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Journal of Molecular Endocrinology (2009) 42 269-282    DOI: 10.1677/JME-08-0142
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Review

The skeletal phenotypes of TR{alpha} and TRβ mutant mice

 J H Duncan Bassett and Graham R Williams

Molecular Endocrinology Group, Division of Medicine, Imperial College London, MRC Clinical Sciences Centre, Hammersmith Hospital, 5th Floor, Clinical Research Building, Du Cane Road, London W12 0NN, UK

(Correspondence should be addressed to J H D Bassett; Email: d.bassett{at}imperial.ac.uk; G R Williams; Email: graham.williams{at}imperial.ac.uk)


   Abstract
Top
 Abstract
Introduction
 Thyroid hormone receptor mutant...
 Mechanism of T3 action
 Future directions
 Declaration of interest
 Funding
 References
 
Analysis of mice harbouring deletions or mutations of T3 receptor {alpha} (TR{alpha}) and β (TRβ) have clarified the complex relationship between central and peripheral thyroid status and emphasised the essential but contrasting roles of T3 in skeletal development and adult bone. These studies indicate that TR{alpha}1 is the predominant TR expressed in bone and that T3 exerts anabolic actions during growth but catabolic actions in the adult skeleton. Examination of key skeletal regulatory pathways in TR mutant mice has identified GH, IGF-1 and fibroblast growth factor signalling and the Indian hedgehog/parathyroid hormone-related peptide feedback loop as major targets of T3 action in chondrocytes and osteoblasts. Nevertheless, although increased osteoclastic resorption is a major feature of thyrotoxic bone loss and altered osteoclast activity is central to the skeletal phenotype of TR mutant mice, it remains unclear whether T3 has direct actions in osteoclasts. Detailed future analysis of the molecular mechanisms of T3 action in bone will enhance our understanding of this emerging field and has the potential to identify novel strategies for the prevention and treatment of osteoporosis.


   Introduction
Top
 Abstract
 Introduction
Thyroid hormone receptor mutant...
 Mechanism of T3 action
 Future directions
 Declaration of interest
 Funding
 References
 
Thyroid hormone is essential for normal skeletal development and the maintenance of adult bone mass. Recent studies of T3 receptor (TR) mutant mice have advanced our understanding and demonstrated the relevance of this field to osteoporosis, a major public health burden that affects half of all women and one-fifth of men over the age of 50, costing the European community {euro}31 billion per annum (Kanis & Johnell 2005).

Systemic thyroid hormone levels are maintained by the hypothalamus–pituitary–thyroid (HPT) feedback axis. The cellular actions of 3,5,3'-L-triiodothyronine (T3) are mediated by TRs, which act as hormone-inducible transcription factors. Unliganded TRs bind T3 response elements (TREs) in T3-target genes and mediate transcriptional repression. T3 binding results in derepression and activation of gene transcription (Yen 2001). The THRA and THRB genes encode three functional receptors TR{alpha}1, TRβ1 and TRβ2 as well as a non-T3-binding isoform of unknown function TR{alpha}2 (Fig. 1). TR{alpha}1 and TRβ1 are expressed widely and the ratio of TR{alpha}1 to TRβ1 is spatio-temporally regulated. Thus, T3-target tissues may predominantly display either TR{alpha}1 or TRβ1 responsiveness or show no TR-isoform specificity. TRβ2 has a more restricted pattern of expression and regulates sensory organ development (Jones et al. 2007) as well as the HPT axis. In the skeleton, chondrocyte and osteoblast lineages express TR{alpha} and TRβ mRNAs, but in osteoclasts the position is less clear as studies have been restricted to precursor cells or in situ hybridisation analysis of osteoclastomas (Williams et al. 1994, Abu et al. 2000, Stevens et al. 2000, Kanatani et al. 2004). Several studies have demonstrated apparent expression of TR proteins in all bone cell lineages, but it is well recognised within the field that available TR antibodies are of low affinity, thus compromising the detection of endogenous TRs (Abu et al. 1997, Robson et al. 2000). For these reasons, a comprehensive understanding of TR expression in bone is lacking and a detailed analysis of cell-specific and temporal expression of TR isoforms is required.


Figure 1
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  		Figure 1 Thyroid hormone receptor isoforms. (A) Schematic of the four functional domains of the thyroid hormone receptor. (B) Products of the Thra and Thrb genes in the mouse. Thra has two promoters, TR{alpha}1 and TR{alpha}2 are derived from the 5' promoter whereas TR{Delta}{alpha}1 and TR{Delta}{alpha}2 are transcribed from an internal promoter in intron 7. TR{alpha}2 and TR{Delta}{alpha}2 result from alternative splicing. TR{alpha}1 is a functional receptor whereas TR{Delta}{alpha}1, TR{alpha}2 and TR{Delta}{alpha}2 do not bind T3 and act as antagonists. Thrb also has two promoters and both N-terminal variants TRβ1 and TRβ2 bind T3 and act as functional receptors.

 
Long bones are formed by endochondral ossification and the skull by intramembranous ossification. During endochondral ossification, mesenchyme-derived chondrocytes form a cartilage model, undergo hypertrophic differentiation and then apoptose. The surrounding collagen X-rich cartilage matrix calcifies and forms a scaffold for bone formation by osteoblasts. Organised columns of proliferating and differentiating chondrocytes persist in the growth plate until adolescence and mediate linear growth and the acquisition of peak bone mass. By contrast, in intramembranous ossification, osteoblasts differentiate from mesenchyme to form bone directly. Adult bone structure and mechanical strength are preserved by a continuous process of skeletal remodelling during which precise coupling of osteoclastic bone resorption and subsequent osteoblastic bone formation is maintained.

The established view that skeletal responses to abnormal thyroid status result exclusively from altered T3 action in bone has been challenged recently by studies proposing a direct role for TSH in bone. We recently discussed this issue elsewhere (Bassett & Williams 2008) and the present review will therefore focus on the analysis of T3 and TR action in bone.


   Thyroid hormone receptor mutant mice
Top
 Abstract
 Introduction
 Thyroid hormone receptor mutant...
Mechanism of T3 action
 Future directions
 Declaration of interest
 Funding
 References
 
Several TR{alpha} knockout mice have been generated and this led to the identification of additional TR{alpha} isoforms expressed from a promoter within intron 7 of the Thra gene (Chassande et al. 1997). As a result only TR{alpha}0/0 mice lack all TR{alpha} isoforms whereas other TR{alpha} mutants retain truncated isoforms with dominant-negative activity (Fig. 1 and Table 1). This review will focus on mice lacking all TR{alpha} (TR{alpha}0/0) or all TRβ (TRβ–/–) isoforms and those harbouring dominant-negative mutations of either TR{alpha} (TR{alpha}1PV/+, TR{alpha}1R384C/+) or TRβ (TRβPV/PV).


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  		Table 1 Skeletal phenotypes of TH receptor mutant mice

 
Thyroid hormone actions during skeletal development are anabolic

The developing skeleton is exquisitely sensitive to thyroid status and childhood hypothyroidism is characterised by growth retardation, delayed bone age and short stature, whereas juvenile thyrotoxicosis accelerates growth and advances bone age but results in short stature due to premature fusion of the epiphyses (Rivkees et al. 1988, Boersma et al. 1996, Segni & Gorman 2001).

Although TR{alpha}0/0 mice are systemically euthyroid, juveniles display post-natal growth retardation with delayed endochondral ossification characterised by impaired chondrocyte differentiation and decreased mineral deposition (Bassett et al. 2007b). TR{alpha}1R384C/+ mice, which harbour a dominant-negative mutation of TR{alpha}, are also euthyroid. They display a similar period of growth retardation and delayed endochondral ossification, but additionally have reduced cortical bone thickness, abnormal cortical bone remodelling and impairment of intramembranous ossification (Fig. 2; Bassett et al. 2007a). TR{alpha}1PV/+ mice, which express a potent dominant-negative TR{alpha} mutant, display a more severe skeletal phenotype. TR{alpha}1PV/+ mice have persistent post-natal growth retardation, markedly delayed endochondral ossification, decreased mineralisation, reduced cortical bone thickness and impaired intramembranous ossification (O'Shea et al. 2005). Similar findings have been reported in mice expressing the potent dominant-negative receptor TR{alpha}1L400R (Quignodon et al. 2007). Consistent with the delayed bone development in juvenile TR{alpha}0/0, TR{alpha}1R384C/+ and TR{alpha}1PV/+ mice, skeletal expression of the T3-target genes, fibroblast growth factor receptors 1 and 3 (FGFR1/3; Stevens et al. 2003, Barnard et al. 2005, O'Shea et al. 2007) were reduced (Barnard et al. 2005, O'Shea et al. 2005, Bassett et al. 2007a,b). Deletion or mutation of TR{alpha} does not affect systemic thyroid status but causes local skeletal hypothyroidism while the presence of a dominant-negative TR{alpha} leads to a more severe skeletal phenotype than receptor deficiency alone.


Figure 2
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  		Figure 2 Skeletal development and growth in TR mutant mice. (A) Skull vaults from P1 mutant mice and littermate controls stained with alizarin red (bone) and alcian blue (cartilage) showing sutures and anterior and posterior fontanelles. Arrows indicate delayed intramembranous ossification in TR{alpha}1PV/+ and TR{alpha}1R384C/+ mice and advanced ossification in TRβ–/– and TRβPV/PV mice. Note that two TRβ–/– strains in different genetic backgrounds were analysed TRβ–/–(a) (Gauthier et al. 2001, Bassett et al. 2007b) and TRβ–/–(b) (Forrest et al. 1996, Ng et al. 2001, Bassett et al. 2007a). Scale bar, 1mm. (B) Graphs of longitudinal growth in mutant mice and littermate controls; *P<0.05; **P<0.01; ***P<0.001 mean tibia/ulna length in mutant versus control; two-tailed Students's t-test.

 
Two TRβ–/– strains have been generated in different genetic backgrounds and both show similar skeletal phenotypes (Table 1; Forrest et al. 1996, Gauthier et al. 1999). Deletion of TRβ results in elevated circulating TSH, T4 and T3 levels consistent with resistance to thyroid hormone (RTH). In contrast to TR{alpha} mutants, juvenile TRβ–/– mice display advanced endochondral ossification, accelerated chondrocyte differentiation, increased mineral deposition and persistent short stature due to premature growth plate quiescence. Furthermore, cortical thickness is increased and intramembranous ossification advanced in TRβ–/– mice (Fig. 2; Bassett et al. 2007b). TRβPV/PV mice express a potent dominant-negative TRβ and display severe RTH with a 400-fold elevation of TSH and 15-fold elevation of T4. TRβPV/PV animals exhibit a more severe phenotype than TRβ–/– mice with accelerated intrauterine growth characterised by advanced endochondral and intramembranous ossification. Premature ossification results in persistent post-natal growth retardation, premature growth plate quiescence, increased mineral deposition and craniosynostosis (O'Shea et al. 2003). Consistent with advanced skeletal development in TRβ–/– and TRβPV/PV mice, expression of the T3-target genes Fgfr1 and Fgfr3 was increased (O'Shea et al. 2003, Barnard et al. 2005, Bassett et al. 2007a,b). Thus, deletion or mutation of TRβ disrupts the HPT axis resulting in increased circulating thyroid hormone levels and skeletal thyrotoxicosis. The presence of a dominant-negative TRβ leads to a greater elevation of systemic thyroid hormone concentration and a more severe skeletal phenotype than receptor deficiency alone.

In the developing skeleton, reduced T3 action in TR{alpha} mutant mice results in delayed ossification and reduced mineralisation whereas increased T3 action in TRβ mutant mice leads to advanced ossification and increased mineralisation. Thus, during growth, T3 actions in bone are anabolic.

Thyroid hormone actions in adult bone are catabolic

Adult thyrotoxicosis results in both increased bone resorption and formation, but uncoupling of these processes favours osteoclastic resorption and leads to a 10% net bone loss per remodelling cycle (Mosekilde et al. 1990). Consequently, thyrotoxicosis is an important cause of secondary osteoporotic fracture (Mosekilde et al. 1990, Cummings et al. 1995, Franklyn et al. 1998, Vestergaard et al. 2000, Vestergaard & Mosekilde 2002, Murphy & Williams 2004) and even subclinical hyperthyroidism has been associated with decreased bone mineral density and increased fracture risk in postmenopausal women (Bauer et al. 2001, Quan et al. 2002, Murphy & Williams 2004, Heemstra et al. 2006, Kim et al. 2006, Morris 2007).

Remarkably, delayed ossification and reduced mineralisation in juvenile TR{alpha}0/0 mice were accompanied by greatly increased trabecular bone mass in adults (Fig. 3; Bassett et al. 2007b). Moreover, the robust and plate-like trabeculae contained highly mineralised calcified cartilage indicating a trabecular bone remodelling defect. Consistent with such a defect, TR{alpha}0/0 mice displayed reduced osteoclast numbers and activity (Bassett et al. 2007b). Trabecular bone mass increased progressively with age in TR{alpha}1R384C/+ mice with adults showing osteosclerosis (Bassett et al. 2007a). Consistent with a remodelling defect, trabeculae were of increased thickness and connectivity, showed increased mineralisation with extensive retention of calcified cartilage and reduced osteoclast numbers and activity (Fig. 4). Remarkably, brief T3 supplementation during growth, sufficient to overcome transcriptional repression by TR{alpha}1R384C, ameliorated the adult skeletal phenotype (Bassett et al. 2007a; Table 1). These data indicate that during development even transient relief from the transcriptional repression mediated by unliganded TR{alpha}1 (apo-TR{alpha}1) has long-term consequences for adult bone structure and mineralisation. Thus, in the adult skeleton, deletion or mutation of TR{alpha} results in persistently impaired bone remodelling. Similarly, the presence of a dominant-negative TR{alpha} leads to a more severe skeletal phenotype than receptor deficiency alone.


Figure 3
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  		Figure 3 Trabecular bone micro-architecture in adult TR mutant mice. (A) Backscattered electron scanning electron microscopy (BSE-SEM) views showing trabecular bone in thyrotoxic wild-type (WT) mice treated with daily sc injections of T3 (30 ng T3/gram body weight) and congenitally hypothyroid Pax8–/– mice. (B) Animals lacking either TR{alpha} or TRβ and (C) mice harbouring a dominant-negative mutation of TR{alpha} (R384C). Scale bar, 200 µm.

 

Figure 4
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  		Figure 4 Trabecular bone micro-mineralisation in adult TR mutant mice. Quantitative backscattered electron scanning electron microscopy (qBSE-SEM) images showing mineralisation densities of trabecular bone from mice lacking TRβ and mice harbouring a dominant-negative mutation of TR{alpha} (R384C) (A). Mineralisation densities were derived from halogenated standards and images pseudo-coloured according to the palette shown in which high mineralisation density is grey. (B) Relative and cumulative frequency histograms of bone micro-mineralisation densities are shown. Black arrow indicates the increased relative frequency of high mineralisation densities that correspond to retained calcified cartilage in TR{alpha}1R384C/+ mice. (C) Higher power views of trabecular bone are shown. Dashed white arrows indicate normal bone cement lines. Solid white arrows indicate retained calcified cartilage within which the outlines of chondrocyte lacunae remain evident. Scale bar 200 µm in all panels. ***P<0.001 micro-mineralisation density in mutant versus WT; Kolmogorov–Smirnov test.

 
Despite a juvenile phenotype of accelerated growth and increased ossification, adult TRβ–/– mice became progressively osteoporotic (Fig. 3; Bassett et al. 2007a). Two TRβ–/– strains in different genetic backgrounds were analysed (Gauthier et al. 2001, Bassett et al. 2007b). In one strain, cortical and trabecular bone mineralisation were both reduced and osteoclast numbers and activity increased (Bassett et al. 2007a,b). However, in the other strain, only trabecular bone mineralisation was affected but this was also accompanied by an increase in osteoclast numbers and activity (Bassett et al. 2007a; Fig. 4). Thus, in the adult skeleton, deletion of TRβ results in accelerated remodelling and bone loss although the severity may depend on genetic background.

In the adult skeleton reduced T3 action in TR{alpha} mutant mice results in osteosclerosis whereas increased T3 action in TRβ mutant mice leads to osteoporosis. Thus, the actions of T3 are catabolic in adult bone.


   Mechanism of T3 action
Top
 Abstract
 Introduction
 Thyroid hormone receptor mutant...
 Mechanism of T3 action
Future directions
 Declaration of interest
 Funding
 References
 
The opposing skeletal phenotypes in TR{alpha} and TRβ mutant mice provide compelling evidence for the complex interaction between central and peripheral thyroid status (Fig. 5). Thus, delayed ossification and impaired bone remodelling in TR{alpha} mutant mice are secondary to the disruption of T3 action in bone, whereas advanced skeletal development and osteoporosis in TRβ mutant mice are due to disruption of the HPT axis, elevated systemic thyroid hormone levels and local supraphysiological stimulation of TR{alpha} in bone (O'Shea et al. 2006). This model is supported by T3-target gene expression in skeletal cells of TR mutant mice and by the demonstration of higher levels of TR{alpha} mRNA expression in bone compared with TRβ (O'Shea et al. 2003, 2005, Barnard et al. 2005, Bookout et al. 2006, Bassett et al. 2007a,b). Nevertheless, it is apparent that TR{alpha}0/0 TRβ–/– mice have a more severe skeletal phenotype than TR{alpha}0/0 mice, while TR{alpha}0/0 mice also remain sensitive to T4 treatment, thus suggesting a residual role for TRβ in skeletal cells. In this context, quantitative RT-PCR analysis has shown that TR{alpha} expression is 10- to 100-fold greater than TRβ expression in adult whole bone (O'Shea et al. 2003, Bookout et al. 2006). However, since the temporo-spatial patterns of TR{alpha} and TRβ expression in skeletal cells are unknown, a role for TRβ is possible. Furthermore, it is unclear whether individual skeletal cell co-express both TR isoforms or whether their patterns of expression are cell type specific.


Figure 5
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  		Figure 5 Proposed molecular mechanism for TR{alpha} and TRβ mutant mice. The pituitary expresses predominantly TRβ T3 and TRβ act via a negative TRE to repress TSH transcription. The skeleton expresses predominantly TR{alpha}1 and T3 acts via TR{alpha}1 to activate target gene expression. Since the levels of TR{alpha} in the pituitary are low, its absence in TR{alpha}0/0 mice does not disrupt pituitary negative feedback and systemic TSH, T4 and T3 concentrations are normal. By contrast, because TR{alpha} predominates in bone, its absence in TR{alpha}0/0 mice results in impaired T3 responsiveness, skeletal hypothyroidism and reduced expression of T3-target genes. Similarly, in TR{alpha}1PV/+ and TR{alpha}1R384C/+ mice, the levels of the dominant-negative TR{alpha} receptor in the pituitary are insufficient to interfere with TRβ and disrupt TSH repression. However, in bone, the higher concentrations of mutant receptor interfere with the actions of wild-type TR{alpha}1. Thus, T3 responses are severely impaired and the skeleton is hypothyroid. In TRβ–/– mice, by contrast, the absence of TRβ disrupts pituitary T3 responses and impairs TSH repression leading to high circulating TSH, T4 and T3 concentrations. Since TRβ levels are low in bone, T3 responses are unaffected in TRβ–/– mice and high circulating levels of TH act via wild-type TR{alpha}1 to induce skeletal thyrotoxicosis. Similarly in TRβPV/PV mice, the dominant-negative TRβ disrupts TSH repression in the pituitary and results in grossly elevated TSH, T4 and T3 concentrations. The low levels of the mutant receptor in bone are insufficient to interfere with TR{alpha}1 and impair T3 responses and thus high circulating levels of TH increase expression of T3-target genes resulting in severe skeletal thyrotoxicosis.

 
Present understanding is that TR{alpha}1 is functionally predominant in bone.

T3 action in the developing skeleton

In vitro T3 inhibits chondrocyte proliferation and promotes differentiation (Robson et al. 2000, Shao et al. 2006; Fig. 6). Since growth plate architecture and linear growth are frequently disrupted in TR mutant mice, key regulators of endochondral ossification have been investigated as targets of thyroid hormone action.


Figure 6
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  		Figure 6 Role of TH in endochondral ossification and bone remodelling. (A) The role of T3 in the growth plate is illustrated and the pattern of TR expression is shown. Reserve cells undergo clonal expansion to form columns of proliferating chondrocytes that secrete cartilage matrix stained blue in this section. Committed prehypertrophic chondrocytes undergo hypertrophic differentiation, enlarge and subsequently apoptose, the residual mineralised cartilage matrix forming the scaffold for trabecular bone formation. In chondrocyte cultures, T3 inhibits proliferation and increases the expression of cyclin-dependent kinase inhibitors P21cip-1 P27kip-1. T3 stimulates matrix synthesis and expression of the differentiation markers collagen X, alkaline phosphatase (ALP), matrix metalloproteinase 13 (MMP13) and aggrecanase 2. GH/insulin-like growth factor 1 (GH/IGF1), Indian hedgehog/parathyroid hormone-related peptide (Ihh/PTHrP) and fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) pathways are T3 targets. Expression of heparan sulphate proteoglycans (HSPGs), which are essential for FGF and Ihh signalling, is negatively regulated by T3. (B) The role of T3 in the bone remodelling cycle, which is characterised by osteoclastic bone resorption followed by osteoblast migration, osteoid matrix deposition and mineralisation, is shown. Osteoclast differentiation requires direct osteoblast–osteoclast interaction mediated by receptor activator of nuclear factor-{kappa}B (RANK) and its ligand RANKL. Osteoprotegerin (OPG) is a decoy receptor secreted by osteoblasts that antagonises this interaction. Osteoclast differentiation also requires co-stimulation by osteoblast-derived cytokines. Thyroid hormone stimulates osteoblast proliferation, differentiation and apoptosis directly and also indirectly by regulating IGF1 and FGF signalling. It remains uncertain whether osteoclast differentiation is regulated directly by T3 or indirectly via T3 actions in osteoblasts.

 
GH and insulin-like growth factor 1 signalling pathways are thought to act as a point of convergence for many growth promoting factors since more than 80% of somatic growth can be attributable to the actions of the GH/IGF1 axis (Lupu et al. 2001). IGF1 is the major determinant of post-natal growth, it mediates both GH-dependent and -independent effects and is implicated in chondrocyte recruitment, proliferation and hypertrophic differentiation (van der Eerden et al. 2003). Examination of the GH/IGF1 pathway revealed that GH receptor (GHR) and Igf1 receptor (IGF1R) mRNA expression was reduced in growth plate chondrocytes in TR{alpha}0/0 and TR{alpha}1PV/+ mice. Furthermore, phosphorylation of their secondary messengers signal tranducer and activator of transcription 5 (STAT5) and protein kinase B (AKT) was also impaired (O'Shea et al. 2005, Bassett et al. 2007b). By contrast, GHR and IFG1R expression was increased in TRβ–/– and TRβPV/PV mice (O'Shea et al. 2005, Bassett et al. 2007b). Thus, GH/IGF1 signalling is also a local downstream mediator of T3 action in the growth plate (Fig. 6).

FGFs and their receptors have key roles in skeletal development with activating mutations of FGFR3 causing achondroplasia, the commonest form of genetic dwarfism. In the developing growth plate, FGFR3 is expressed in reserve and proliferating chondrocytes and negatively regulates their proliferation and differentiation (Murakami et al. 2004). By contrast, FGFR1 is expressed in prehypertrophic and hypertrophic chondrocytes and its location suggests a role in differentiation, matrix synthesis and apoptosis (Ornitz 2005). FGFR1 is also expressed in the osteoblast lineage with activating mutations result in Pfeiffer craniosynostosis. Investigation of the FGF/FGFR signalling pathway in TR mutant mice demonstrated that Fgfr3 and Fgfr1 expression was reduced in growth plates of TR{alpha}0/0, TR{alpha}1R384C/+ and TR{alpha}1PV/+ mice and Fgfr1 expression was reduced in osteoblasts from TR{alpha}0/0 and Pax8–/– mice (Stevens et al. 2003, Barnard et al. 2005, O'Shea et al. 2005, Bassett et al. 2007a,b, 2008). By contrast, Fgfr3 and Fgfr1 expression was increased in growth plates of TRβ–/– and TRβPV/PV mice and Fgfr1 expression was increased in osteoblasts from TRβPV/PV mice (O'Shea et al. 2003, Barnard et al. 2005, Bassett et al. 2007a,b). Thus, FGF/FGFR signalling is a downstream mediator of T3 action in chondrocytes and osteoblasts (Fig. 6).

The pace of chondrocyte differentiation is precisely regulated by the Indian hedgehog/parathyroid hormone-related peptide paracrine (Ihh/PTHrP) negative feedback loop. Prehypertrophic chondrocytes secrete Ihh which diffuses to periarticular cells to induce synthesis of PTHrP. PTHrP, acting via its receptor PTHR1, then completes the loop by stimulating chondrocyte proliferation and inhibiting further hypertrophic differentiation (Vortkamp et al. 1996, Dentice et al. 2005). Although this pathway has not been studied in TR mutant mice, previous experiments in thyroid-manipulated rats demonstrated increased PTHrP mRNA expression in hypothyroid animals and decreased PTHrP receptor mRNA expression in growth plates of thyrotoxic animals (Stevens et al. 2000). Furthermore, recent studies in chicken tibia explants have shown that Ihh stimulates degradation of the type 2 deiodinase enzyme resulting in an induction of PTHrP expression (Dentice et al. 2005). Together, these findings suggesting that thyroid hormone can inhibit chondrocyte proliferation and promote differentiation by local regulation of the Ihh/PTHrP negative feedback loop (Fig. 6).

T3 is essential for normal cartilage matrix synthesis. Heparan sulphate proteoglycans (HSPGs) are a key matrix component and are essential for functional FGF/FGFR signalling and extracellular diffusion of Ihh. Studies in thyroid manipulated rats and TR{alpha}0/0β–/– and Pax8–/– mice revealed reduced HSPG expression in thyrotoxic animals, increased expression in TR{alpha}0/0β–/–mice and more markedly increased expression in hypothyroid rats and congenitally hypothyroid Pax8–/– mice (Bassett et al. 2008).

These studies suggest T3 coordinately regulates FGF/FGFR and Ihh/PTHrP signalling within the growth plate.

T3 actions in the bone remodelling cycle

In vitro studies suggest that thyroid hormone stimulates osteoblast proliferation, differentiation and apoptosis by direct and indirect actions. Thus, T3 increases synthesis of osteocalcin, type 1 collagen, alkaline phosphatase and matrix metalloproteinases 9 and 13 (Pereira et al. 1999, Huang et al. 2000, Gouveia et al. 2001, Bassett & Williams 2003) and also regulates IGF1, parathyroid hormone (PTH) and FGF signalling (Huang et al. 2000, Gu et al. 2001, Pepene et al. 2001, Bassett & Williams 2003, Stevens et al. 2003, O'Shea et al. 2007; Fig. 6). In vivo, activation of FGFR1 stimulates osteoblast proliferation and differentiation (Zhou et al. 2000). Consistent with this, Fgfr1 expression in osteoblasts is reduced in the hypothyroid skeleton and increased in thyrotoxic bone (O'Shea et al. 2003, Stevens et al. 2003, Bassett et al. 2007a). Although osteoclasts have been reported to express TRs (Allain et al. 1992, Abu et al. 1997, 2000, Kanatani et al. 2004), it remains uncertain whether T3 regulates osteoclast differentiation directly or indirectly (Siddiqi et al. 1998, Miura et al. 2002, Varga et al. 2004). Previous studies are contradictory; some demonstrating that T3 acts directly in osteoclasts while others report indirect effects mediated via osteoblasts.


   Future directions
Top
 Abstract
 Introduction
 Thyroid hormone receptor mutant...
 Mechanism of T3 action
 Future directions
Declaration of interest
 Funding
 References
 
Analyses of TR mutant and congenitally hypothyroid Pax8–/– mice have identified a key role for thyroid hormone and TR{alpha}1 in both the developing skeleton and adult bone. However, it remains unclear how the skeletal effects of apo-TR{alpha}1 differ from those of TR{alpha}1 deficiency and to what extent the skeletal effects of thyroid hormones result from central, systemic and local actions of T3. The more severe skeletal phenotype observed in congenitally hypothyroid Pax8–/– mice as compared with TR{alpha}0/0β–/– mice suggests that unliganded TRs may be more detrimental to skeletal development than TR deficiency (Mansouri et al. 1998, Flamant et al. 2002, Bassett et al. 2008; Table 1). In support of this, amelioration of the Pax8–/– skeletal phenotype in Pax8–/–TR{alpha}0/0 mice but not in Pax8–/–TRβ–/– mice suggests that some of the detrimental effects of hypothyroidism are mediated by unliganded TR{alpha}1 in bone (Flamant et al. 2002). Despite this, it is important to note from an additional study (Mittag et al. 2005) that deletion of TR{alpha}1 alone in Pax8–/–TR{alpha}1–/– mice did not prevent weight loss, early mortality and pituitary abnormalities although the skeletal consequences were not investigated. Thus, it remains possible that TR{alpha}2 has an additional and essential role in the manifestation of the Pax8–/– phenotype. This importance of apo-TR{alpha}1 is further supported by the more severe skeletal phenotype present in mice harbouring dominant-negative mutations of TR{alpha}1 (TR{alpha}1R384C/+ and TR{alpha}1PV/+) as compared with mice lacking all TR{alpha} isoforms (TR{alpha}0/0; O'Shea et al. 2005, Bassett et al. 2007a,b) and by the amelioration of the adult skeletal phenotype in TR{alpha}1R384C/+ mice following a transient reversal of TR{alpha}1R384C apo-receptor activity during development (Bassett et al. 2007a). Nevertheless, a complete understanding of the molecular mechanism of thyroid hormone action in bone will require at least two experimental approaches. First, it is clear that phenotyping of the existing mouse models is incomplete and more detailed studies including quantitative histomorphometry, mechanical testing and analysis of primary bone cell cultures will help to clarify the picture. However, such an approach cannot identify the cellular targets of T3 action in the skeleton in vivo and this will require the use of cell-specific gene-targeting strategies.

Analysis of TR{alpha} and TRβ mutant mice has demonstrated the complex relationship between central and peripheral thyroid status and established the predominant role of TR{alpha}1 in bone. These studies also highlight contrasting responses of the skeleton to T3 during developing and in adulthood. Although understanding of the molecular mechanism of T3 action in bone is still limited, coordinate regulation of key signalling pathways has now been identified in chondrocytes and osteoblasts. By contrast, the molecular mechanism of T3 action in the osteoclast lineage remains unclear. A more detailed understanding of the molecular basis of T3 action in bone will provide the rational for the development of novel strategies for the prevention and treatment of osteoporosis.


   Declaration of interest
Top
 Abstract
 Introduction
 Thyroid hormone receptor mutant...
 Mechanism of T3 action
 Future directions
 Declaration of interest
Funding
 References
 
There is no conflict of interest.


   Funding
Top
 Abstract
 Introduction
 Thyroid hormone receptor mutant...
 Mechanism of T3 action
 Future directions
 Declaration of interest
 Funding
References
 
This work was supported by the Medical Research Council (grant numbers G108/502 and G0501486) and the Wellcome Trust (grant number GR076584).


   Acknowledgements
 
We wish to thank Prof. Alan Boyde, Queen Mary University of London, for BSE-SEM imaging, valuable advice and continuing collaboration.


   References
Top
 Abstract
 Introduction
 Thyroid hormone receptor mutant...
 Mechanism of T3 action
 Future directions
 Declaration of interest
 Funding
 References
 
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Received in final form 28 November 2008
Accepted 24 December 2008
Made available online as an Accepted Preprint 29 December 2008





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