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Thyroid Hormone Regulates Heparan Sulfate Proteoglycan Expression in the Growth Plate

Molecular Endocrinology Group, Division of Medicine and Medical Research Council Clinical Sciences Centre, Faculty of Medicine (J.H.D.B., R.S., G.R.W.), Imperial College London, Hammersmith Hospital, London W12 0NN, United Kingdom; Biomatériaux et Réparation Tissulaire Institut National de la Santé et de la Recherche Médicale U-443 (O.C.), Université de Bordeaux 2, Zone Nord, 33076 Bordeaux, France; and Laboratoire de Biologie Moléculaire et Cellulaire de l’Ecole Normale Supérieure (J.S.), Unité Mixte de Recherche 5665 Centre National de la Recherche Scientifique, LA 913 Institut National de la Recherche Agronomique, 69364 Lyon Cedex, France

Address all correspondence and requests for reprints to: Dr. G. R. Williams or Dr. J. H. D. Bassett, Molecular Endocrinology Group, 5th Floor, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. E-mail: graham.williams{at}imperial.ac.uk or d.bassett{at}imperial.ac.uk.

Thyroid hormone is essential for normal skeletal development. Hypothyroidism is associated with growth arrest, failure of chondrocyte differentiation, and abnormal matrix synthesis. Thyroid hormone modulates the Indian hedgehog/PTHrP feedback loop and regulates fibroblast growth factor (FGF)/FGF receptor signaling. Because heparan sulfate (HS) proteoglycans (Prgs) (HSPGs) are absolutely required by these signaling pathways, we have investigated whether thyroid status affects HSPG expression within the growth plate. Tibial growth plate sections were obtained from 12-wk-old rats rendered euthyroid, thyrotoxic, or hypothyroid at 6 wk of age, 14-d-old congenitally hypothyroid Pax8-null mice, and TR/TRß double-null mice lacking all thyroid hormone receptors. HS and chondroitin sulfate Prg expression was determined by immunohistochemistry using three monoclonal antibodies. There was increased HS staining in growth plates from hypothyroid animals predominantly within the extracellular matrix of reserve and proliferative zones. Cellular HS staining was also increased particularly in prehypertrophic chondrocytes. T₃ regulation of HSPG core protein and HS synthetic and modification enzyme expression was studied in ATDC5 cells using semiquantitative RT-PCR. Thyroid hormone negatively regulated expression of the core protein Gpc6, the polymerase Ext1, and the modification enzyme Hs6st2. These studies demonstrate that the expression and distribution of growth plate Prgs are regulated by thyroid hormone, and the regulation of HSPG expression provides an important additional link between FGF and Indian hedgehog signaling and T₃. These novel observations suggest that the cartilage matrix and especially HSPGs are critical mediators of the skeletal response to thyroid hormone.