Role of skeletal thyroid hormone receptors in the regulation of bone mass
Lead Research Organisation:
Imperial College London
Department Name: Unlisted
Abstract
Thyroid hormone (T3) is essential for development of the skeleton and mineralization of bone during growth. In adults, an excess of T3 causes bone loss and is a risk factor for osteoporosis and fracture. Osteoporosis is characterized by reduced bone density and increased susceptibility to fracture. It is a common disease that affects half of the women and one in five men over 50, and costs the NHS over #1.7 billion per annum. The major cause of accelerated bone loss and osteoporosis is oestrogen deficiency, but it is not clear how a lack of oestrogen actually induces bone loss. Oestrogen normally preserves bone whereas T3 promotes bone resorption. We propose that these opposing actions are involved in the development of osteoporosis. Specifically, we hypothesise that, at the menopause, accelerated bone loss occurs because the bone resorbing actions of T3 are not antagonized by oestrogen. Studies of humans with resistance to the actions of thyroid hormones and animal models, in which thyroid hormone receptors have been deleted, suggest that the thyroid hormone receptor alpha is primarily important for the regulation of skeletal development and bone maintenance by thyroid hormone. T3 also acts in tissues other than bone, and the current understanding of T3 effects on the skeleton is limited by the fact that clinical studies and available animal models cannot separate specific T3-actions in bone from more general effects that also influence skeletal metabolism. To resolve this problem we will generate mouse models in which thyroid hormone receptors have been removed only from bone cells. These models will allow us to characterize the bone-specific actions of T3 and investigate how T3 and oestrogen interact in the normal regulation of bone maintenance. We will also determine whether selective antagonists of T3 receptor alpha preserve bone mass and prevent bone loss resulting from oestrogen deficiency. These studies will help us to understand what determines accelerated bone loss and may lead to the development of new drugs for the treatment of osteoporosis. Details of results from these studies will be publicised in Research and Development newsletters and websites published by Imperial College and Hammersmith Hospital.
Technical Summary
Osteoporosis is characterized by low bone mass and increased susceptibility to fracture. Oestrogen (E2) conserves bone mass whereas thyroid hormone (T3) stimulates bone resorption, suggesting their opposing interactions are important in the pathogenesis of bone loss. T3-action is mediated by two receptors (TR alpha and beta), which are expressed in distinct ratios in different tissues. TR beta is the major isoform in pituitary and controls negative feedback regulation of TSH. TR alpha is predominant in bone and is the main regulator of skeletal development and bone maintenance. Global inactivation of TR alpha causes skeletal hypothyroidism and delayed ossification, but preserves bone mass in adults. Global inactivation of TR beta accelerates growth and bone development, but causes osteoporosis in adults. The consequences of TR alpha-inactivation result from impaired T3-action in bone, whereas TR beta-inactivation affects the pituitary causing impaired negative feedback of TSH, which results in thyrotoxic levels of circulating thyroid hormones that act via TR alpha in bone to induce skeletal thyrotoxicosis. T3 also regulates activity of other pathways that influence bone mass, as well as exerting direct actions in bone. Thus, local T3-actions in bone and the systemic effects of altered thyroid status cannot be separated by global gene targeting. These studies aim to characterize skeletal T3-actions, and interactions with E2, using tissue-specific gene targeting strategies to address the hypotheses that (i) T3-dependent bone growth and mineralization is necessary to establish normal bone structure in adulthood, (ii) E2-deficiency exposes the skeleton to the pro-resorptive actions of T3 leading to accelerated bone loss, and (iii) T3-induced bone loss following E2 withdrawal is mediated by TR alpha. We will generate tissue-specific knockouts of TR alpha, beta or both receptors in chondrocytes and osteoblasts, and characterize their effects on the skeleton. To investigate interactions between E2 and T3, we will determine the effects of ovariectomy in osteoblast-specific TR-knockouts. To characterize the role of TR alpha in bone maintenance, effects of treatment with a TR alpha-selective antagonist will be determined. Phenotypes will be demonstrated by histology, in situ hybridization and immunohistochemistry during development and by quantitative back-scattered electron scanning electron microscopy analysis of 3D bone structure and micromineralization in adulthood. These studies will provide a new understanding of T3 action in bone and its role in the pathogenesis of accelerated bone loss, and a rationale for therapeutic targeting of TR alpha in osteoporosis prevention and treatment.
Organisations
- Imperial College London, United Kingdom (Collaboration, Lead Research Organisation)
- National Cancer Institute (NCI) (Collaboration)
- VU University Medical Center (Collaboration)
- Medical University of Warsaw (Collaboration)
- Dartmouth College, United States (Collaboration)
- University of Chicago, United States (Collaboration)
- Karolinska Institute, Sweden (Collaboration)
- Erasmus MC (Collaboration)
- University of Sheffield, United Kingdom (Collaboration)
- École normale supérieure de Lyon (ENS Lyon) (Collaboration)
- Johns Hopkins University, United States (Collaboration)
People |
ORCID iD |
Graham Williams (Principal Investigator) |
Publications

Bassett JH
(2016)
Role of Thyroid Hormones in Skeletal Development and Bone Maintenance.
in Endocrine reviews

Bassett JH
(2010)
Optimal bone strength and mineralization requires the type 2 iodothyronine deiodinase in osteoblasts.
in Proceedings of the National Academy of Sciences of the United States of America

Bassett JH
(2014)
Thyroid hormone receptor a mutation causes a severe and thyroxine-resistant skeletal dysplasia in female mice.
in Endocrinology

Bassett JH
(2008)
Critical role of the hypothalamic-pituitary-thyroid axis in bone.
in Bone

Bassett JH
(2015)
Thyrostimulin Regulates Osteoblastic Bone Formation During Early Skeletal Development.
in Endocrinology

Bassett JH
(2008)
A lack of thyroid hormones rather than excess thyrotropin causes abnormal skeletal development in hypothyroidism.
in Molecular endocrinology (Baltimore, Md.)

Bassett JH
(2007)
Thyroid status during skeletal development determines adult bone structure and mineralization.
in Molecular endocrinology (Baltimore, Md.)

Bassett JH
(2007)
Thyroid hormone excess rather than thyrotropin deficiency induces osteoporosis in hyperthyroidism.
in Molecular endocrinology (Baltimore, Md.)

Bassett JH
(2009)
The skeletal phenotypes of TRalpha and TRbeta mutant mice.
in Journal of molecular endocrinology

Bianco AC
(2014)
American Thyroid Association Guide to investigating thyroid hormone economy and action in rodent and cell models.
in Thyroid : official journal of the American Thyroid Association
Description | E-RARE |
Geographic Reach | Asia |
Policy Influence Type | Participation in advisory committee |
Description | E-RARE 2013 |
Geographic Reach | Asia |
Policy Influence Type | Participation in advisory committee |
Description | Member and Chairman Academy of Finland Research Council for Health, Grant Review Panel |
Geographic Reach | Asia |
Policy Influence Type | Participation in advisory committee |
Description | NC3Rs Studentship Assessment Panel |
Geographic Reach | National |
Policy Influence Type | Influenced training of practitioners or researchers |
Description | President British Thyroid Association |
Geographic Reach | National |
Policy Influence Type | Participation in a national consultation |
Description | Sanger Institute Mouse & Zebrafish Programme Working Group |
Geographic Reach | National |
Policy Influence Type | Participation in advisory committee |
Description | Wellcome Trust Physiological Sciences Committee |
Geographic Reach | National |
Policy Influence Type | Participation in advisory committee |
Description | ARC Equipment Grant |
Amount | £35,000 (GBP) |
Organisation | Versus Arthritis |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2008 |
End | 12/2008 |
Description | ARUK Clinical Research Training Fellowship |
Amount | £251,784 (GBP) |
Organisation | Versus Arthritis |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2011 |
End | 10/2014 |
Description | BBSRC Research Grant |
Amount | £596,000 (GBP) |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2008 |
End | 03/2011 |
Description | BTF Research Grant |
Amount | £10,000 (GBP) |
Organisation | British Thyroid Foundation (BTF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2007 |
End | 12/2007 |
Description | Early Career Award (J Logan) |
Amount | £10,000 (GBP) |
Organisation | Society for Endocrinology |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2013 |
End | 03/2014 |
Description | Hammersmith Hospital Research Committee, Project Grant |
Amount | £20,000 (GBP) |
Organisation | Imperial College Healthcare NHS Trust |
Sector | Hospitals |
Country | United Kingdom |
Start | 01/2007 |
End | 12/2007 |
Description | Imperial College Divisional PhD Studentship |
Amount | £75,000 (GBP) |
Organisation | Imperial College London |
Sector | Academic/University |
Country | United Kingdom |
Start | 01/2007 |
End | 12/2011 |
Description | MRC Clinical Training Fellowship |
Amount | £293,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2009 |
End | 09/2012 |
Description | MRC Clinical Training Fellowship |
Amount | £205,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start |
Description | MRC Research Grant |
Amount | £623,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start |
Description | Wellcome Trust Project Grant |
Amount | £475,778 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2012 |
End | 04/2015 |
Description | Wellcome Trust Strategic Award |
Amount | £2,682,771 (GBP) |
Funding ID | 101123/Z/13/A |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2014 |
End | 04/2019 |
Title | ROSA26D3 |
Description | Generation of two new floxed mouse strains that over-express a metabolizing enzyme following cre-mediated excision of a floxed stop cassette. These have taken 3 years to develop and this has involved design and construction of targeting vectors, verification of vectors and generation of transgenic as well as homologous recombination targeted mouse strains. The strains have not yet been published or made available as preliminary crosses with apporpriate cre expressing mice are underway and early phenotype analyses are emerging but not published. |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Provided To Others? | No |
Impact | These strains will have significant impact as tissue specific function of the enzyme pathways can be investigated in any tissue for which Cre expressing mice are available. It is envisaged that this will lead to wide collaboration internationally. |
Description | Alicja Nauman collaboration |
Organisation | Medical University of Warsaw |
Department | Department of Biochemistry and Molecular Biology |
Country | Poland |
Sector | Academic/University |
PI Contribution | Provision of reagents - plasmids and tissues togetehr with collaborative experimental design |
Collaborator Contribution | PMID: 20691260 |
Impact | PMID: 20691260 |
Start Year | 2008 |
Description | Anita Boelen collaboration |
Organisation | VU University Medical Center |
Country | Netherlands |
Sector | Academic/University |
PI Contribution | Study to phenotype mice with thyrostimulin deficiency |
Collaborator Contribution | Mouse breeding and provision of samples |
Impact | Manuscript published in 2015 |
Start Year | 2009 |
Description | Bjorn Vennstrom collaboration |
Organisation | Karolinska Institute |
Country | Sweden |
Sector | Academic/University |
PI Contribution | Research collaborator |
Collaborator Contribution | Research collaborator, provision of reagents |
Impact | PubMed 17488972 |
Start Year | 2006 |
Description | Jacques Samarut collaboration |
Organisation | École normale supérieure de Lyon (ENS Lyon) |
Department | Laboratory of Molecular and Cellular Biology (UMR 5665 CNRS) |
Country | France |
Sector | Academic/University |
PI Contribution | rESEARCH COLLABORATOR |
Collaborator Contribution | Research collaborator, provision of reagents |
Impact | PubMed 17327419, 17932107 |
Description | Pascale Guillot collaboration |
Organisation | Imperial College London |
Department | Institute of Reproductive and Developmental Biology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Research collaborator |
Collaborator Contribution | Research collaborator |
Impact | PubMed 17967940 |
Start Year | 2007 |
Description | Paul Yen collaboration |
Organisation | Johns Hopkins University |
Country | United States |
Sector | Academic/University |
PI Contribution | Research collaboration |
Collaborator Contribution | Research collaborator |
Impact | PubMed 17218414 |
Start Year | 2006 |
Description | Richard Eastell collaboration |
Organisation | University of Sheffield |
Department | Department of Biomedical Science |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Data and database exchange, data management and analysis, publication |
Collaborator Contribution | PMID: 20410228 |
Impact | PMID: 20410228 |
Start Year | 2006 |
Description | Sam Refetoff collaboration |
Organisation | University of Chicago |
Country | United States |
Sector | Academic/University |
PI Contribution | Research collaborator |
Collaborator Contribution | Research collaborator |
Impact | PubMed 17932107 |
Start Year | 2007 |
Description | Sheue-yann Cheng collaboration |
Organisation | National Cancer Institute (NCI) |
Country | United States |
Sector | Public |
PI Contribution | Research collaboration |
Collaborator Contribution | Research collaboration, post-doctoral training |
Impact | PubMed 16862217, 17761769 |
Description | Theo Visser collaboration |
Organisation | Erasmus MC |
Country | Netherlands |
Sector | Academic/University |
PI Contribution | Research collaborator |
Collaborator Contribution | Training of post doc, research collaborator |
Impact | PubMed 18468505 |
Start Year | 2007 |
Description | Valerie Galton collaboration |
Organisation | Dartmouth College |
Department | Geisel School of Medicine |
Country | United States |
Sector | Academic/University |
PI Contribution | Scientific collaboration with exhange of reagents, scientific ideas etc. |
Collaborator Contribution | PMID: 20368437 |
Impact | PMID: 20368437 |
Start Year | 2007 |
Description | BTF news |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Participants in your research and patient groups |
Results and Impact | Contributions to the newsletter of the British Thyroid Foundation patient support group Feedback from patients and from BTF describing letters of interest in our work |
Year(s) Of Engagement Activity | 2008,2009 |
Description | British Thyroid Foundation London Support Group |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | >50 patients with thyroid disease, who are members of the BTF patient support group attended a London Group Workshop at which I presented the lay relevance of our work and then engaged in a Q&A session of an hour and a half. One of the patients is a public figure and because the talk captured his interest he is now going to join the BTF as a trustee and will actively pursue Charity fundraising. |
Year(s) Of Engagement Activity | 2011 |
Description | Hammersmith research newsletter |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Health professionals |
Results and Impact | Article in research newsletter Recruitment of medical students into laboratory for periods of research training |
Year(s) Of Engagement Activity | 2006 |
Description | School visit - London |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Presentation of research to 6th form students Heard that several members of the audience had pursued application to University to study medicine and were successful |
Year(s) Of Engagement Activity | 2007 |