The thyroid hormone receptor beta-specific agonist GC-1 selectively affects the bone development of hypothyroid rats.
We investigated the effects of GC-1, a TRbeta-selective thyromimetic, on bone development of hypothyroid rats. Whereas T3 reverted the IGF-I deficiency and the skeletal defects caused by hypothyroidism, GC-1 had no effect on serum IGF-I or on IGF-I protein expression in the epiphyseal growth plate of the femur, but induced selective effects on bone development. Our findings indicate that T3 exerts some essential effects on bone development that are mediated by TRbeta1.


BACKGROUND
We investigated the role of the thyroid hormone receptor beta1 (TRbeta1) on skeletal development of rats using the TRbeta-selective agonist GC-1.


METHODS
Twenty-one-day-old female rats (n = 6/group) were rendered hypothyroid (Hypo) and treated for 5 weeks with 0.3 ug/100 g BW/day of T3 (1xT3), 5xT3, or equimolar doses of GC-1 (1xGC-1 and 5xGC-1). Serum triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), and insulin-like growth factor (IGF)-I concentrations were determined by radioimmunoassay (RIA). BMD and longitudinal bone growth were determined by DXA. Trabecular bone histomorphometry and epiphyseal growth plate (EGP) morphometry were performed in the distal femur. Expressions of IGF-I protein and of collagen II and X mRNA were evaluated by immunohistochemistry and in situ hybridization, respectively. To determine hormonal effects on ossification, skeletal preparations of hypothyroid-, 5xGC-1-, and 5xT3-treated neonatal rats were compared.


RESULTS
Hypothyroidism impaired longitudinal body growth and BMD gain, delayed ossification, reduced the number of hypertrophic chondrocytes (HCs; 72% versus Euthyroid [Eut] rats; p < 0.001), and resulted in disorganized columns of EGP chondrocytes. Serum IGF-I was 67% reduced versus Eut rats (p < 0.001), and the expression of IGF-I protein and collagen II and X mRNA were undetectable in the EGP of Hypo rats. T3 completely or partially normalized all these parameters. In contrast, GC-1 did not influence serum concentrations or EGP expression of IGF-I, failed to reverse the disorganization of proliferating chondrocyte columns, and barely affected longitudinal growth. Nevertheless, GC-1 induced ossification, HC differentiation, and collagen II and X mRNA expression and increased EGP thickness to Eut values. GC-1-treated rats had higher BMD gain in the total tibia, total femur, and in the femoral diaphysis than Hypo animals (p < 0.05). These changes were associated with increased trabecular volume (48%, p < 0.01), mineralization apposition rate (2.3-fold, p < 0.05), mineralizing surface (4.3-fold, p < 0.01), and bone formation rate (10-fold, p < 0.01).


CONCLUSIONS
Treatment of hypothyroid rats with the TRbeta-specific agonist GC-1 partially reverts the skeletal development and maturation defects resultant of hypothyroidism. This finding suggests that TRbeta1 has an important role in bone development.
Freitas
Fatima R S
FR
Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil.
Capelo
Luciane P
LP
O'Shea
Patrick J
PJ
Jorgetti
Vanda
V
Moriscot
Anselmo S
AS
Scanlan
Thomas S
TS
Williams
Graham R
GR
Zorn
Telma M T
TM
Gouveia
Cecilia H A
CH
D015502:Absorptiometry, Photon; D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D049628:Body Size; D015519:Bone Density; D001846:Bone Development / Q000187:drug effects*; D001842:Bone and Bones / Q000378:metabolism; D002454:Cell Differentiation; D019902:Chondrocytes / Q000378:metabolism; D024043:Collagen Type II / Q000378:metabolism; D024121:Collagen Type X / Q000378:metabolism; D005260:Female; D006132:Growth Plate / Q000378:metabolism; D006801:Humans; D007037:Hypothyroidism / Q000473:pathology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000378:metabolism; D010012:Osteogenesis; D010636:Phenols / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D011988:Receptors, Thyroid Hormone / Q000819:agonists* / Q000502:physiology*; D037042:Thyroid Hormone Receptors beta; D013997:Time Factors
D000085:Acetates; D024043:Collagen Type II; D024121:Collagen Type X; C413355:GC 1 compound; D010636:Phenols; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D037042:Thyroid Hormone Receptors beta; D007334:Insulin-Like Growth Factor I