Role of glucocorticoid-induced leucine zipper (GILZ) in inflammatory bone loss

Abstract

TNF-α plays a key role in the development of rheumatoid arthritis (RA) and inflammatory bone loss. Unfortunately, treatment of RA with anti-inflammatory glucocorticoids (GCs) also causes bone loss resulting in osteoporosis. Our previous studies showed that overexpression of glucocorticoid-induced leucine zipper (GILZ), a mediator of GC’s anti-inflammatory effect, can enhance osteogenic differentiation in vitro and bone acquisition in vivo. To investigate whether GILZ could antagonize TNF-α-induced arthritic inflammation and protect bone in mice, we generated a TNF-α-GILZ double transgenic mouse line (TNF-GILZ Tg) by crossbreeding a TNF-α Tg mouse, which ubiquitously expresses human TNF-α, with a GILZ Tg mouse, which expresses mouse GILZ under the control of a 3.6kb rat type I collagen promoter fragment. Results showed that overexpression of GILZ in bone marrow mesenchymal stem/progenitor cells protected mice from TNF-α-induced inflammatory bone loss and improved bone integrity (TNF-GILZ double Tg vs. TNF-αTg, n = 12–15). However, mesenchymal cell lineage restricted GILZ expression had limited effects on TNF-α-induced arthritic inflammation as indicated by clinical scores and serum levels of inflammatory cytokines and chemokines.

Glucocorticoid-Induced Leucine Zipper Promotes Neutrophil and T-Cell Polarization with Protective Effects in Acute Kidney Injury

“…This search has led to the discovery of the glucocorticoid-induced leucine zipper (GILZ) protein, a member of the TSC-22D family with remarkable similarity in amino acid sequence between human and mouse, as a very predictive and responsive target of glucocorticoids and mediator of their anti-inflammatory effects (D'Adamio et al, 1997;Riccardi et al, 1999;Cannarile et al, 2001;Ayroldi and Riccardi, 2009;Fan and Morand, 2012;Bereshchenko et al, 2014;Ronchetti et al, 2015). Consequently, GILZ is shown to beneficially impact several conditions associated with dysregulation of immune and inflammatory responses including myocardial infarction (Cannarile et al, 2009;Beaulieu et al, 2010;Fan and Morand, 2012;Jones et al, 2015;Baban et al, 2017;Srinivasan and Lahiri, 2017;Yang et al, 2017). However, the impact of GILZ on pathologies involving the kidney remains largely unexplored.…”

Synthetic Glucocorticoid-Induced Leucine Zipper Peptide Inhibits Lipopolysaccharide-Induced Ocular Inflammation in Rats

“…Recent research has demonstrated that GILZ is lacking during chronic inflammation and the inflammation arising from trauma [17,18], and that it exerts anti-inflammatory and immunosuppressive effects in these diseases. The biological activity of a full-length GILZ fusion protein has previously been described [19][20][21][22]. Our previous studies have found that full-length GILZ suppressed ICAM-1 and MCP-1 expression by dephosphorylating NF-κB p65 in retinal endothelial cells in vitro [23] and inhibited LPSinduced retinal inflammation in rats in vivo [10].…”

A Novel Approach to Safer Glucocorticoid Receptor–Targeted Anti-lymphoma Therapy via REDD1 (Regulated in Development and DNA Damage 1) Inhibition

“…Moreover, they also negatively affected basal GR activity when applied individually, with LY294002 being the most effective. Attenuation of GR TA was further confirmed by Q-PCR analysis of known GR-target genes including GR chaperone FKBP51 (12,14), mediator of Gcs anti-inflammatory effects GILZ (22,23), transcriptional activator KLF9 (24), and inhibitor of cytokine production MKP-1 (ref. 25; Fig.…”