The HPT axis in control of skeletal development
Graham R Williams
Hypothyroidism delays bone development, whilst thyrotoxicosis causes osteoporosis. Recent studies have challenged understanding of skeletal responses to thyroid hormone by proposing TSH as a negative regulator of bone turnover and suggesting bone loss in hyperthyroidism results from TSH deficiency and not T3-excess. To investigate, we characterised mice with mutations or deletions of the genes encoding T3 receptor (TR) α and TRβ. Endochondral ossification was retarded in TRα mutant mice but advanced in TRβ mutants. TRα mutants had increased cortical and trabecular bone width, increased trabecular bone volume and greater microarchitectural complexity, whereas TRβ mutants were osteoporotic. Analysis of downstream signalling revealed skeletal hypothyroidism in TRα mutant mice but skeletal thyrotoxicosis in TRβ mutants. TRα was expressed at 15-fold higher levels than TRβ in bone, whereas TRβ predominates in hypothalamus and pituitary and controls feedback regulation of TSH. Accordingly, TRα mutant mice were euthyroid, whereas TRβ mutants had pituitary resistance to thyroid hormone with elevated circulating thyroid hormones. Thus, TRα is the major functional TR in bone, whereas skeletal responses to TRβ disruption result from effects on systemic thyroid status. To investigate the importance of TSH, we compared Pax8−/− and hyt/hyt mice with congenital hypothyroidism due to thyroid agenesis or the presence of a mutant TSHR. Pax8−/− mice have 1900-fold increased TSH levels and a normal TSHR, whereas hyt/hyt mice have 2300-fold elevated TSH but a non-functional TSHR. We reasoned these mice must display opposing skeletal phenotypes if TSH has a major role in bone. Pax8−/− and hyt/hyt mice both displayed delayed ossification, reduced cortical bone, a trabecular bone remodelling defect and reduced bone mineralisation, indicating skeletal abnormalities of congenital hypothyroidism are independent of TSH. These data exclude a role for TSH in the skeleton in vivo and indicate the HPT axis regulates bone via TRα-mediated T3 actions.