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Doctoral Thesis
Full name
Fatima Rodrigues de Sousa e Freitas
Knowledge Area
Date of Defense
São Paulo, 2008
Ferreira, Cecilia Helena de Azevedo Gouveia (President)
Carvalho, Aluizio Barbosa de
Chopard, Renato Paulo
Oliveira, Manuel Herminio de Aguiar
Pereira, Rosa Maria Rodrigues
Title in Portuguese
Efeito da reposição do hormônio do crescimento (GH) no desenvolvimento ósseo de ratas hipotireoideas tratadas com o agonista seletivo do receptor b de hormônio tireoideano GC-1.
Keywords in Portuguese
Desenvolvimento ósseo
Fator de crescimento semelhante a insulina (IGF-1)
Hormônio do crescimento
Hormônio tireoideano
Receptores de hormônio tireoideano.
Abstract in Portuguese
Sabe-se que o hipotireoidismo (Hipo) resulta em supressão do eixo hormônio de crescimento (GH)/ insulin-like growth factor I (IGF-I) e em atraso no desenvolvimento esquelético. Em um estudo anterior, vimos que o tratamento de ratas jovens Hipo com GC-1, um análogo da triiodotironina (T3) seletivo pela isoforma b de receptor de hormônio tireoideano (TRb), não teve efeito sobre o IGF-I sérico ou sobre a expressão protéica de IGF-I nas lâminas epifisiais, mas parcialmente reverteu alterações esqueléticas decorrentes do Hipo, o que sugere que: (i) o desenvolvimento esquelético requer ações do T3 mediadas pelo TRa1 e TRb1 (isoformas de TR expressas no osso); ou (ii) requer interações entre o eixo GH/IGF-I e o hormônio tireoideano. Neste estudo, investigamos essas hipóteses tratando ratas recém desmamadas Hipo com T3 ou GC-1 em associação ou não com o GH por 4 semanas. Os nossos achados mostram que o T3 e GH interagem para promover o desenvolvimento ósseo, mas que uma série de efeitos do T3 nesse processo independe do eixo GH/IGF-I e são mediadas pelo TRa e/ou TRb.
Title in English
Effect of growth hormone (GH) replacement on bone development of hypothyroid rats treated with the thyroid hormone receptor b-selective agonist GC-1.
Keywords in English
Bone de development
Growth hormone
Insulin-like growth factor (IGF-1)
Thyroid hormone
Thyroid hormone receptors (TRs)
Abstract in English
Thyroid hormone (TH) has important effects on bone development and metabolism. It is known that triiodotyronine (T3) has indirect actions in the skeleton through its influence on the production and secretion of growth hormone (GH)/ insulin-like growth factor (IGF-I) and/or other factors. On the other hand, direct actions of T3 on bone are recognized but not yet clear. Most of T3 action is mediaded by its nuclear receptors (TRs). TRa1, TRb1 e TRb2 bind T3, while TRa2 does not bind T3 and acts as an antagonist of genic transcription of TRa1 and TRb1. All these receptors, except TRb2, are expressed in chondrocytes of growth plate, osteoblasts and osteoclastos. However, the functional roles of each TR isoformas in the bone development are incompletely understood. A few years, it is development GC-1, a synthetic analog of T3 which is selectivwe for TRb1 over TRa1. In recent study, we showed that treatment of hypothyroid young rats with T3 revert the IGF-I deficiency and skeleton defects caused by hypothyroidism. Since GC-1 treatment does not effects on serum levels of IGF-I or protein expression of IGF-I in the growth plate, but revert some bone alterations induced by T3 deficiency. Considering the selectivity of GC-1 for TRb, these findings suggest that T3 has effects on bone development that are mediated by TRb and independent of GH/IGF-I axis. On the other hand, the inability of GC-1 in completely revert the alterations of bone development suggests that the normal skeleton development require (i) T3 actions mediated by TRa1 and TRb1, or (ii) synergic or additive actions between GH/IGF-I axis and thyroid hormone. To investigate these hypotheses, 21 day-old hypothyroid female rats were treated with T3 or GC-1 in association or not with GH for 4 weeks. Our findings show that T3 interacts with GH to promote body growth, differentiation of growth plate hypertrofic chondrocytes, intramembranous ossification of cranial bone, and increased of bone resistance and other biomechanics parameters that contribute to the best bone quality. On the other hand, ours results suggest strongly that TH acts in bone mass acquisition, in organization of growth plate chondrocytes and endocondral ossification mainly independent of GH/IGF-I axis and via TRa and/or TRb.
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