Dexamethasone Impairs Growth Hormone (GH)-Stimulated Growth by Suppression of Local Insulin-Like Growth Factor (IGF)-I Production and Expression of GH- and IGF-I-Receptor in Cultured Rat Chondrocytes*

Abstract

Growth depression as a side effect of glucocorticoid therapy in childhood is partially mediated by alterations of the somatotropic hormone axis. The mechanisms of interaction between glucocorticoids and somatotropic hormones on the cellular and molecular level are poorly understood. In an experimental model of primary cultured rat growth plate chondrocytes, basal as well as GH (40 ng/ml) or insulin-like growth factor (IGF)-I (60 ng/ml)-stimulated growth was suppressed dose dependently (10(-l2)-10(-7)M) by dexamethasone (Dexa). An IGF-I antibody specifically and dose dependently inhibited the GH- but not the basic fibroblast growth factor (bFGF)-stimulated cell proliferation. GH increased the IGF-I concentration in conditioned serum-free culture medium; this was reversed by concomitant Dexa. Dexa time dependently suppressed the transcription of GH receptor (GHR) messenger RNA (mRNA) and down-regulated the basal and GH-stimulated expression of GHR. Whereas no suppressive effect on basal type I IGF-receptor (IGFR) was observed, Dexa blocked the IGF-I induced increase of IGF binding. These results were confirmed by GHR and IGFR immunostaining. We conclude that Dexa impairs the GH-induced stimulation of local secretion and paracrine action of IGF-I and reduces the homologous increase of IGFR and GHR expression. The above experiments give further insight on the interaction between GH and glucocorticoids on the cellular and molecular level of growth plate chondrocytes.

Glucocorticoids, Thyroid Hormone and Growth Hormone Interactions: Implications for the Growth Plate

“…Furthermore, IGF-I neutralizing antibodies block the proliferative effects of GH [3], supporting the local somatomedin hypothesis, whilst animal studies indicate that GH effects on the growth plate are mediated predominantly via IGF-I but also by direct independent actions [11]. These findings are consistent with the distribution of IGF-I, together with GH and IGF-I receptors (GHR, IGF-IR), within the growth plate (fig.…”

“…The growth impairment may be associated with a decrease in GH secretion or IGF-I responsiveness to GH, but the main site of action of GC appears to be the cartilage growth plate. This interpretation is supported by the requirement for pharmacological doses of GH, which only partially overcome growth retardation in GC excess [3]. Exposure to excess hormone should be corrected early, or GC treatment can be limited by intermittent dosing regimens, although these may not prevent bone loss.…”

CCAAT/Enhancer-binding Protein δ Is a Critical Regulator of Insulin-like Growth Factor-I Gene Transcription in Osteoblasts

“…IGF-I is synthesized by many cells including osteoblasts (1,2) and can act as a growth and differentiation factor within the skeleton as well as in other tissues (2)(3)(4). Production of IGF-I by skeletal cells is controlled by local and systemic agents, including hormones (5)(6)(7)(8)(9)(10). Both parathyroid hormone and prostaglandin E 2 (PGE 2 ) stimulate IGF-I synthesis in cultured osteoblasts by enhancing IGF-I gene expression (11,12) through mechanisms that are secondary to hormonal induction of cAMP accumulation (5,7,11).…”

No Influence of Prednisolone on IGFBP-3 Proteolysis in Healthy Young Men

“…The exact nature of this decreased IGF-I bioactivity with unchanged/increased total IGF-I levels is unclarified. It could be changes in molar concentrations or binding activity of IGFBPs, production of unknown IGF-I inhibitors, and IGF-I resistance at tissue level [27, 28]. Furthermore, other metabolic systems sensitive to glucocorticoids such as the ATP-ubiquitin-proteosome pathway and calcium-dependent protein degradation may be important factors [29].…”