Thyroid Hormones Regulate Hypertrophic Chondrocyte Differentiation and Expression of Parathyroid Hormone-Related Peptide and Its Receptor During Endochondral Bone Formation

Abstract

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-T 4 )-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 ␣1(TR␣1), TR␣2, and TR␤1 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. (J Bone Miner Res 2000;15:2431-2442)

Excesso de tiroxina materna associado ao hipertireoidismo pós-natal reduz o crescimento ósseo e o perfil proliferativo e angiogênico das cartilagens de crescimento de ratos

“…A alteração na estrutura das zonas da placa epifisária evidenciada neste estudo também já foi descrita por outros pesquisadores (Stevens et al, 2000;Freitas et al, 2005;Desjardin et al, 2014), pois T3 é um regulador fundamental para a maturação da cartilagem e expansão clonal da zona de repouso e subsequente diferenciação (Rabier et al, 2006;Bassett et al, 2007). Os condrócitos apresentam comportamentos específicos para regular sua própria morfogênese, exemplificadas pela orientação do plano de divisão mitótica e pela formação da coluna de condrócitos na zona proliferativa.…”

“…É fato que o hipertireoidismo pode aumentar a quantidade de tecido ósseo quando há supremacia da aposição em relação à reabsorção óssea. No entanto, as consequências dessa disfunção sobre o tecido ósseo são variáveis e dependentes de fatores, como dose de tiroxina administrada, perfil sérico dos hormônios sexuais, curso da doença (Serakides et al, 2004), sítio ósseo (Suwanwalaikorn et al, 1996;Milne et al, 1998) e idade (Nicholls et al, 2012). Assim, no hipertireoidismo, a massa óssea pode estar aumentada, normal ou reduzida (Mundy et al, 1976;Allain et al, 1995;Karga et al, 2004;Serakides et al, 2004;Desjardin et al, 2014).…”

The effects of hypothyroidism on the proximal femoral physis in miniature swine

“…8,9 Thyroid hormone has been linked to regulation of type X collagen synthesis, physeal chondrocyte hypertrophy, and terminal chondrocyte differentiation. [10][11][12] Hypothyroid physeal chondrocytes express decreased levels of several genes, including types I and X collagen mRNA, and increased production of parathyroid hormone-related protein.…”

“…[10][11][12] Hypothyroid physeal chondrocytes express decreased levels of several genes, including types I and X collagen mRNA, and increased production of parathyroid hormone-related protein. 9,[13][14][15] These numerous biochemical and structural changes suggest that thyroid hormone plays an important role in growth plate maturation and function. Hypothyroidism in children results in short stature and delayed bone age, oftentimes with fragmented secondary centers of their femoral heads resembling those in Legg-Perthes disease.…”

“…1,2,[17][18][19] Similarities between hypothyroidism and SCFE growth plates suggest possible commonality of growth plate response. 9,20 SCFE growth plate evaluations have identified structural and gene expression alterations that include disorganized chondrocyte columns and decreased extracellular matrix. 20 There are fewer cells and increased cellular apoptosis in growth plates of SCFE patients, 21 and SCFE growth plate analysis utilizing reverse transcription-quantitative polymerase chain reaction (RT-qPCR) showed significant decreases in gene expression of type II collagen and aggrecan.…”