Molecular Endocrinology Group

The Group is currently funded by the Medical Research Council, Biotechnology and Biological Sciences Research Council and Wellcome Trust.  The laboratory enjoys an outstanding infrastructure in all aspects of endocrinology, genetics, cell biology and molecular biology.  In addition to the MRC/Imperial College microarray centre in the next door laboratory, there are core facilities that include automated sequencing, real-time PCR, con-focal microscopy, FACS, gene targeting and transgenics.  A vast number of laboratories with expertise in all the biomedical sciences are on site and the many experienced post docs, clinical scientists, research assistants, technicians and PhD students create a stimulating environment for research, training and collaboration.  Regular meetings within the Molecular Endocrinology Group and seminars in all disciplines occur throughout the week, and these lectures attract an impressive range of international speakers.

RESEARCH

Bone and cartilage disorders affect 50% of adults over 50 yrs resulting in a huge burden to society and massive cost to the health services.  Osteoporosis is the leading cause of hospital admission for women over 50 and costs the NHS around £2.3 billion per annum, whilst osteoarthritis is the second most common cause of absence from work with costs estimated at 1% of gross national product.  Current treatments for osteoporosis reduce fracture risk by only 50% and there are few possibilities to stimulate bone and cartilage repair.  No treatments can prevent or retard osteoarthritis and other skeletal disorders are equally poorly served.  Thus, there are urgent clinical and economic needs to enhance understanding of the pathogenesis of skeletal disorders and develop targeted therapeutic strategies. 

A primary aim of the Molecular Endocrinology Group is to develop new models and methods to investigate skeletal development and the hormonal control of adult bone maintenance.  Our major focus has been to study the mechanisms of thyroid hormone action in bone.  More recently, we have been developing high throughput screening techniques to investigate bone structure and mineralization in order to establish a collaborative UK Bone & Cartilage Phenotyping Centre.

Thyroid physiology

Systemic Circulation

The thyroid hormones, thyroxine (T4) and triiodothyronine (T3) are secreted by the thyroid gland, and thyroid hormone production and secretion is controlled by a classic endocrine feedback loop involving the hypothalamic-pituitary-thyroid axis in which thyrotrophin releasing hormone (TRH) and thyroid stimulating hormone (TSH) are negatively regulated by thyroid hormones.  T4 is a pro-hormone that is converted to the active hormone T3 in peripheral tissues following removal of an outer ring 5’-iodine atom by the type 1 and 2 iodothyronine deiodinase enzymes (D1 and D2).  D1 is expressed in liver and kidney and is thought to contribute to the circulating pool of T3 although its physiological action is poorly defined.  D2 is expressed in T3 target tissues where it regulates intra-cellular availability of T3, thus controlling T3 action by modulating pre-receptor availability of hormone.  Target cell availability of thyroid hormones is further controlled by a third deiodinase, D3, which removes an inner ring 5-iodine atom to inactivate T4 and T3.  The balance of D2 and D3 activities in target cells is an important mechanism controlling cellular responses to T3.  T3 acts via two nuclear receptors, TRα and TRβ, which function as hormone inducible transcription factors that regulate expression of T3 target genes.  The TRs are expressed in all tissues but the relative levels of expression of the two isoforms are regulated in a temporo-spatial manner during development.  Thus, thyroid hormone action is controlled at many complex levels to ensure the homeostatic maintenance of normal euthyroid status in both serum and target cells.

Relationship between thyroid status and bone

Thyroid hormones are essential for bone formation, post-natal linear growth and the establishment of peak bone mass.  Thyroid hormone deficiency in children results in growth arrest and delayed bone formation, whereas thyroid hormone excess accelerates growth and advances bone age.  In adults, thyrotoxicosis is an established cause of high bone turnover osteoporosis, whilst hypothyroidism is also associated with increased fracture risk suggesting that homeostatic control of thyroid status is essential for optimal maintenance of bone mineralization and strength.  In a large population study, we recently showed that physiological variation of thyroid status in healthy euthyroid post-menopausal women is related to bone mineral density and non-vertebral fracture.  Thyroid status within the upper normal range was associated with reduced bone density and an increased risk of non-vertebral fracture, indicating that thyroid status may be a life-long determinant of bone maintenance and strength.

By characterising skeletal phenotypes resulting from global deletion or mutation of TRα or TRβ, we have established that TRα is the predominant receptor expressed in bone and shown that its actions stimulate bone formation during development but promote bone loss in the adult.  These studies identify TRα as a novel drug target for manipulation of bone turnover and growth.  Recently we demonstrated that D2 is expressed only in bone forming osteoblasts and showed the enzyme is required for optimal bone mineralization and strength, thus identifying D2 as another likely drug target.

Specific actions of thyroid hormones in skeletal cells

In order to characterize T3 action in the skeleton definitively, it is necessary to dissociate the central actions of T3 as a negative regulator of the hypothalamic-pituitary-thyroid axis from its direct actions in bone.  To investigate this problem, we are adopting tissue-specific cre-lox mediated gene targeting approaches and cell culture systems to investigate the chondrocyte, osteoblast and osteoclast cell lineages.  As a consequence, we have generated several novel reagents that enable the tissue effects of thyroid hormones to be dissociated from their central actions for the first time.  These reagents are of general applicability and can be used to investigate T3 action in other target tissues.

 Laboratory methods

Laboratory Methods

In addition to expertise in gene targeting, cell biology and molecular biology, we have developed cutting-edge quantitative imaging and biomechanical techniques to characterize murine skeletal phenotypes.

Collaborations

In order to maintain the international prominence of the Molecular Endocrinology Group, we maintain numerous links and collaborations with leading experts in thyroid and skeletal research.

Thyroid

Over many years the Molecular Endocrinology Group has worked with an extensive network of collaborating laboratories form all over the world.  We are currently working in collaboration with well-known laboratories in Europe (Nauman, Center for Postgraduate Medical Education Warsaw;  Samarut, ENS Lyon; Vassart, Free University of Brussels; Vennstrom, Karolinska Institute Stockholm; Visser, Erasmus University Rotterdam), USA (Cheng, National Cancer Institute NIH; Galton, Dartmouth; Refetoff, University of Chicago) and Asia (Murata, University of Nagoya; Yoshimura, University of Nagoya; Yen, National University of Singapore), and have collaborated productively with many other leading groups previously.

Bone

Much of our research requires detailed and highly specialized imaging of bone and cartilage that includes digital x-ray microradiography, computerized micro-tomography (microCT), histomorphometry, dynamic dual-fluorescent labeling of bone and back scattered electron scanning electron microscopy (BSE SEM).  We collaborate closely with Professor Alan Boyde (QMUL, London) in many of these areas, but especially for BSE SEM and related quantitative techniques, and with Professor Peter Croucher (University of Sheffield) in studies requiring micro CT analysis of bone.  Our expertise in skeletal phenotype analysis has resulted in collaborations with Professors Allan Bradley at the Wellcome Trust Sanger Institute, Steve Brown at MRC Harwell and Raj Thakker (University of Oxford) to develop a Bone & Cartilage Phenotyping Centre along with Peter Croucher and Alan Boyde.

Selected Publications

Bassett JHD, Boyde A, Howell PGT, Bassett RH, Galliford TM, Archanco M, Evans H, Croucher PI, St. Germain DL, Galton VA, Williams GR (2010) Optimal bone mineralization and strength requires the type 2 iodothyronine deiodinase in osteoblasts.  Proc. Natl. Acad. Sci. USA (in press). PDF

Murphy E, Glüer C, Reid DM, Felsenberg D, Roux C, Eastell R, Williams GR (2010) Thyroid function within the upper normal range is associated with reduced bone mineral density and an increased risk of nonvertebral fractures in healthy euthyroid postmenopausal women.  J. Clin. Endocrinol. Metab. (in press). PDF

Bassett JHD, van der Spek A, Gogakos AI, Williams GR (2010) Quantitative x-ray imaging of rodent bone: Methods in Molecular Biology Series: Bone Research Protocols, 2nd Edition, (Helfrich MH & Ralston SH Eds), Humana Press, Totowa, NJ, USA. (in press).

Cheung MS, Gogakos A, Bassett JHD, Williams GR (2010) Thyroid disease and osteoporosis. The Oxford Textbook of Endocrinology. 2nd Edition, (Bilezikian J, Section Ed). Oxford University Press, Oxford, UK (in press).

Bassett JHD, Williams GR (2009) The skeletal phenotypes of TRα and TRβ mutant mice.  J. Mol. Endocrinol. 42:269-282. PDF 

Williams GR (2009) Does serum TSH level have thyroid hormone-independent effects on bone turnover?  Nature Clin. Pract. Endocrinol. Metab. 5:10-11. DOI

Bassett JHD & Williams GR (2008) Critical role of the hypothalamic-pituitary-thyroid axis in bone.  Bone 43:418-426. DOI

Williams AJ, Robson H, Kester MHA, van Leeuwen JPTM, Shalet SM, Visser TJ, Williams GR (2008) Iodothyronine deiodinase enzyme activities in bone.  Bone 43:126-134. DOI

Guillot PV, Abass O, Bassett JHD, Shefelbine SJ, Bou-Gharios G, Chan J, Kurata H, Williams GR, Polak JM, Fisk NM (2008) Intrauterine transplantation of human fetal mesenchymal stem cells from first trimester blood repairs bone and reduces fractures in osteogenesis imperfecta mice.  Blood 111:1717-1725.  DOI

Bassett JHD, Williams AJ, Murphy E, Boyde A, Howell PGT, Swinhoe R, Archanco M, Flamant F, Samarut J, Costagliola S, Vassart G, Weiss RE, Refetoff S, Williams GR (2008) A lack of thyroid hormones rather than excess TSH causes abnormal skeletal development in congenital hypothyroidism.  Mol. Endocrinol. 22:501-512. DOI

O’Shea PJ, Guigon CJ, Williams  GR, Cheng SY (2007) Regulation of fibroblast growth factor receptor-1 by thyroid hormone: identification of a thyroid hormone response element in the murine Fgfr1 promoter.  Endocrinology 148:5966-5976. DOI

Bassett JHD, Nordström K, Boyde A, Howell PGT, Kelly S, Vennström B, Williams GR (2007) Thyroid status during skeletal development determines adult bone structure and mineralization.  Mol. Endocrinol. 21:1893-1904.   DOI

Bassett JHD, O’Shea PJ, Sriskantharajah S, Rabier B, Boyde A, Howell PGT, Weiss RE, Roux JP, Malaval L, Clément-Lacroix P, Samarut J, Chassande O, Williams GR (2007) Thyroid hormone excess rather than thyrotropin deficiency induces osteoporosis in hyperthyroidism. Mol. Endocrinol. 21:1095-1107. DOI

Harvey CB, Bassett JHD, Maruvada P, Yen PM, Williams GR (2007) The rat thyroid hormone receptor (TR) Δβ3 displays cell-, TR isoform- and thyroid hormone response element specific actions.  Endocrinology 148:1764-1773. DOI