Biphasic response of rat tibial growth to thyroxine administration

1990 ◽  
Vol 122 (3) ◽  
pp. 336-340 ◽  
Author(s):  
Song Guang Ren ◽  
Ze Huang ◽  
Donald E. Sweet ◽  
Saul Malozowski ◽  
Fernando Cassorla
Keyword(s):  
Growth Rate ◽  
Growth Plate ◽  
Male Rats ◽  
Longitudinal Growth ◽  
Epiphyseal Growth Plate ◽  
Biphasic Response ◽  
Dose Response Relationship ◽  
Igf I ◽  
Rat Tibia ◽  
Plate Width

Abstract To evaluate the dose-response relationship between thyroxine and tibial growth, 60 male rats age 21 days were rendered hypothyroid by administration of methimazole in the drinking water. Twenty-one days later, the hypothyroid rats were randomly divided into 5 groups which received 0, 2, 8, 32, or 64 μg·kg−1·day−1 of T4 im for 21 days. All animals were sacrificed at age 64 days. Rat tibia were removed for measurement of epiphyseal growth plate width and longitudinal growth rate. Serum T4 and IGF-I levels were determined by RIA. Methimazole therapy significantly decreased serum T4, IGF-I, epiphyseal growth plate width, and longitudinal growth rate compared to controls. Epiphyseal growth plate width gradually increased when T4 was administered at doses from 2 to 32 μg·kg−1·day−1 (271±14, 311±15 and 324±11 μm), and subsequently decreased when T4 was given at a dose of 64 μg·kg−1·day−1 (267±8 μm). A similar profile was observed for longitudinal growth rate and IGF-I. We conclude that rat tibial growth has a biphasic response to exogenous T4 administration, and that the effects of T4 on tibial growth may be mediated through IGF-I secretion.

Direct administration of testosterone increases rat tibial epiphyseal growth plate width

1989 ◽  
Vol 121 (3) ◽  
pp. 401-405 ◽  
Author(s):  
Song Guang Ren ◽  
Saul Malozowski ◽  
Prosper Sanchez ◽  
Donald E. Sweet ◽  
D. Lynn Loriaux ◽  
...  
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Serum Testosterone ◽  
Male Rats ◽  
Testosterone Enanthate ◽  
Epiphyseal Growth Plate ◽  
Igf I ◽  
Direct Administration ◽  
Tibial Epiphyseal ◽  
Plate Width

Abstract. Local injection of hormones into the tibial epiphyseal growth plate offers a possible model to answer whether sex steroids can affect bone growth directly. To answer this question, we injected different doses of testosterone enanthate (4, 40, 120 and 400 μg/100 g of rat weight) once into the tibial epiphyseal growth plate of castrated 35-day-old male rats. The contralateral tibia was injected with sesame oil and served as control. All animals were sacrificed at age 42 days. Tibias were removed for measurement of epiphyseal growth plate width and blood was collected for measurement of serum IGF-I and testosterone. The lower doses of testosterone enanthate (4, 40 and 120 μg/100 g) did not produce any significant change in epiphyseal growth plate width. Testosterone at the largest dose tested (400 μg/100 g) increased epiphyseal growth plate width by about 15% compared to control (p < 0.01). At this dose, serum testosterone was not increased, suggesting that the effect on epiphyseal growth plate width was not due to higher systemic testosterone concentrations. No differences in IGF-I levels were observed among the groups. We conclude that direct administration of testosterone enanthate at a dose of 400 μg/100 g into the rat tibial epiphyseal growth plate can increase epiphyseal growth plate width.

scholarly journals The aromatase inhibitor letrozole increases epiphyseal growth plate height and tibial length in peripubertal male mice

2004 ◽  
Vol 182 (1) ◽  
pp. 165-172 ◽  
Author(s):  
R Eshet ◽  
G Maor ◽  
T Ben Ari ◽  
M Ben Eliezer ◽  
G Gat-Yablonski ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Body Weight ◽  
Aromatase Inhibitor ◽  
Growth Plate ◽  
Growth Potential ◽  
Longitudinal Growth ◽  
Male Mice ◽  
Epiphyseal Growth Plate ◽  
Plate Height ◽  
Igf I

Sex hormones may influence longitudinal growth, either indirectly, by affecting the growth-hormone-insulin-like growth factor I (IGF-I) axis, or directly, by affecting changes within the epiphyseal growth plate (EGP). The aim of the present study was to investigate the effects of letrozole, an aromatase inhibitor, on longitudinal growth and changes in the EGP in vivo. Eighteen peripubertal male mice were divided into three groups. The first group was killed at baseline, the second was injected with letrozole (Femara) s.c., 2 mg/kg body weight/day, for 10 days, and the third was injected with the vehicle alone. Serum testosterone levels were found to be significantly higher in the treated group than in the controls. Letrozole induced a significant increase in body weight, tail length and serum growth hormone level, but had no significant effect on the level of serum IGF-I. On histomorphometric study, there was a significant increase (12%) in EGP height in the treated animals compared with controls. Immunohistochemistry showed a 3.4-fold letrozole-induced increase in the proliferation of the EGP chondrocytes, as estimated by the number of proliferation cell nuclear antigen-stained cells, and a decrease in the differentiation of the EGP chondrocytes, as estimated by type X collagen staining. Letrozole did not interfere with type II collagen levels. The study group also showed a twofold increase in the number of IGF-I receptor-positive cells compared with controls. In conclusion, the aromatase inhibitor, letrozole, appears to increase the linear growth potential of the EGP in mice.

scholarly journals Evidence for genomic and nongenomic actions of estrogen in growth plate regulation in female and male rats at the onset of sexual maturation

2002 ◽  
Vol 175 (2) ◽  
pp. 277-288 ◽  
Author(s):  
BC van der Eerden ◽  
J Emons ◽  
S Ahmed ◽  
HW van Essen ◽  
CW Lowik ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Growth Plate ◽  
Sexual Maturation ◽  
Body Weight Gain ◽  
Male Rats ◽  
Longitudinal Growth ◽  
Zone Width ◽  
Tibial Length ◽  
Plate Width

Recently, both estrogen receptor (ER) alpha and beta were detected in growth plate chondrocytes of rats before sexual maturation, implying a role for estrogen at this stage. In this study, therefore, we investigated the effects of ovariectomy (OVX) or estrogen supplementation on parameters of longitudinal growth in 26-day-old rats, which were sexually immature at the start of the experiment. OVX caused an increase in body weight gain, tibial length and growth plate width due to an increased proliferating zone. This increase correlated with an increase in cell number, with a decrease in cell diameter and with increased proliferating cell nuclear antigen (PCNA) immunostaining compared with sham. Interestingly, the increase in proliferation was not caused by an increase in insulin-like growth factor-I (IGF-I) mRNA expression in the growth plate as assessed by real-time PCR. In contrast to OVX, 17beta-estradiol (E(2)) supplementation (0.5 mg/21 days) of 26-day-old female rats caused a strong decrease in body weight gain, tibial length and growth plate width. The latter was explained by a reduction of the proliferating zone width, which correlated with a reduced number of PCNA-positive cells (not significant) and by a reduction of the hypertrophic zone width. In male rats supplemented with E(2), similar effects were observed compared with the females. ERalpha and beta immunostaining was found predominantly in late proliferating and early hypertrophic chondrocytes. OVX did not affect ER expression but E(2) supplementation strongly decreased immunostaining for both ERalpha and beta in both sexes. Besides E(2), desoxyestrone (DE), an activator of nongenomic estrogen-like signaling (ANGEL) and 2-methoxyestradiol (2-MeO-E(2)), a tissue-selective naturally occurring metabolite of E(2), were administered to female and male rats of the same age. Compared with E(2), these compounds had less pronounced, though significant, effects on some parameters of longitudinal growth in both sexes, especially on growth plate characteristics. In conclusion, E(2) may exert effects on longitudinal growth before and at the onset of sexual maturation, despite very low endogenous serum levels at these stages. There may be a role for nongenomic signaling in body weight gain, tibial length and growth plate width but genomic signaling prevails.

Mitigating smoothened inhibitor-induced growth plate closure with parathyroid hormone.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9562-9562
Author(s):  
Yoav E Timsit ◽  
Diane E Gunson ◽  
Thomas Krucker ◽  
Judit E Markovits ◽  
Silvia Buonamici ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Growth Plate ◽  
Clinical Chemistry ◽  
Male Rats ◽  
Preclinical Model ◽  
Epiphyseal Growth Plate ◽  
Growth Plates ◽  
Subcutaneous Injections ◽  
Once Daily ◽  
Continuous Delivery

9562 Background: The Hedgehog pathway plays an important role in regulating growth plate patency by activating PTH/PTHrP signaling, and loss of PTH/PTHrP signaling is an expected pharmacological effect of smoothened (Smo) inhibition. LDE225, a Smo inhibitor currently in phase I/II trials for the treatment of basal cell carcinoma (BCC) and medulloblastoma (MB), causes closure of the epiphyseal (growth) plate in rodents and dogs. As a therapeutic strategy to mitigate these effects, we investigated whether administration of human parathyroid hormone (PTH amino acids 1-34 or PTH1-34) could prevent premature growth plate closure caused by LDE225. Methods: Oral LDE225 was given once daily to rapidly growing male rats (starting at 4 or 6 weeks of age) in combination with hPTH1-34 administered subcutaneously as a continuous infusion (to mimic signaling by locally-produced PTHrP) or as once-daily injections. Femur and tibial growth plates were scanned by microCT and growth plate volumes were calculated. Growth plates were also assessed histologically. Results: Continuous delivery of hPTH1-34 provided the greatest effect for maintaining patent growth plates compared to once-daily subcutaneous injections. However, the dose of continuous hPTH1-34 giving the greatest protection was not well-tolerated beyond 1 week due to PTH-induced hyperparathyroidism, confirmed by clinical chemistry and histological assessment. Reduction in the dose of continuous hPTH1-34 improved tolerability, but provided less protection to the growth plate. Once-daily hPTH1-34 injection for two weeks was well-tolerated, with anabolic effects clearly observed by histology and microCT. The extent of closure in animals co-treated with LDE225 and once-daily hPTH1-34 injections was less compared to that caused by LDE225 treatment alone. Conclusions: As shown in this preclinical model, hPTH1-34 administration mitigates LDE225-induced growth plate closure. Although hPTH1-34 shows promise experimentally, current use is restricted in pediatric patients and further study will be needed before considering hPTH1-34 treatment concurrent with LDE225 therapy in children or adolescents.

scholarly journals Defined Carboxy-Terminal Fragments of Insulin-Like Growth Factor (IGF) Binding Protein-2 Exert Similar Mitogenic Activity on Cultured Rat Growth Plate Chondrocytes as IGF-I

Endocrinology ◽  
2008 ◽  
Vol 149 (10) ◽  
pp. 4901-4911 ◽  
Author(s):  
Daniela Kiepe ◽  
Anke Van Der Pas ◽  
Sonia Ciarmatori ◽  
Ludger Ständker ◽  
Burkhardt Schütt ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Biological Activity ◽  
Growth Plate ◽  
Longitudinal Growth ◽  
Growth Plate Chondrocytes ◽  
Igf I ◽  
Rat Growth ◽  
Igf Binding ◽  
Carboxy Terminal ◽  
Igf Binding Protein

The IGF/IGF binding protein (IGFBP) system is an important component in the hormonal regulation of longitudinal growth. Evidence from in vitro studies indicates that IGFBPs may have IGF-independent effects. We analyzed the biological activity of intact IGFBP-2 and defined carboxy-terminal IGFBP-2 fragments isolated from human hemofiltrate in two cell culture systems of the growth plate: rat growth plate chondrocytes in primary culture and the mesenchymal chondrogenic cell line RCJ3.1C5.18. The IGFBP-2 fragments IGFBP-2167–279, IGFBP-2167–289, and IGFBP-2104–289 exerted a strong (2- to 3-fold) mitogenic effect on growth plate chondrocytes, which was comparable with IGF-I in equimolar concentrations (7.8 nm) but was not mediated through the type 1 IGF receptor. In a dose-response experiment, the most effective concentration of IGFBP-2104–289 for the stimulation of cell proliferation was 10 nm. This biological activity of IGFBP-2 fragments was associated with cell membrane binding, demonstrated by Western blot analysis of fractionated cell lysates and immunohistochemistry. Whereas intact IGFBP-2 did not modulate chondrocyte proliferation, partially reduced (by dithiothreitol) full-length IGFBP-2 stimulated cell proliferation to a comparable extent (3.4-fold) as carboxy-terminal IGFBP-2 fragments. The mitogenic activity of these IGFBP-2 fragments and of partially reduced full-length IGFBP-2 was mediated through the use of the MAPK/ERK 1/2. These data imply a novel role of naturally occurring IGFBP-2 fragments for the endocrine and paracrine/autocrine regulation of longitudinal growth.

scholarly journals Locally produced estrogen promotes fetal rat metatarsal bone growth; an effect mediated through increased chondrocyte proliferation and decreased apoptosis

2006 ◽  
Vol 188 (2) ◽  
pp. 193-203 ◽  
Author(s):  
A S Chagin ◽  
D Chrysis ◽  
M Takigawa ◽  
E M Ritzen ◽  
L Sävendahl
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Longitudinal Growth ◽  
Epiphyseal Growth Plate ◽  
Chondrocyte Proliferation ◽  
Growth Plate Cartilage ◽  
Ici 182,780 ◽  
Metatarsal Bones ◽  
Fetal Rat ◽  
Estrogen Synthesis

The importance of estrogens for the regulation of longitudinal bone growth is unequivocal. However, any local effect of estrogens in growth plate cartilage has been debated. Recently, several enzymes essential for estrogen synthesis were shown to be expressed in rat growth plate chondrocytes. Local production of 17β-estradiol (E2) has also been demonstrated in rat costal chondrocytes. We aimed to determine the functional role of locally produced estrogen in growth plate cartilage. The human chondrocyte-like cell line HCS-2/8 was used to study estrogen effects on cell proliferation (3H-labeled thymidine uptake) and apoptosis (cell death detection ELISA kit). Chondrocyte production of E2 was measured by RIA and organ cultures of fetal rat metatarsal bones were used to study the effects of estrogen on longitudinal growth rate. We found that significant amounts of E2 were produced by HCS-2/8 chondrocytes (64.1 ± 5.3 fmol/3 days/106cells). The aromatase inhibitor letrozole (1 μM) and the pure estrogen receptor antagonist ICI 182,780 (10 μM) inhibited proliferation of HCS-2/8 chondrocytes by 20% (P<0.01) and almost 50% (P<0.001), respectively. Treatment with ICI 182,780 (10 μM) increased apoptosis by 228% (P<0.05). Co-treatment with either caspase-3 or pan-caspase inhibitors completely blocked ICI 182,780-induced apoptosis (P<0.001 vs ICI 182,780 only). Moreover, both ICI 182,780 (10 μM) and letrozole (1 μM) decreased longitudinal growth of fetal rat metatarsal bones after 7 days of culture (P<0.01). In conclusion, our data clearly show that chondrocytes endogenously produce E2 and that locally produced estrogen stimulates chondrocyte proliferation and protects from spontaneous apoptosis. In addition, longitudinal growth is promoted by estrogens locally produced within the epiphyseal growth plate.

scholarly journals Effects of Laser Acupuncture on Longitudinal Bone Growth in Adolescent Rats

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Mijung Yeom ◽  
Sung-Hun Kim ◽  
Bina Lee ◽  
Xiuyu Zhang ◽  
Hyangsook Lee ◽  
...  
Keyword(s):  
Growth Rate ◽  
Growth Plate ◽  
Bone Growth ◽  
Growth Potential ◽  
Male Rats ◽  
Adolescent Male ◽  
Laser Acupuncture ◽  
Longitudinal Bone Growth ◽  
Level Laser ◽  
Adolescent Rats

Longitudinal bone growth is the results of chondrocyte proliferation and hypertrophy and subsequent endochondral ossification in the growth plate. Recently, laser acupuncture (LA), an intervention to stimulate acupoint with low-level laser irradiation, has been suggested as an intervention to improve the longitudinal bone growth. This study investigated the effects of laser acupuncture on growth, particularly longitudinal bone growth in adolescent male rats. Laser acupuncture was performed once every other day for a total of 9 treatments over 18 days to adolescent male rats. Morphometry of the growth plate, longitudinal bone growth rate, and the protein expression of BMP-2 and IGF-1 in growth plate were observed. The bone growth rate and the heights of growth plates were significantly increased by laser acupuncture. BMP-2 but not IGF-1 immunostaining in growth plate was increased as well. In conclusion, LA promotes longitudinal bone growth in adolescent rats, suggesting that laser acupuncture may be a promising intervention for improving the growth potential for children and adolescents.

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