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Glucocorticoid-induced effects on the growth plate and the IGF system

By Jeske Johanna Smink


Glucocorticoids (GCs) are widely used as anti-inflammatory and immunosuppressive drugs. The use of these potent drugs, however, often results in side-effects, such as growth retardation in children. For already many years, this GC-induced growth retardation is suggested to involve impaired action of the components of the growth hormone (GH) - insulin-like growth factor (IGF) system. The components of this system are among the main regulators of postnatal longitudinal bone growth. Longitudinal bone growth is regulated by the growth plates, layers of cartilage (containing cartilage cells, chondrocytes) located at the proximal and distal ends of the long bones. The growth plate is a specialised and organised structure and the chondrocytes in the growth plates follow a tightly controlled program of proliferation and differentiation (resulting in the different zones of the growth plate), which is part of the process of endochondral ossification, resulting in the formation of new bone. This bone formation is responsible for longitudinal bone growth. GC-induced growth retardation involves a mechanism intrinsic to the growth plate. However, not much is known about the molecular mechanism underlying this growth retardation. In my PhD thesis project, I have studied the molecular mechanisms by which GCs bring about their effects on the growth plate, with the main emphasis on the components of the IGF system, using both in vitro and in vivo model systems. We have treated mice with GCs for a short-term (1 week) and a long-term (4 weeks) period. We detected expression of three components of the IGF system in the growth plate: IGF-I, IGF-II and IGFBP-2 (one of the IGF binding proteins). GC treatment only affected IGF-I expression, after 1 week we could show a down-regulation, in contrast, after 4 weeks of treatment we detected an upregulation of IGF-I expression. Besides these changes in gene expression, changes in the proliferation and differentiation of the growth plate chondrocytes were also detected. The initial decrease in IGF-I could contribute to the GC-induced growth retardation, whereas the subsequent increase could be part of a compensatory mechanism to minimise the GC-induced growth retardation at the longer term. We have also studied the effects of GCs on angiogenesis and apoptosis in the growth plate, two essential processes for endochondral ossification to occur. In piglets treated with GCs, apoptosis was increased and blood vessel formation was severely disturbed. The GC treatment down-regulated VEGF expression, which is an important growth factor for angiogenesis. We confirmed the down-regulation of VEGF expression by GCs in primary chondrocyte cultures, derived from neonatal piglets. In these same chondrocyte cultures we have studied the effects of GCs on proliferation and gene expression of the IGF system. In this in vitro model system, GCs down-regulated IGFBP-2 expression, at the transcriptional level (as shown by promoter studies). The obtained data suggest that the IGF system is indeed impaired by GCs at the local level of the growth plate, probably both involving proliferation and differentiation, which is probably part of the molecular mechanism underlying GC-induced growth retardation

Topics: Geneeskunde, growth plate, chondrocytes, growth retardation, glucocorticoids, IGF, IGFBP, VEGF, angiogenesis, apoptosis, expression
Year: 2003
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