRNA levels were determined by real-time PCR. cAMP was determined by radioimmunoassay (RIA) after fibroblast incubation with the substances to test. Results: Orbital differentiated fibroblasts became rounded and acquired lipid droplets. The amount of TSHr mRNA in these fibroblasts was higher than fibroblasts not subjected to adipocytic differentiation. Immunocytochemical analysis showed TSHr protein in differentiated orbital fibroblasts. Differentiated orbital fibroblasts stimulated with bovine (b) TSH showed a cAMP production greater than that in paired undifferentiated cultures. A specific thyroid-inhibiting antibody (TBAb) inhibited cAMP production after bTSH challenge, and a thyroid-stimulating antibody (TSAb) stimulated cAMP production in differentiated fibroblasts. Conclusions: We suggest that orbital fibroblasts subjected to adipocytic differentiation increase TSHr expression that responds specifically to bTSH and TSAb stimulation, and to TBAb inhibition. European Journal of Endocrinology 152 777-784

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“…Results of these studies were in general agreement and demonstrated the presence of TSHR mRNA and protein in orbital adipose tissue specimens and derivative cultures from patients with GO and from patients without GO. [13][14][15] However, additional studies showed that levels of TSHR are in fact higher in orbital adipose tissue from patients with GO than from patients without GO, suggesting that increased TSHR expression in the orbit might be involved in disease development. 16 This concept is further supported by the finding of a positive correlation between GO patients' TSHR mRNA levels in orbital adipose tissues excised during decompression surgery and the patients' clinical activity score.…”

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confidence: 99%

Pathogenesis of Graves Ophthalmopathy: Implications for Prediction, Prevention, and Treatment

Garrity

Bahn

2006

American Journal of Ophthalmology

212

158

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PURPOSE-To review current concepts regarding the pathogenesis of Graves ophthalmopathy (GO). We have presented this information in the context of potential target sites for novel disease therapies. DESIGN-Review of recent literature. METHODS-Synthesis of recent literature.RESULTS-Enlargement of the extraocular muscle bodies and expansion of the orbital fatty connective tissues is apparent in patients with GO. These changes result from abnormal hyaluronic acid accumulation and edema within these tissues and expanded volume of the orbital adipose tissues. Recent studies have suggested that the increase in orbital fat volume is caused by stimulation of adipogenesis within these tissues. The orbital fibroblast appears to be the major target cell of the autoimmune process in GO. A subset of these cells is capable of producing hyaluronic acid and differentiating into mature adipocytes, given appropriate stimulation. In addition, orbital fibroblasts from patients with GO have been shown to display immunoregulatory molecules and to express both thyrotropin receptors (TSHRs) and insulin-like growth factor 1 receptors (IGF-1Rs). Increased TSHR expression in the GO orbit appears to be the result of stimulated adipocyte differentiation. The activation of IGF-1R on orbital fibroblasts by immunoglobulins from GO patients results in increased production of both hyaluronic acid and molecules that stimulate the infiltration of activated T cells into areas of inflammation.

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Detection of TSH Receptor RNA in Cultured Fibroblasts from Patients with Graves' Ophthalmopathy and Pretibial Dermopathy

Cited by 163 publications

References 17 publications

TSH stimulates adipogenesis in mouse embryonic stem cells

TSH stimulates adipogenesis in mouse embryonic stem cells

Evidence for protein and mRNA TSHr expression in fibroblasts from patients with thyroid-associated ophthalmopathy (TAO) after adipocytic differentiation

Pathogenesis of Graves Ophthalmopathy: Implications for Prediction, Prevention, and Treatment

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