Trends in Endocrinology & Metabolism
The molecular actions of thyroid hormone in bone
Section snippets
Clinical effects of TH in bone
The actions of TH have a key role in normal skeletal development, linear growth and the maintenance of adult bone mass (Fig. 3, Fig. 4). Childhood hypothyroidism is characterized by growth arrest, epiphyseal dysgenesis, delayed bone age and short stature. In juvenile rats, growth plates are grossly disorganized, with defective hypertrophic chondrocyte differentiation, extracellular matrix production and angiogenesis [3]. Childhood thyrotoxicosis results in accelerated growth, advanced bone age
T3 actions on skeletal cells
The craniofacial skeleton is formed via direct intramembranous ossification, whereas most of the skeleton results from endochondral bone formation onto a cartilage anlage (Fig. 3).
Genetically modified mice
Analysis of Thr-null, Pax8-null and Thr-‘knock-in’ mice has provided important new insights into the complexity of T3 actions and the relative roles of the TR isoforms 28, 29 (Table 2). The analysis of TRα-deficient mice has led to important insights into the multiple isoforms expressed from the Thra gene, although it initially resulted in confusion regarding the true Thra-null phenotype. Thus, Thra(0/0) mice lack all known products of the Thra gene and represent a complete knockout, whereas
Novel areas of investigation
In the skeleton, many of the molecular mechanisms of TH action remain poorly defined and here we highlight prereceptor ligand metabolism, nuclear receptor crosstalk, HSPGs and angiogenesis as possible new areas for study.
Conclusion
TH has a central role in the development and maintenance of endochondral and intramembranous bone. T3 deficiency or excess results in severe skeletal abnormalities in childhood, and thyrotoxicosis is associated with osteoporosis and an increased risk for fracture in adults. In the growth plate, T3 inhibits chondrocyte proliferation but promotes hypertrophic differentiation, matrix synthesis, mineralization and angiogenesis. It also promotes osteoblastic proliferation, differentiation and
Acknowledgements
This work was supported by a Medical Research Council (MRC) Career Establishment Grant and an Arthritis Research Campaign Project Grant to GRW, an MRC Clinician Scientist Fellowship to JHDB and by PhD Studentships awarded by the MRC and The Oliver Bird Fund (Nuffield Foundation) to GRW. We acknowledge the continuing collaborative support and helpful discussions provided by Olivier Chassande, Jacques Samarut and Sheue-yann Cheng.
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