Iodothyronine deiodinase enzyme activities in bone.
Euthyroid status is essential for normal skeletal development and maintenance of the adult skeleton, but the mechanisms which control supply of thyroid hormone to bone cells are poorly understood. Thyroid hormones enter target cells via monocarboxylate transporter-8 (MCT8), which provides a functional link between thyroid hormone uptake and metabolism in the regulation of T3-action but has not been investigated in bone. Most circulating active thyroid hormone (T3) is derived from outer ring deiodination of thyroxine (T4) mediated by the type 1 deiodinase enzyme (D1). The D2 isozyme regulates intra-cellular T3 supply and determines saturation of the nuclear T3-receptor (TR), whereas a third enzyme (D3) inactivates T4 and T3 to prevent hormone availability and reduce TR-saturation. The aim of this study was to determine whether MCT8 is expressed in the skeleton and whether chondrocytes, osteoblasts and osteoclasts express functional deiodinases. Gene expression was analyzed by RT-PCR and D1, D2 and D3 function by sensitive and highly specific determination of enzyme activities. MCT8 mRNA was expressed in chondrocytes, osteoblasts and osteoclasts at all stages of cell differentiation. D1 activity was undetectable in all cell types, D2 activity was only present in mature osteoblasts whereas D3 activity was evident throughout chondrocyte, osteoblast and osteoclast differentiation in primary cell cultures. These data suggest that T3 availability especially during skeletal development may be limited by D3-mediated catabolism rather than by MCT8 mediated cellular uptake or D2-dependent T3 production.
Williams
Allan J
AJ
Molecular Endocrinology Group, Division of Medicine and Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
Robson
Helen
H
Department of Clinical Research, Christie Hospital National Health Service (NHS) Trust, Manchester, M20 4BX, UK; Cancer Tissue Bank Research Centre, Department of Pathology, Duncan Building, University of Liverpool, Daulby Street, L69 3GA, UK.
Kester
Monique H A
MHA
Department of Internal Medicine, Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands.
van Leeuwen
Johannes P T M
JPTM
Department of Internal Medicine, Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands.
Shalet
Stephen M
SM
Department of Endocrinology, Christie Hospital NHS Trust, Manchester, M20 4BX, UK.
Visser
Theo J
TJ
Department of Internal Medicine, Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands.
Williams
Graham R
GR
Molecular Endocrinology Group, Division of Medicine and Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. Electronic address: graham.williams@imperial.ac.uk.
D000818:Animals; D001842:Bone and Bones / Q000201:enzymology*; D005260:Female; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D011919:Rats, Inbred Strains; D020133:Reverse Transcriptase Polymerase Chain Reaction
D007453:Iodide Peroxidase