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
E-mail address: graham.williams@imperial.ac.uk
0003-4266/$ – see front matter © 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ando.2011.03.006
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-
G.R. Williams / Annales d’Endocrinologie 72 (2011) 68–73
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
69
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
G.R. Williams / Annales d’Endocrinologie 72 (2011) 68–73
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-
71
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.
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