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

Tove Lekva, Jens Bollerslev, Cybéle Kristo, Ole Kristoffer Olstad, Thor Ueland, Rune Jemtland
2010 Journal of Clinical Endocrinology and Metabolism  
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
more » ... ated 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 GILZsilenced 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. (J Clin Endocrinol Metab 95: 246 -255, 2010)
doi:10.1210/jc.2009-0595 pmid:19875485 fatcat:v22zniqhtbd37pgkdkiewujrfa