Role of thyroid hormone receptors in osteoclast differentiation and function
Lead Research Organisation:
Imperial College London
Department Name: Dept of Medicine
Abstract
Osteoporosis is a major health priority affecting half of women and one in five men over 50 and costing the NHS #1.7 billion a year. Thyrotoxicosis is an established cause of osteoporotic fracture but the underlying mechanism of bone loss has not been determined. Our recent studies, however, indicate that thyroid hormone receptor alpha (TRalpha) has a critical role in skeletal development, acquisition and maintenance of adult bone and thyrotoxic bone loss. Moreover, our studies suggest that TRalpha has an important role in regulating the activity of bone resorbing osteoclasts. Although the mechanism is unknown these studies identify TRalpha as a potential new drug target for the treatment and prevention of osteoporosis. Importantly, the therapeutic potential of TR-isofom specific compounds has already been demonstrated in patients with for high cholesterol. In the proposed studies Dr Bassett and Professor Williams at the MRC Clinical Sciences Centre, Imperial College London, will characterise the actions of T3 in osteoclasts and their subsequent effects on bone structure and strength. These studies are critical and timely as it is essential that the molecular mechanism of thyrotoxic bone loss is defined, before new drugs, acting on TRalpha are developed for the treatment of osteoporosis.
Technical Summary
Aims: Thyrotoxicosis is an established cause of osteoporosis and fracture but the mechanism of thyrotoxic bone loss is controversial as it is unclear whether thyroid hormone (T3) excess or TSH deficiency mediates bone loss. Although T3 receptors (TRs) and the TSH receptor (TSHR) are expressed in bone cells, our recent studies of TR and TSHR deficiency have directly addressed this controversy and established that the actions of TRs predominate. Furthermore, the skeletal phenotypes of TR deficient mice are characterised by abnormal osteoclastic bone resorption.
I hypothesis that accelerated bone loss in hyperthyroidism is mediated by the direct actions of thyroid hormone (T3) in osteoclasts.
Objectives: To address this hypothesis, I will:
1) Determine if T3 acts directly via TRs expressed in osteoclasts.
2) Determine the mechanism of T3-action in osteoclasts.
Experimental Design and Methodology:
The skeletal effects of TR deficiency restricted to the osteoclast-lineage will be determined in mice using cre-lox technology. Skeletal development in juveniles and bone structure in adult mice will be determined by light, confocal and back-scattered electron scanning electron microscopy. Bone strength will be determined by destructive three-point bending and compression studies. The molecular mechanism of T3-induced bone loss will be determined using gene expression profiling and quantitative RT-PCR analysis in primary cultures of wild type and TR-deficient osteoclasts. The role of TRs in osteoblastic regulation of osteoclast differentiation will be investigated in co-cultures of wild-type and TR-deficient calvarial osteoblasts and splenic osteoclast progenitor cells.
Scientific Opportunities: The project arises from our finding that TRalpha deficiency results in increased bone mass and reduced osteoclast activity, whereas TRbeta deficiency causes osteoporosis secondary to increased osteoclastic bone resorption. Although hyperthyroidism increases bone loss, the mechanisms are unclear and reports of TR expression and T3 responsiveness in osteoclasts are conflicting. It is now essential to demonstrate whether T3 regulates osteoclast activity directly.
Medical Opportunities: Osteoporotic fractures cost the NHS #1.7 billion each year. Our preliminary data identify TRalpha as a potential drug target for the prevention and treatment of osteoporosis. These studies will determine the mechanism of T3 action in bone and generate in vitro and in vivo models in which to evaluate the pharmacological manipulation of TRs.
I hypothesis that accelerated bone loss in hyperthyroidism is mediated by the direct actions of thyroid hormone (T3) in osteoclasts.
Objectives: To address this hypothesis, I will:
1) Determine if T3 acts directly via TRs expressed in osteoclasts.
2) Determine the mechanism of T3-action in osteoclasts.
Experimental Design and Methodology:
The skeletal effects of TR deficiency restricted to the osteoclast-lineage will be determined in mice using cre-lox technology. Skeletal development in juveniles and bone structure in adult mice will be determined by light, confocal and back-scattered electron scanning electron microscopy. Bone strength will be determined by destructive three-point bending and compression studies. The molecular mechanism of T3-induced bone loss will be determined using gene expression profiling and quantitative RT-PCR analysis in primary cultures of wild type and TR-deficient osteoclasts. The role of TRs in osteoblastic regulation of osteoclast differentiation will be investigated in co-cultures of wild-type and TR-deficient calvarial osteoblasts and splenic osteoclast progenitor cells.
Scientific Opportunities: The project arises from our finding that TRalpha deficiency results in increased bone mass and reduced osteoclast activity, whereas TRbeta deficiency causes osteoporosis secondary to increased osteoclastic bone resorption. Although hyperthyroidism increases bone loss, the mechanisms are unclear and reports of TR expression and T3 responsiveness in osteoclasts are conflicting. It is now essential to demonstrate whether T3 regulates osteoclast activity directly.
Medical Opportunities: Osteoporotic fractures cost the NHS #1.7 billion each year. Our preliminary data identify TRalpha as a potential drug target for the prevention and treatment of osteoporosis. These studies will determine the mechanism of T3 action in bone and generate in vitro and in vivo models in which to evaluate the pharmacological manipulation of TRs.
