Lekva T, Bollerslev J, Kristo C, Olstad OK, Ueland T, Jemtland R
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. [JOURNAL ARTICLE]
J Clin Endocrinol Metab 2009 Oct 29.
Context: 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.
Objective: 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).
Patients: Nine patients with endogenous Cushing's syndrome participated in the study. Research Design and
Methods: 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.
Results: 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.
Conclusion: Taken together, these results implicate the transcription factor GILZ in the pathophysiology of GIO by regulating osteoblast maturation and bone turnover.
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