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.

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.

scholarly journals The Somatostatin Analog Octreotide Inhibits GH-Stimulated, But Not IGF-I-Stimulated, Bone Growth in Hypophysectomized Rats

Endocrinology ◽  
2002 ◽  
Vol 143 (8) ◽  
pp. 2944-2952 ◽  
Author(s):  
Jürgen Zapf ◽  
Martina Gosteli-Peter ◽  
Gisbert Weckbecker ◽  
Ernst B. Hunziker ◽  
Manfred Reinecke
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Body Weight Gain ◽  
Somatostatin Analog ◽  
Hypertrophic Zone ◽  
Gh Secretion ◽  
Proliferative Zone ◽  
Igf I ◽  
Hypophysectomized Rats ◽  
Tibial Epiphyseal

Abstract IGF-I mediates growth-promoting actions of GH. In the present study we investigated whether the somatostatin analog octreotide blunts the stimulatory effects of GH and/or IGF-I on bone growth in hypophysectomized rats infused for 6 d with vehicle, GH, or IGF-I. We found that octreotide significantly suppressed the GH-induced rise in liver IGF-I mRNA (−27%) and peptide (−32%) and the serum IGF-I level (−26%) and concomitantly inhibited GH-stimulated, but not IGF-I-stimulated, body weight gain (−31%), tibial epiphyseal width (−14%), and bone growth rate (−24%). Furthermore, octreotide significantly reduced the GH-induced increase in the number of IGF-I immunoreactive chondrocytes in all layers (except in the upper hypertrophic zone) of the tibial growth plate cartilage (P &lt; 0.0001 for stem cell and proliferative zone; P &lt; 0.0005 for lower hypertrophic zone). These findings demonstrate that octreotide does not interfere with IGF-I action, but does interfere with local GH-stimulated IGF-I production in the growth plate. Thus, besides inhibiting pituitary GH secretion, octreotide exerts inhibitory peripheral effects on GH-stimulated longitudinal bone growth.

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.

Ultrastructure of the tibial epiphyseal growth plate in microphthalmic (mi/mi) mice

1989 ◽  
Vol 34 (2) ◽  
pp. 77-84 ◽  
Author(s):  
D. Paxinos-Maroudas ◽  
R.N. Powell ◽  
G.M. Newcomb
Keyword(s):  
Growth Plate ◽  
Epiphyseal Growth Plate ◽  
Tibial Epiphyseal

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 Expression of vascular endothelial growth factor in the growth plate is stimulated by estradiol and increases during pubertal development

2010 ◽  
Vol 205 (1) ◽  
pp. 61-68 ◽  
Author(s):  
Joyce Emons ◽  
Andrei S Chagin ◽  
Torun Malmlöf ◽  
Magnus Lekman ◽  
Åsa Tivesten ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Growth Plate ◽  
Bone Growth ◽  
Pubertal Development ◽  
Mrna Levels ◽  
Vascular Endothelial ◽  
Epiphyseal Growth Plate ◽  
Vegf Expression ◽  
Endothelial Growth Factor

Longitudinal bone growth is regulated in the growth plate. At the end of puberty, growth velocity diminishes and eventually ceases with the fusion of the growth plate through mechanisms that are not yet completely understood. Vascular endothelial growth factor (VEGF) has an important role in angiogenesis, but also in chondrocyte differentiation, chondrocyte survival, and the final stages of endochondral ossification. Estrogens have been shown to up-regulate VEGF expression in the uterus and bone of rats. In this study, we investigated the relation between estrogens and VEGF production in growth plate chondrocytes both in vivo and in vitro. The expression of VEGF protein was down-regulated upon ovariectomy and was restored upon estradiol (E2) supplementation in rat growth plates. In cultured rat chondrocyte cell line RCJ3.1C5.18, E2 dose dependently stimulated 121 and 189 kDa isoforms of VEGF, but not the 164 kDa isoform. Finally, VEGF expression was observed at both protein and mRNA levels in human growth plate specimens. The protein level increased during pubertal development, supporting a link between estrogens and local VEGF production in the growth plate. We conclude that estrogens regulate VEGF expression in the epiphyseal growth plate, although the precise role of VEGF in estrogen-mediated growth plate fusion remains to be clarified.

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