Role of MCT8 in Skeletal Development and Maintenance of Adult Bone Mass

Dr John Howard Duncan Bassett and Professor Graham Richard Williams, Molecular Endocrinology Group, Hammersmith Hospital, London

Final report

Thyrotoxicosis is an important cause of secondary osteoporosis and thyroid hormone plays a critical role in skeletal development and regulation of bone mass in adults. The actions of thyroid hormones in bone cells are determined by the local availability of T3 to its nuclear receptor. Intracellular T3 concentration is regulated by membrane transporter proteins and three iodothyronine deiodinase enzymes D1, D2 and D3. Monocarboxylate transporter-8 (MCT8) is a highly specific T4/T3 transporter, D1 and D2 converts the pro-hormone T4 to the active hormone T3 and D3 inactivates both T4 and T3. We recently demonstrated MCT8 expression in chondrocytes, osteoblasts and osteoclasts (Williams et al. 2008) and therefore hypothesised that MCT8 is essential for normal skeletal development and maintenance of adult bone mass.

With the generous support of the 2007 British Thyroid Foundation Research Award we have been able to show for the first time that active thyroid hormone transport is essential for normal skeletal development. Our studies demonstrate that global deletion of MCT8 results in impaired postnatal linear growth, delayed endochondral ossification and reduced mineralisation despite normal or elevated circulating T3 levels. Consistent with our previous findings additional deletion of D1 and D2 did not significantly affect the skeletal phenotype during growth. The pattern of morphological and histological abnormalities observed in MCT8 deficiency is consistent with the recognised features of skeletal hypothyroidism and suggests that MCT8 expression in chondrocytes is required to maintain normal intracellular T3 levels during growth. Additional studies are currently underway to determine the consequences of MCT8 deficiency in the mature adult skeleton.

These studies will form the basis for a competitive application for further research funding and will be submitted for publication in the near future. Research into this novel area would not have been possible without the generous support of the British Thyroid Foundation and we are very grateful for your continued support. We hope these studies will yield important new insights into the regulation of both skeletal development and adult bone turnover and provide the basis for new approaches to prevent bone loss in patients with elevated thyroid hormone levels.

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