Thyroid Hormone and the Growth Plate

Abstract

Thyroid hormone (T₃) 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 T₃ (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 T₃ in skeletal development and metabolism. However, the molecular mechanisms following T₃ 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 T₃. Hypertrophic differentiation can also be promoted by T₃ through alternative pathways as T₃ induces cyclin-dependent kinase inhibitors to regulate the G1-S cell cycle set point. In rat femur organ cultures, T₃ reduces longitudinal growth and stimulates chondrocyte differentiation. In primary chondrocyte cultures, T₃ 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 T₃ coordinately regulates chondrogenesis, matrix synthesis, angiogenesis and mineralization. In the skeleton, many of the mechanisms of T₃ action have still to be defined. Prereceptor ligand metabolism, nuclear receptor crosstalk, influence of T₃ on heparan sulfate proteoglycan matrix and angiogenesis will likely be new areas for study.