Spared bone mass in rats treated with thyroid hormone receptor TRβ-selective compound GC-1

Abstract

Thyrotoxicosis is frequently associated with increased bone turnover and decreased bone mass. To investigate the role of thyroid hormone receptor-beta (TR beta) in mediating the osteopenic effects of triiodothyronine (T3), female adult rats were treated daily (64 days) with GC-1 (1.5 microg/100 g body wt), a TR beta-selective thyromimetic compound. Bone mass was studied by dual-energy X-ray absorptiometry of several skeletal sites and histomorphometry of distal femur, and the results were compared with T3-treated (3 microg/100 g body wt) or control animals. As expected, treatment with T3 significantly reduced bone mineral density (BMD) in the lumbar vertebrae (L2-L5), femur, and tibia by 10-15%. In contrast, GC-1 treatment did not affect the BMD in any of the skeletal sites studied. The efficacy of GC-1 treatment was verified by a reduction in serum TSH (-52% vs. control, P < 0.05) and cholesterol (-21% vs. control, P < 0.05). The histomorphometric analysis of the distal femur indicated that T3 but not GC-1 treatment reduced the trabecular volume, thickness, and number. We conclude that chronic, selective activation of the TR beta isoform does not result in bone loss typical of T3-induced thyrotoxicosis, suggesting that the TR beta isoform is not critical in this process. In addition, our findings suggest that the development of TR-selective T3 analogs that spare bone mass represents a significant improvement toward long-term TSH-suppressive therapy.

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…The molecules in the GC family (i.e., GC-1 and GC-24) are noniodinated compounds that were designed based on experimental data obtained for the TR structure (309). The use of these molecules has suggested the possible existence of a ''therapeutic window'' through which predominantly TRbmediated biological effects (e.g., lowering serum cholesterol and acceleration of energy expenditure) can be triggered with relatively little activation TRa-dependent pathways (310)(311)(312)(313)(314)(315)(316). However, it is uncertain whether tissue specificity in vivo is due to selectivity for TR binding or tissue concentration of these molecules or both.…”

O efeito molecular e estrutural do hormônio tiroideano no esqueleto

“…Essa característica faz do GC-1 uma importante ferramenta para o estudo do papel fisiológico das diferentes isoformas de TR e tem a vantagem de não afetar o equilíbrio entre o TRα e TRβ. Estudos mostram que o GC-1 apresenta ações seletivas no tecido adiposo marrom, no desenvolvimento cerebelar e no metabolismo e desenvolvimento ósseos (62)(63)(64)(65). Nós mostramos que o GC-1 parcialmente reverte alterações esqueléticas decorrentes do hipotiroidismo em ratas (64).…”

“…Esse estudo mostrou que o TRβ medeia ações importantes do T 3 durante o desenvolvimento, e que essas ações são indepentes do eixo GH/IGF-1. Em um outro estudo, utilizamos o GC-1 como ferramenta farmacológica para investigar o papel do TRβ em mediar os efeitos osteopênicos do T 3 em ratas (65). Nós mostramos que o tratamento crônico com dose suprafisiológica de T 3 causou uma perda de massa óssea generalizada, enquanto que o tratamento equivalente com GC-1 não alterou a massa óssea.…”

“…Nós mostramos que o tratamento crônico com dose suprafisiológica de T 3 causou uma perda de massa óssea generalizada, enquanto que o tratamento equivalente com GC-1 não alterou a massa óssea. Ao mesmo tempo, o GC-1, assim como o T 3 , promoveu efeitos previamente conhecidos, tais como a redução dos níveis séricos de colesterol e TSH (65). Considerando-se que o GC-1 atua predominantemente via TRβ, esses achados sugerem que os efeitos osteopênicos do T 3 são mediados pelo TRα.…”

Influence of experimental hypothyroidism on bone tissue metabolism and mineral exchange

“…Как правило, они влияют на значительный диапазон типов клеток в большинстве органов и тканей, включая костную ткань. Остеобласты и остеокласты экспрессируют обе изоформы рецептора тиреоидных гормонов -TRβ и TRα, однако экспрессия TRα в 10 раз выше, чем TRβ, это свидетельствует, что TRα слу-жит основным медиатором действия три-йодтиронина (Т 3 ) на скелет [2].…”