The glucocorticoid-induced leucine zipper gene (GILZ) expression decreases after successful treatment of patients with endogenous Cushing's syndrome and may play a role in glucocorticoid-induced osteoporosis.

Abstract

Glucocorticoid-induced bone loss is a serious complication in patients with endogenous Cushing's syndrome. However, the mechanism(s) by which excess glucocorticoids influence bone metabolism is not completely understood. The aim of the study was to investigate the functional role of glucocorticoid-induced leucine zipper (GILZ) in bone remodeling with special focus on glucocorticoid-induced osteoporosis (GIO). Nine patients with endogenous Cushing's syndrome participated in the study. We analyzed bone biopsies from Cushing's patients before and after treatment to screen for expressional candidate genes with putative roles in GIO. Microarray analysis combined with real-time RT-PCR revealed that the gene encoding GILZ ranked among the topmost regulated genes and was selected for functional characterization in vitro. GILZ mRNA was expressed by human fetal osteoblasts (hFOB), human mesenchymal stem cells (hMSC), osteoblasts differentiated from hMSC, and osteoclasts. GILZ was increased by dexamethasone in a time- and dose-dependent manner in hFOB. Inhibition of GILZ in hFOB cells by small interfering RNA decreased typical osteoblast-related genes, suggesting a physiological role in promoting osteoblast maturation. Our data further support a functional role for GILZ in normal bone remodeling by modulating expression of TNF-(ligand) receptor superfamily/osteoprotegerin in favor of increased ratio in hFOB. Finally, osteoclasts exposed to conditioned media from GILZ-silenced hFOB indicated effects on osteoclast activity. Taken together, these results implicate the transcription factor GILZ in the pathophysiology of GIO by regulating osteoblast maturation and bone turnover.