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.

Publications

10 25 50
 
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 £205,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start  
 
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 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