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      Thyroid Hormone and the Growth Plate

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          Abstract

          Thyroid hormone (T<sub>3</sub>) plays a key role in normal skeletal development, linear growth and the acquisition and maintenance of bone mass. Childhood hypothyroidism is characterized by growth arrest, delayed bone age and epiphyseal dysgenesis, eventually resulting in short stature if not treated. In contrast, childhood thyrotoxicosis results in growth acceleration, advanced bone age and, in severe cases, premature epiphyseal fusion with craniosynostosis. Heterozygous mutations of thyroid hormone receptor (TR)-β resulting in a dominant-negative receptor causes resistance to T<sub>3</sub> (RTH). Short stature, advanced bone age, increased bone turnover, osteoporosis, fractures, craniofacial abnormalities and craniosynostosis have recently been described in a murine model of RTH, but the skeletal consequences of human RTH have not been investigated in detail. These observations demonstrate the importance of T<sub>3</sub> in skeletal development and metabolism. However, the molecular mechanisms following T<sub>3</sub> binding to its receptors are only partially understood. In rat growth plates, TRα1, -α2 and -β1 isoforms can be detected immunohistochemically in reserve and proliferative chondrocytes but not in chondrocytes of the hypertrophic zone. The growth plates of hypothyroid rats are characterized by a failure of hypertrophic differentiation, decreased collagen X, increased parathyroid hormone-related peptide (PTHrP) synthesis, and abnormalities of heparan sulfate proteoglycan synthesis and angiogenesis. Their growth plates are grossly disorganized. In growth plates of thyrotoxic rats, PTHrP receptor synthesis is reduced. Thus, the set point of the Indian hedgehog-bone morphogenetic protein-PTHrP feedback loop that regulates the rate of chondrocyte differentiation is modified by T<sub>3</sub>. Hypertrophic differentiation can also be promoted by T<sub>3</sub> through alternative pathways as T<sub>3</sub> induces cyclin-dependent kinase inhibitors to regulate the G1-S cell cycle set point. In rat femur organ cultures, T<sub>3</sub> reduces longitudinal growth and stimulates chondrocyte differentiation. In primary chondrocyte cultures, T<sub>3</sub> inhibits clonal expansion and proliferation, simultaneously promoting hypertrophic differentiation and mineralization. In murine ATDC5 cell cultures, it also reduces proliferation, accelerates differentiation, and increases matrix and alkaline phosphatase synthesis. Taken together, these findings suggest that T<sub>3</sub> coordinately regulates chondrogenesis, matrix synthesis, angiogenesis and mineralization. In the skeleton, many of the mechanisms of T<sub>3</sub> action have still to be defined. Prereceptor ligand metabolism, nuclear receptor crosstalk, influence of T<sub>3</sub> on heparan sulfate proteoglycan matrix and angiogenesis will likely be new areas for study.

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          Author and article information

          Journal
          HRE
          Horm Res Paediatr
          10.1159/issn.1663-2818
          Hormone Research in Paediatrics
          S. Karger AG
          978-3-8055-7833-2
          978-3-318-01154-8
          1663-2818
          1663-2826
          2004
          October 2004
          17 November 2004
          : 62
          : Suppl 3
          : 116
          Affiliations
          aUniversity Children’s Hospital, Leipzig, Germany; Departments of bClinical Research and cEndocrinology, Christie Hospital NHS Trust, Manchester, UK; dICSM Molecular Endocrinology Group, Division of Medicine and MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, UK
          Article
          80511 Horm Res 2004;62(suppl 3):116
          10.1159/000080511
          © 2004 S. Karger AG, Basel

          Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

          Page count
          Pages: 1
          Categories
          ESPE Research Fellowship Grant Lecture andPlenary Lecture

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