Mechanisms of thyroid hormone receptor action during skeletal development and bone maintenance
Lead Research Organisation:
Imperial College London
Department Name: Dept of Medicine
Abstract
o What is the scientific or medical context of the research?
o To which disease(s)/condition(s), if any, is the research relevant?
o What is the research trying to achieve?
o Why is this important?
o Who is carrying out the research?
o How, briefly, is the research to be conducted (i.e. Is it a clinical trial? Will it use human samples?)
In children, thyroid hormone (T3) deficiency impairs bone formation and retards growth whilst T3-excess accelerates bone development. In adults, T3-excess increases susceptibility to osteoporosis, a condition that causes over 230,000 fractures each year, costing the NHS over £1.7 billion. T3 acts via two receptors (TRa and TRß), but their mechanisms of action in bone remain unclear. It is unknown whether TRa and TRß are found in the same cells or whether their activities differ during development and in adulthood. For example, T3 increases bone formation during growth but accelerates bone loss in adults; the mechanisms responsible for this divergence are unknown. Dr. Galliford and Professor Williams, at the MRC Clinical Sciences Centre, Imperial College London, will characterise when TRa and TRß appear in bone during development and where they continue to be present during growth and in adulthood. They will also determine where three key enzymes and a thyroid hormone transporter, that are required for T3 access to responsive tissues, are present relative to where TRa and TRß are found. Further studies will identify how T3-excess induces bone loss in the adult skeleton and may lead to development of new drugs that target TR proteins for treatment of osteoporosis.
o To which disease(s)/condition(s), if any, is the research relevant?
o What is the research trying to achieve?
o Why is this important?
o Who is carrying out the research?
o How, briefly, is the research to be conducted (i.e. Is it a clinical trial? Will it use human samples?)
In children, thyroid hormone (T3) deficiency impairs bone formation and retards growth whilst T3-excess accelerates bone development. In adults, T3-excess increases susceptibility to osteoporosis, a condition that causes over 230,000 fractures each year, costing the NHS over £1.7 billion. T3 acts via two receptors (TRa and TRß), but their mechanisms of action in bone remain unclear. It is unknown whether TRa and TRß are found in the same cells or whether their activities differ during development and in adulthood. For example, T3 increases bone formation during growth but accelerates bone loss in adults; the mechanisms responsible for this divergence are unknown. Dr. Galliford and Professor Williams, at the MRC Clinical Sciences Centre, Imperial College London, will characterise when TRa and TRß appear in bone during development and where they continue to be present during growth and in adulthood. They will also determine where three key enzymes and a thyroid hormone transporter, that are required for T3 access to responsive tissues, are present relative to where TRa and TRß are found. Further studies will identify how T3-excess induces bone loss in the adult skeleton and may lead to development of new drugs that target TR proteins for treatment of osteoporosis.
Technical Summary
Aims: Thyroid hormone (T3) regulates bone development and stimulates post-natal growth. In adults, hyperthyroidism causes bone loss and osteoporosis. Although T3 receptors (TR) a and ß are both expressed in bone, preliminary data suggests that TRa expression is 12-fold higher than TRß. We hypothesise that T3 actions on skeletal development and bone maintenance are principally mediated via TRa.
Objectives: To test this hypothesis, we will:
1. Determine the temporo-spatial skeletal expression of TRa and ß, and key genes that determine thyroid hormone availability, during development, growth and adulthood.
2. Characterise the effects of thyroid manipulation on structure and mineralisation of the adult skeleton.
Design and Methodology: Skeletal expression of TRa1, a2 and ß1, the thyroid hormone transporter (MCT-8) and the iodothyronine deiodinase enzymes (D1, D2 and D3) will be localised by in situ hybridisation, and quantified in tissue extracts by RT-PCR. Adult bone structure will be examined using back-scattered electron scanning electron microscopy (BSE SEM), confocal autofluorescence scanning light microscopy (CSLM) and micro-CT.
Scientific Opportunities: The project arises from findings, which indicate that TRa is predominant in bone. This hypothesis has never been tested and there is evidence that TRß exerts discrete actions during bone formation and can partially compensate for loss of TRa. Although hyperthyroidism increases bone loss, the mechanisms responsible are unclear and it remains controversial whether bone resorbing osteoclasts express TRs or whether T3 effects on osteoclast function are mediated by paracrine factors. To determine the roles of individual TR isoforms in bone, it is necessary to establish where specific TRs are expressed and whether TRa and ß are co-expressed in individual cells. This is essential to understand the mechanism of T3-action in bone.
Medical Opportunities: Osteoporosis is characterised by low bone mass, bone fragility and fracture. Over 230,000 osteoporotic fractures each year cost the NHS more than £1.7 billion. These figures will rise substantially based on projected increases in life expectancy. Thyroid hormone excess is an established risk factor for osteoporosis and the prevalence of thyroid disease rises with age. Over 3% of women over 50 receive thyroxine, indicating that thyroid disease may contribute substantially to the burden of osteoporosis. Despite this, mechanisms underlying increased fracture susceptibility in hyperthyroidism remain unknown. These studies will provide new understanding of the relationship between bone acquisition during growth and bone loss in adulthood, and will determine whether targeting of TRa or TRß is a therapeutic option for osteoporosis.
Objectives: To test this hypothesis, we will:
1. Determine the temporo-spatial skeletal expression of TRa and ß, and key genes that determine thyroid hormone availability, during development, growth and adulthood.
2. Characterise the effects of thyroid manipulation on structure and mineralisation of the adult skeleton.
Design and Methodology: Skeletal expression of TRa1, a2 and ß1, the thyroid hormone transporter (MCT-8) and the iodothyronine deiodinase enzymes (D1, D2 and D3) will be localised by in situ hybridisation, and quantified in tissue extracts by RT-PCR. Adult bone structure will be examined using back-scattered electron scanning electron microscopy (BSE SEM), confocal autofluorescence scanning light microscopy (CSLM) and micro-CT.
Scientific Opportunities: The project arises from findings, which indicate that TRa is predominant in bone. This hypothesis has never been tested and there is evidence that TRß exerts discrete actions during bone formation and can partially compensate for loss of TRa. Although hyperthyroidism increases bone loss, the mechanisms responsible are unclear and it remains controversial whether bone resorbing osteoclasts express TRs or whether T3 effects on osteoclast function are mediated by paracrine factors. To determine the roles of individual TR isoforms in bone, it is necessary to establish where specific TRs are expressed and whether TRa and ß are co-expressed in individual cells. This is essential to understand the mechanism of T3-action in bone.
Medical Opportunities: Osteoporosis is characterised by low bone mass, bone fragility and fracture. Over 230,000 osteoporotic fractures each year cost the NHS more than £1.7 billion. These figures will rise substantially based on projected increases in life expectancy. Thyroid hormone excess is an established risk factor for osteoporosis and the prevalence of thyroid disease rises with age. Over 3% of women over 50 receive thyroxine, indicating that thyroid disease may contribute substantially to the burden of osteoporosis. Despite this, mechanisms underlying increased fracture susceptibility in hyperthyroidism remain unknown. These studies will provide new understanding of the relationship between bone acquisition during growth and bone loss in adulthood, and will determine whether targeting of TRa or TRß is a therapeutic option for osteoporosis.