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 growth arrest, while thyrotoxicosis accelerates growth rate and advances bone age. To determine the effects of thyroid hormones on endochondral bone formation, we examined epiphyseal growth plates in control, hypothyroid, thyrotoxic, and hypothyroid-thyroxine (hypo-T4)-treated rats. Hypothyroid growth plates were grossly disorganized, contained an abnormal matrix rich in heparan sulfate, and hypertrophic chondrocyte differentiation failed to progress. These effects correlated with the absence of collagen X expression and 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 inhibitor of hypertrophic chondrocyte differentiation that acts in a negative feedback loop with the secreted factor Indian hedgehog (Ihh) to regulate endochondral bone formation. Thyroid hormone receptor alpha1(TRalpha1), TRalpha2, and TRbeta1 proteins were localized to reserve zone progenitor cells and proliferating chondrocytes in euthyroid rat cartilage; regions in which PTHrP and PTHrP-R expression were affected by thyroid status. Thus, dysregulated Ihh/PTHrP feedback loop activity may be a key mechanism that underlies growth disorders in childhood thyroid disease.