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Short-term glucocorticoid treatment of piglets causes changes in growth plate morphology and angiogenesis
J J Smink1, I M Buchholz, N Hamers
1Department of Metabolic and Endocrine Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.
Insights
Glucocorticoid treatment in piglets reduced growth plate width and increased chondrocyte apoptosis. This treatment also suppressed vascular endothelial growth factor (VEGF) expression, impairing blood vessel development and bone formation, contributing to growth retardation.
Area of Science:
- Endocrinology
- Pediatric Growth and Development
- Skeletal Biology
Background:
- Glucocorticoid therapy in children can cause growth retardation.
- The specific growth plate targets responsible for this effect are not fully understood.
- Vascular Endothelial Growth Factor (VEGF) is crucial for angiogenesis in the growth plate, a process vital for endochondral ossification.
Purpose of the Study:
- To investigate the hypothesis that in vivo glucocorticoid treatment down-regulates VEGF expression in the growth plate.
- To determine if this leads to disturbed angiogenesis and contributes to glucocorticoid-induced growth retardation.
Main Methods:
- Prepubertal piglets were treated with prednisolone for 5 days.
- Tibial growth plate sections were analyzed for apoptosis, VEGF, and MMP-9 expression.
- Capillary development was assessed using CD31 immunostaining, and growth plate morphology was measured.
Main Results:
- Prednisolone treatment significantly decreased growth plate width, particularly the proliferative zone.
- Increased chondrocyte apoptosis was observed in the hypertrophic zone of treated animals.
- VEGF expression was undetectable in the growth plates of treated piglets, and metaphyseal vascularization was reduced and disorganized.
Conclusions:
- Short-term glucocorticoid treatment severely impacts growth plate width, chondrocyte apoptosis, VEGF expression, and angiogenesis.
- These disruptions in endochondral ossification dynamics likely contribute to glucocorticoid-induced growth retardation.
- VEGF suppression and impaired vascularization are key mechanisms underlying glucocorticoid's effect on growth.
Objective:
Glucocorticoid treatment of children often leads to growth retardation, and the precise target(s) in the growth plate responsible for this effect are unknown. Angiogenesis is an important part of the endochondral ossification process, and VEGF expressed in the growth plate is essential for proper angiogenesis to occur. Since glucocorticoid treatment down-regulates VEGF expression in cultured chondrocytes, we hypothesized that in vivo glucocorticoid treatment could result in VEGF down-regulation in the growth plate and disturbed angiogenesis, thus contributing to the growth retardation.
Design:
We treated 6-week-old prepubertal piglets (10 kg) for 5 days with prednisolone (50 mg/day). Tibial growth plate sections were studied for apoptosis and the expression of VEGF protein and mRNA and MMP-9 protein. Capillaries in the metaphysis were visualized by CD31 immunostaining. Growth plate morphology (width of various zones) was determined by interactive measurements on hematoxylin/eosin stained sections and apoptotic cells were detected by TUNEL assay.
Results:
In the prednisolone-treated animals, the total width of the growth plate decreased to 81% of controls (P<0.02), which was explained by a decrease of the width of the proliferative zone to 73% (P<0.05). The treatment had no effect on the orderly organization of the chondrocyte columns. In the growth plates of control animals, apoptosis was shown in 5.8% of the hypertrophic chondrocytes and was limited to the terminal hypertrophic chondrocytes. In prednisolone-treated animals, 40.5% of the hypertrophic chondrocytes was apoptotic (P<0.02), with apoptotic chondrocytes also appearing higher in the hypertrophic zone. We observed fewer capillaries and loss of their parallel organization in the metaphysis in the prednisolone-treated animals. The capillaries were shorter and chaotic in appearance. In contrast to controls, in prednisolone-treated animals VEGF mRNA and protein could not be detected in the hypertrophic zone of the growth plate. Trabecular bone length in the primary spongiosa was also diminished by the treatment. No changes were observed in the expression pattern of MMP-9, a matrix metalloproteinase, which is also important for angiogenesis and bone formation.
Conclusions:
These results indicate that short-term glucocorticoid treatment of growing piglets severely disturbs the width of the growth plate, apoptosis of chondrocytes, VEGF expression by hypertrophic chondrocytes, the normal invasion of blood vessels from the metaphysis to the growth plate and bone formation at the chondro-osseous junction. These effects could alter the dynamics of endochondral ossification and thus contribute to glucocorticoid-induced growth retardation.
