title: 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: BACKGROUND
  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).
  
  
  METHODS
  Nine patients with endogenous Cushing's syndrome participated in the study.
  
  
  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.
  
  
  CONCLUSIONS
  Taken together, these results implicate the transcription factor GILZ in the pathophysiology of GIO by regulating osteoblast maturation and bone turnover.
authors.affiliation: Section of Endocrinology, Department of Medicine, Research Institute for Internal Medicine, Oslo University Hospital, Rikshospitalet, N-0027 Oslo, Norway.
authors.forename: Tove
authors.initials: T
authors.lastname: Lekva
authors.forename: Jens
authors.initials: J
authors.lastname: Bollerslev
authors.forename: Cybéle
authors.initials: C
authors.lastname: Kristo
authors.forename: Ole Kristoffer
authors.initials: OK
authors.lastname: Olstad
authors.forename: Thor
authors.initials: T
authors.lastname: Ueland
authors.forename: Rune
authors.initials: R
authors.lastname: Jemtland
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D018246:Adrenocortical Adenoma / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D000328:Adult; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001706:Biopsy; D016723:Bone Remodeling / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D003480:Cushing Syndrome / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000601:surgery*; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D005938:Glucocorticoids / Q000009:adverse effects* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010024:Osteoporosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D005938:Glucocorticoids; C404226:TSC22D3 protein, human; D014157:Transcription Factors