Thyroid hormone, but not parathyroid hormone, partially restores glucocorticoid-induced growth retardation.

Growth retardation is a serious side effect of long-term glucocorticoid (GC) treatment. In order to prevent or diminish this deleterious effect, a combination therapy including growth hormone (GH), a stimulator of bone growth, is often recommended. Parathyroid hormone (PTH) and thyroid hormone (T(4)) are important hormonal regulators of bone growth, and might also be helpful anabolic agents for counteracting the negative effects of GCs. Therefore, we studied the interaction of GCs in combination with a single dose of either PTH or T(4) on GC-induced growth retardation. Dexamethasone (Dex) treatment of mice for four weeks induced a significant growth inhibition of body length and weight and weights of several organs. PTH or T(4) alone did not affect the normal growth pattern. However, T(4) could partially restore the Dex-induced growth inhibition, whereas PTH could not. Although PTH did not affect total body growth, it did affect the height of the proliferative zone, which could be counteracted by Dex. This contrasts with T(4) treatment alone or in combination with Dex, which both resulted in a disturbed morphology of the growth plate. IGF-I mRNA, one of the mediators of longitudinal bone growth, was present in proliferative and hypertrophic chondrocytes. However, its expression was not affected by any of the treatments. In conclusion, T(4) but not PTH can partially counteract the effects of Dex on general body growth, with possible implications for future treatments of GC-induced growth retardation. Additionally, both T(4) and PTH, alone or in combination with Dex, have differential effects on the morphology of the growth plate.

Glucocorticoids inhibit vascular endothelial growth factor expression in growth plate chondrocytes.

Vascular endothelial growth factor (VEGF) plays an essential role in angiogenesis in the growth plate and ultimately in regulating endochondral ossification. Since longitudinal bone growth is often disturbed in children who are treated with glucocorticoids, we investigated the effects of dexamethasone on VEGF expression by epiphyseal chondrocytes. Cells were cultured from tibial growth plates of neonatal piglets. Using Northern blotting and RT-PCR techniques, the chondrocyte-specific markers aggrecan, collagen II and CD-RAP were detected. Also the glucocorticoid receptor (GR) was expressed. VEGF protein secreted from these cells was examined by ELISA and Western immunoblotting. The VEGF(121) and VEGF(165) isoforms were detected in the supernatant. As determined by RT-PCR, all three major mRNA splice variants were produced, including the species encoding VEGF(189). Dexamethasone (100 nM) inhibited both protein and mRNA expression by approximately 45%. Hydrocortisone (cortisol) and prednisolone also inhibited VEGF secretion, but they were less active than dexamethasone. The inhibitory actions of dexamethasone were almost completely blocked by the GR antagonist Org34116, indicating that the GR mediates these actions. Degradation of the VEGF mRNA was not accelerated by dexamethasone. Therefore, a transcriptional mechanism seems likely. Downregulation of this important growth factor could lead to disruption of the normal invasion of blood vessels in the growth plate, which could contribute to disturbed endochondral ossification and growth.