Thyroid hormones regulate hypertrophic chondrocyte differentiation and expression of parathyroid hormone-related peptide and its receptor during endochondral bone formation

Hypothyroidism in children causes developmental abnormalities in bone and g rowth arrest, while thyrotoxicosis accelerates growth rate and advances bon e age, To determine the effects of thyroid hormones on endochondral bone fo rmation, we examined epiphyseal growth plates in control, hypothyroid, thyr otoxic, and hypothyroid-thyroxine (hypo-T-4)-treated rats. Hypothyroid grow th plates were grossly disorganized, contained an abnormal matrix rich in h eparan sulfate, and hypertrophic chondrocyte differentiation failed to prog ress. These effects correlated with the absence of collagen X expression an d increased parathyroid hormone-related protein (PTHrP) messenger RNA (mRNA ) expression. In thyrotoxic growth plates, histology essentially was normal but PTHrP receptor (PTHrP-R) mRNA was undetectable. PTHrP is a potent inhi bitor of hypertrophic chondrocyte differentiation that acts in a negative f eedback loop with the secreted factor Indian hedgehog (Ihh) to regulate end ochondral bone formation. Thyroid hormone receptor alpha1(TR alpha1), TR al pha2, and TR beta1 proteins were localized to reserve zone progenitor cells and proliferating chondrocytes in euthyroid rat cartilage; regions in whic h PTHrP and PTHrP-R expression were affected by thyroid status. Thus, dysre gulated Ihh/PTHrP feedback loop activity may be a key mechanism that underl ies growth disorders in childhood thyroid disease.