Extrathyroidal expression of TSH receptor

Annales d’Endocrinologie 72 (2011) 68–73

Journées Klotz 2011

Extrathyroidal expression of TSH receptor Expression thyroïdienne du récepteur de TSH G.R. Williams Molecular Endocrinology Group, Room 7Na, 7th Floor Commonwealth Building, Hammersmith Hospital, Du Cane Road, W12 0NN London, United Kingdom Available online 20 April 2011

Résumé Le récepteur de TSH s’exprime à la surface des cellules folliculaires de la thyroïde et possèdent un rôle crucial dans la régulation de la fonction et de la croissance de la glande thyroïde. Ces dernières années, il est apparu évident que le récepteur de la TSH est aussi exprimé largement dans une variété de tissus extrathyroïdiens incluant l’antéhypophyse, l’hypothalamus, l’ovaire, le testicule, la peau, le rein, le système immun, la moelle osseuse et les cellules sanguines circulantes, le tissu adipeux blanc et brun, les fibroblastes orbitaires préadipocytaires, et l’os. Un grand nombre de preuves émergent démontrant le rôle fonctionnel du récepteur de TSH à ces différents sites, même si en plusieurs circonstances leur importance physiologique constitue un sujet de controverses et d’intérêt. La compréhension actuelle des actions du récepteur de TSH dans le tissu extrathyroïdien et de leurs possibles implications physiologiques est ici discutée. © 2011 Elsevier Masson SAS. Tous droits réservés. Mots clés : TSH ; Récepteur de TSH ; Thyrostimuline ; Extrathyroïdien

Abstract The TSH receptor expressed on the cell surface of thyroid follicular cells plays a pivotal role in the regulation of thyroid status and growth of the thyroid gland. In recent years it has become evident that the TSH receptor is also expressed widely in a variety of extrathyroidal tissues including: anterior pituitary; hypothalamus; ovary; testis; skin; kidney; immune system; bone marrow and peripheral blood cells; white and brown adipose tissue; orbital preadipocyte fibroblasts and bone. A large body of evidence is emerging to describe the functional roles of the TSH receptor at these various sites but their physiological importance in many cases remains a subject of controversy and much interest. Current understanding of the actions of the TSH receptor in extrathyroidal tissues and their possible physiological implications is discussed. © 2011 Elsevier Masson SAS. All rights reserved. Keywords: Thyroid stimulating hormone; TSH; TSH receptor; Thyrostimulin; Extra-thyroidal

1. Introduction The thyroid stimulating hormone (TSH) receptor (TSHR) is a 7-transmembrane domain G protein-coupled receptor expressed at high levels in thyroid follicular cells. Binding of TSH to the TSHR principally activates cAMP signaling and results in increased iodide uptake, thyroid hormone synthesis and secretion, and proliferation and growth of thyroid follicular cells [1,2]. These responses mediate an important role for the TSHR in maintenance of thyroid status by the hypothalamic-pituitarythyroid (HPT) axis, which maintains thyroid hormones and TSH

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in a reciprocal relationship. Despite these well-established physiological actions that control thyroid follicular cell growth and thyroid hormone production, it is now recognized that the TSHR is also expressed widely in extrathyroidal tissues. 2. Anterior pituitary Gland In the anterior pituitary gland, TSHR expression has been identified in folliculo-stellate cells and postulated to mediate short paracrine feedback inhibition of TSH secretion from anterior pituitary thyrotrophs [3,4]. This activity of the TSHR in folliculo-stellate cells may further contribute to control of thyroid status by the HPT axis. Intriguingly, a novel high affinity ligand for the TSHR was also identified recently. Thyrostim-

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ulin is a glycoprotein hormone, comprised of ␣ and ␤-subunits encoded by GPA2 and GPB5, which stimulates cAMP production after binding the TSHR [5]. It is expressed in the anterior pituitary and hypothalamus and, although its physiological role is unclear, thyrostimulin may also be involved in paracrine regulation of TSH signaling via local actions mediated by TSHR expressed in the pituitary [5–7]. 3. Hypothalamus The TSHR also has unexpected but important actions in the regulation of seasonal reproduction. The changing seasons are critical for animals living in temperate zones and for migratory birds, in which reproduction must be controlled according to seasonal variations in the day-night photoperiod. Sensing of the photoperiod and subsequent control of gonadal growth by light-induced leutinizing hormone (LH) secretion is localized in the mediobasal hypothalamus. Detailed studies in the Japanese quail (Coturnix japonica) have shown the photoperiod response is triggered by light-induced expression of TSH in the pars tuberalis [8]. TSH from the pars tuberalis activates a TSHRcAMP mediated pathway in ependymal cells of the mediobasal hypothalamus that involves the type 2 iodothyronine deiodinase enzyme and results in LH secretion and gonadal growth [9]. In mammals the photoperiod response is initiated by melatonin but is otherwise conserved and also involves TSH, TSHR and the type 2 iodothyronine deiodinase. Thus, seasonal reproduction in mammals and birds is controlled by conserved mechanisms that involve activation of the TSHR in the mediobasal hypothalamus [10,11]. 4. Gonads Further studies in the European sea bass (Dicentrarchus labrax) indicate that seasonal effects of TSH on gonadal growth may also be mediated directly by the TSHR expressed in ovary and testis [12]. Seasonal alterations in TSHR mRNA expression were identified associated with seasonal changes in gametogenesis and gonadal maturation, indicating a possible direct role for TSHR in the ovary and testis. Intriguingly, recent studies in the rat also identified TSHR expression in the ovary. In these studies TSHR mRNA was regulated positively by gonadotrophins and negatively by oestrogen in granulosa cells [13]. Expression of the thyrostimulin subunits Gpa2 and Gpb5 was also identified in developing oocytes, and studies with a TSHR-expressing human ovarian cell line treated with recombinant thyrostimulin demonstrated increased cAMP activity in the presence of follicle stimulating hormone. These findings were interpreted to suggest the presence of a local paracrine signaling pathway in the ovary that is regulated by FSH and oestrogen and which involves thyrostimulin secreted from the developing oocyte acting at the TSHR expressed on granulosa cells [13]. 5. Epidermis and hair follicles Additional studies outside the central nervous and reproductive systems suggest further diverse roles for the TSHR and

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HPT axis. Components of the axis including thyrotrophin releasing hormone (TRH), TRH receptor, TSH, thyrostimulin and the TSHR are expressed in cells of the skin epidermis and in hair follicles [14–17]. Treatment of organ cultures with TSH resulted in altered hair follicle gene expression and stimulation of epidermal cell differentiation, whilst treatment with TRH stimulated hair growth [16,17]. Furthermore, skin was found to synthesize a local supply of TSH that was regulated by TRH and thyroid hormones in a way that is analogous to feedback control of the classical HPT axis [15]. The physiological importance of these findings, however, will require further study as detection of HPT axis components in the skin and hair follicle requires highly sensitive RT-PCR and immunodetection techniques. Nevertheless, the intriguing possibility of a functional local HPT axis in the skin is an emerging avenue of research. 6. Kidney Demonstration of TSH expression by ribonuclease protection and immunohistochemistry has also been demonstrated in normal human kidney and adrenal tissue [18]. Additional studies confirmed TSHR expression in the kidney by RT-PCR. Furthermore, treatment of primary human kidney cells with TSH resulted in increased cAMP production, suggesting the TSHR may be functional in renal cells [19], although more extensive studies will be necessary to investigate the implications of this work. 7. Immune system and circulating blood A body of evidence is now accumulating in support of a role for TSHR expression and signaling in bone marrow, thymus, peripheral blood and immune cells, tissue T lymphocytes and dendritic cells [18,20–26]. In the bone marrow, immature CD45-positive leukocyte precursors synthesize and secrete TSH whilst cluster of differentiation molecule 11b (CD11b) negative lymphocyte precursor cells secrete tumour necrosis factor-␣ (TNF-␣) in response to TSH, suggesting a local paracrine TSH-TSHR signaling pathway that regulates haematopoietic responses to TNF-␣ [20]. More recent studies indicate that TSH also inhibits cytokine-induced TNF-␣ production from CD11bpositive bone marrow cells via a pathway involving activation of the activator protein-1 (AP-1) and nuclear factor kappa-lightchain-enhancer of activated B-cells (NF␬B) transcription factors [21]. Thus, the role of TSHR signaling in bone marrow is complex with opposing effects on TNF-␣ secretion observed in different stromal cell subsets. In addition to the suggested effects of TSH-stimulated TNF-␣ production on haematopoiesis, the effect of TSH to inhibit TNF-␣ production from CD11b-positive cells has been proposed to inhibit osteoclast formation and bone resorption [21]. In peripheral blood the TSHR is expressed on erythrocytes where it may influence activity of the Na(+)/K(+)-ATPase [22], and on lymphocytes where its effects are less clear [23,24]. In the intestinal epithelium the TSHR receptor is expressed on intraepithelial lymphocytes and local production of TSH by intestinal epithelial cells regulates recruitment, development and

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immunoregulatory functions of a specific subset of intraepithelial tissue lymphocytes [25,26]. Further detailed studies using immunoprecipitation and flow cytometry techniques have also identified high levels of TSHR expression in a distinct fraction of adult dendritic cells (CD45RBhigh ) purified from lymph node T cells. TSH stimulation of these cells resulted in increased phagocytic activity with enhanced cytokine responses following activation of phagocytosis [27].

role for the TSHR in brown fat. Hyt/hyt mice received TSHR gene transfer into brown adipose tissue and displayed some protection from cold-induced hypothermia, suggesting a role for the TSHR in thermogenesis [39]. These preliminary studies suggest a functional role for TSHR in brown adipose tissue but further more physiological studies will be required to confirm this and elucidate its possible importance. 10. Orbital preadipocyte fibroblasts

8. White adipose tissue There is similar accumulating evidence of a role for the TSHR in adipocytes. TSHR expression in preadipocytes and differentiated adipocytes was demonstrated in early studies in which TSH treatment resulted in increased cAMP production [28,29]. Levels of TSHR mRNA expression were related to the stage of adipocyte differentiation suggesting a role for TSH in adipogenesis [28,29], although this hypothesis was controversial [30]. Subsequent studies suggested roles for TSHR in preadipocyte cell survival via a mechanism independent of cAMP signaling [31], in the stimulation of interleukin-6 (IL-6) release from omental and subcutaneous fat cells [32], and in the direct stimulation of adipogenesis via a cAMP-dependent pathway [33]. The diversity of these studies may reflect different adipocyte cell models studied between laboratories, but they also highlight the need for further studies to clarify the range of TSHR actions in adipocytes and their physiological importance. Recently, Elgadi et al. have taken an in vivo approach to investigate TSHR function in white adipose tissue by deleting the TSHR in adipocytes using a Cre-lox gene targeting approach [34]. Floxed Tshr mice were generated and crossed with Fabp4-Cre mice expressing Cre-recombinase under control of the fatty acid binding protein 4 promoter [35]. Mice lacking TSHR in adipocytes displayed reduced responsiveness to TSH-induced lipolysis and had larger adipocytes. The findings were interpreted to indicate the TSHR is a physiological regulator of adipocyte growth and development [34]. However, other studies have shown that in Fabp4-Cre mice Cre-recombinase is also expressed in brown fat as well as white adipose tissue and in various regions of the brain, peripheral nervous system, developing cartilage and vertebrae [36,37]. Ectopic expression of Cre-recombinase in tissues that influence adipose tissue development and function thus potentially confounds interpretation of the metabolic phenotype of floxed Tshr mice crossed with Fabp4-Cre mice [34]. Even though the role of TSHR in adipose tissue remains unclear at present, the generation of floxed Tshr mice [34] represents an important advance to investigate the physiological actions of TSHR in adipose tissue when adipocyte-selective Cre-expressing mice are available. 9. Brown adipose tissue In addition to white adipose tissue, the TSHR is expressed in brown adipocytes. Stimulation of brown adipocytes with TSH resulted in increased cAMP activity, reduced Tshr mRNA expression and increased expression of the type 2 iodothyronine deiodinase and uncoupling protein-1 (UCP-1) [38]. Studies in hyt/hyt mice, which lack a functional TSHR, also supported a

In addition to white and brown adipose tissues, the TSHR is also expressed in orbital preadipocyte fibroblasts, where it is proposed to act as an autoantigen in the pathogenesis of Graves’ ophthalmopathy [40–47]. Initial studies identified TSHR mRNA expression and immunoreactivity in orbital preadipocytes and fibroblasts from Graves’ ophthalmopathy patients [40] and showed increased expression of functional TSHR in differentiating human orbital preadipocyte fibroblasts [41]. Stimulation of orbital preadipocytes with TSH resulted in increased cAMP activity and activation of the p70 S6 serine/threonine kinase [41,42]. Subsequent studies identified that IL-6 and roziglitazone, a peroxisome proliferator activated receptor-␥ (PPAR␥) ligand, increased TSHR expression in orbital preadipocytes, thus implicating IL-6 and PPAR␥ signaling in the pathogenesis of Graves’ ophthalmopathy [43,44]. Studies in differentiating Graves’ orbital adipocytes demonstrated increased expression of a TSH-responsive functional TSHR in differentiated adipocytes that was also activated or inhibited by stimulatory or inhibitory TSHR antibodies, respectively [45]. Recent studies in differentiated Graves’ orbital fibroblasts indicate that treatment with TSHR stimulating antibodies results in an increased accumulation of hyaluronans via a mechanism that appears to be largely independent of cAMP signaling, thus suggesting the possibility of tissue-specific activity of the TSHR [46]. Another recent study further supports a direct role for TSHR stimulating antibodies in Graves’ orbital peradipocytes, which act at the TSHR to stimulate expression and secretion of IL-6 and may play a role in modulating activity of Graves’ disease [47]. Taken together, there is now broad evidence in support a role for the TSHR in orbital peradipocyte fibroblasts and adipocytes in the pathogenesis of Graves’ ophthalmopathy. Additional effects on the regulation of orbital preadipocyte differentiation, however, will require further studies to demonstrate direct causative actions of the TSHR. 11. Bone Recently, TSH was controversially proposed to act directly in bone cells and inhibit bone turnover and remodeling [48]. Tshr knockout mice displayed a high bone turnover osteoporotic phenotype and expression of the TSHR was demonstrated both in bone-forming osteoblasts and bone-resorbing osteoclasts. In cell culture studies TSH inhibited activities of both osteoblasts and osteoclasts via cAMP-independent pathways. These studies led to the proposal that bone loss in thyrotoxicosis results from absent inhibitory actions of TSH on the skeleton in contrast to thyroid hormone excess [48]. Further studies, however, have

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been conflicting as TSH has also been shown to stimulate [49,50] or have no effect [51] on osteoblast differentiation, whilst TSH effects on osteoclasts were either inhibitory [49,50] or absent [51]. Detailed analysis of the TSHR expressed in osteoblasts and osteoclasts subsequently revealed that receptor expression is very low compared to thyroid follicular cells and that TSH treatment does not stimulate cAMP activity [21,51,52]. Nevertheless, TSH treatment does influence TNF-␣, AP-1 and NF␬B signaling in bone, suggesting that in skeletal cells the TSHR may be coupled to an alternative G-protein other than Gs␣ through which it activates cAMP. In vivo studies of the effects of intermittent administration of low doses of TSH to ovariectomized rodents demonstrated that TSH elicited antiresorptive and anabolic responses that resulted in prevention of estrogen-induced bone loss [49,50]. To investigate the possible role of the TSHR in bone further, the skeletal phenotypes of congenitally hypothyroid hyt/hyt and Pax8 knockout mice were compared [51]. Hyt/hyt mice carry a non functional mutation in the Tshr gene, whereas Pax8 knockout mice have a deletion of the thyroid specific transcription factor Pax8 and congenital hypothyroidism results from thyroid agenesis. Both hyt/hyt and Pax8 knockout mice have grossly elevated circulating levels of TSH but differ because hyt/hyt mice have a non-functional TSHR whereas in Pax8 knockout mice the TSHR functions normally. The skeletal phenotypes of both mice during development and growth were indistinguishable, thus indicating that the consequences of hypothyroidism in bone during growth are independent of TSH signaling and result from thyroid hormone deficiency [51]. Studies in thyroid hormone receptor knockout and mutant mice further suggest that skeletal responses to thyrotoxicosis principally result from thyroid hormone excess and not TSH deficiency [53,54]. The role of TSH in the skeleton, therefore, remains unclear and it continues to be uncertain whether the TSHR is expressed in bone cells at physiologically important levels. Numerous clinical studies investigating osteoporosis and fracture in relation to altered thyroid status have also been conflicting regarding whether bone loss in thyrotoxicosis results from thyroid hormone excess or TSH deficiency [55]. In individuals and animal models in which the HPT axis is intact, and maintains a reciprocal physiological relationship between thyroid hormones and TSH, this continues to be a difficult question to resolve [56]. Interpretations of clinical studies focus either on TSH deficiency or thyroid hormone excess as the underlying cause of bone loss in hyperthyroidism, but either standpoint fails to account for the inverse relationship between thyroid hormones and TSH maintained by the HPT axis [56]. A recent large prospective European population study of healthy euthyroid post-menopausal women showed that bone mineral density (BMD) and fracture susceptibility are related to variations in normal thyroid status [57]. Thus, thyroid status at the upper end of the normal range in healthy post-menopausal women was associated with lower BMD and an increased risk of non-vertebral fracture. Importantly, even though correlations between BMD and fracture were only evident in relation to changes in thyroid hormone rather than TSH levels, these findings are best interpreted to reflect thyroid sta-

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tus as a whole instead of focusing on the relative importance of thyroid hormone or TSH action in bone [57]. 12. Conclusion The possibility that the TSHR has diverse functions in a variety of extrathyroidal tissues has attracted considerable interest and is a subject of controversy. It has been difficult to establish the physiological relevance of TSHR expression outside the thyroid gland for several reasons. Most importantly, the normal reciprocal relationship between circulating concentrations of TSH and thyroid hormones make it difficult to distinguish the relative actions of TSH deficiency and thyroid hormone excess, or vice versa, and thus confound interpretation of in vivo and clinical studies [56]. Several studies have tried to circumvent this by investigating mice with global disruption of thyroid hormone receptor or Tshr genes but these studies are complicated by the necessity to correct perturbations of thyroid status due to the gene disruption. Furthermore, the thyroid hormone and TSH receptors are co-expressed in many peripheral tissues, often at very low levels, and this makes it particularly difficult to distinguish opposing responses to thyroid hormones or TSH and ascribe function confidently. A further complexity is the potential for local production of TSH or thyrostimulin in several extra-thyroidal tissues, thus providing additional problems in determining whether TSHR actions reflect systemic or paracrine responses. Progress in understanding of the cell- and tissue-specific actions of the TSHR has thus been problematic, but the recent generation of floxed Tshr mice [34] represents an important advance. Tshr floxed mice provide the opportunity to study in vivo tissue-specific actions of TSH in isolation from systemic disruption of thyroid status. Experiments can theoretically be performed to investigate any putative TSH target tissue providing specific Cre-recombinase expressing mice are available. Specificity, however, is the key proviso [36,37] and such studies will need to be performed rigorously to obtain clear and definitive conclusions. Nevertheless, the field of TSHR action in extrathyroidal tissues is one of controversy and interest that is sure to become even more fascinating in the coming years. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] De Felice M, Di Lauro R. Thyroid development and its disorders: genetics and molecular mechanisms. Endocr Rev 2004;25:722–46. [2] Rapoport B, Chazenbalk GD, Jaume JC, McLachlan SM. The thyrotropin (TSH)-releasing hormone receptor: interaction with TSH and autoantibodies. Endocr Rev 1998;19:673–716. [3] Prummel MF, Brokken LJ, Meduri G, Misrahi M, Bakker O, Wiersinga WM. Expression of the thyroid-stimulating hormone receptor in the folliculo-stellate cells of the human anterior pituitary. J Clin Endocrinol Metab 2000;85:4347–53. [4] Prummel MF, Brokken LJ, Wiersinga WM. Ultra short-loop feedback control of thyrotropin secretion. Thyroid 2004;14:825–9.

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