PMID- 15647824
OWN - NLM
STAT- MEDLINE
DCOM- 20050607
LR  - 20121115
IS  - 0884-0431 (Print)
IS  - 0884-0431 (Linking)
VI  - 20
IP  - 2
DP  - 2005 Feb
TI  - The thyroid hormone receptor beta-specific agonist GC-1 selectively affects the 
      bone development of hypothyroid rats.
PG  - 294-304
AB  - 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. 
      INTRODUCTION: We investigated the role of the thyroid hormone receptor beta1 
      (TRbeta1) on skeletal development of rats using the TRbeta-selective agonist 
      GC-1. MATERIALS AND 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.
FAU - Freitas, Fatima R S
AU  - Freitas FR
AD  - Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, 
      Sao Paulo, SP, Brazil.
FAU - Capelo, Luciane P
AU  - Capelo LP
FAU - O'Shea, Patrick J
AU  - O'Shea PJ
FAU - Jorgetti, Vanda
AU  - Jorgetti V
FAU - Moriscot, Anselmo S
AU  - Moriscot AS
FAU - Scanlan, Thomas S
AU  - Scanlan TS
FAU - Williams, Graham R
AU  - Williams GR
FAU - Zorn, Telma M T
AU  - Zorn TM
FAU - Gouveia, Cecilia H A
AU  - Gouveia CH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20041122
PL  - England
TA  - J Bone Miner Res
JT  - Journal of bone and mineral research : the official journal of the American 
      Society for Bone and Mineral Research
JID - 8610640
RN  - 0 (Acetates)
RN  - 0 (Collagen Type II)
RN  - 0 (Collagen Type X)
RN  - 0 (GC 1 compound)
RN  - 0 (Phenols)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Thyroid Hormone)
RN  - 0 (Thyroid Hormone Receptors beta)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
SB  - IM
MH  - Absorptiometry, Photon
MH  - Acetates/*pharmacology
MH  - Animals
MH  - Body Size
MH  - Bone Density
MH  - Bone Development/*drug effects
MH  - Bone and Bones/metabolism
MH  - Cell Differentiation
MH  - Chondrocytes/metabolism
MH  - Collagen Type II/metabolism
MH  - Collagen Type X/metabolism
MH  - Female
MH  - Growth Plate/metabolism
MH  - Humans
MH  - Hypothyroidism/*pathology
MH  - Immunohistochemistry
MH  - In Situ Hybridization
MH  - Insulin-Like Growth Factor I/biosynthesis/metabolism
MH  - Osteogenesis
MH  - Phenols/*pharmacology
MH  - RNA, Messenger/metabolism
MH  - Radioimmunoassay
MH  - Rats
MH  - Rats, Wistar
MH  - Receptors, Thyroid Hormone/*agonists/*physiology
MH  - Thyroid Hormone Receptors beta
MH  - Time Factors
EDAT- 2005/01/14 09:00
MHDA- 2005/06/09 09:00
CRDT- 2005/01/14 09:00
PHST- 2004/02/27 00:00 [received]
PHST- 2004/08/16 00:00 [revised]
PHST- 2004/09/14 00:00 [accepted]
PHST- 2005/01/14 09:00 [pubmed]
PHST- 2005/06/09 09:00 [medline]
PHST- 2005/01/14 09:00 [entrez]
AID - 10.1359/JBMR.041116 [doi]
PST - ppublish
SO  - J Bone Miner Res. 2005 Feb;20(2):294-304. doi: 10.1359/JBMR.041116. Epub 2004 Nov 
      22.