Abstract
Glucocorticoids (GCs) have both anabolic and catabolic effects on bone. However, no GC anabolic effect mediator has been identified to date. Here we show that targeted expression of glucocorticoid-induced leucine zipper (GILZ), a GC anti-inflammatory effect mediator, enhances bone acquisition in mice. Transgenic mice, in which the expression of GILZ is under the control of a 3.6-kb rat type I collagen promoter, exhibited a high bone mass phenotype with significantly increased bone formation rate and osteoblast numbers. The increased osteoblast activity correlates with enhanced osteogenic differentiation and decreased adipogenic differentiation of bone marrow stromal cell cultures in vitro. In line with these changes, the mRNA levels of key osteogenic regulators (Runx2 and Osx) increased, and the level of adipogenic regulator peroxisome proliferator-activated receptor (PPAR) γ2 decreased significantly. We also found that GILZ physically interacts with C/EBPs and disrupts C/EBP-mediated PPARγ gene transcription. In conclusion, our results showed that GILZ is capable of increasing bone acquisition in vivo, and this action is mediated via a mechanism involving the inhibition of PPARγ gene transcription and shifting of bone marrow MSC/progenitor cell lineage commitment in favor of the osteoblast pathway.
Highlights
The in vivo role of glucocorticoid-induced leucine zipper (GILZ), a glucocorticoid-indicible protein, in bone acquisition is unknown
Our results showed that GILZ is capable of increasing bone acquisition in vivo, and this action is mediated via a mechanism involving the inhibition of peroxisome proliferator-activated receptor (PPAR)␥ gene transcription and shifting of bone marrow mesenchymal stem cells (MSCs)/progenitor cell lineage commitment in favor of the osteoblast pathway
Tg-M expressed GILZ transgene at a level comparable to that normally seen in cultured bone marrow MSCs induced by dexamethasone (100 nM for 6 h) [14]
Summary
The in vivo role of GILZ, a glucocorticoid-indicible protein, in bone acquisition is unknown. Our results showed that GILZ is capable of increasing bone acquisition in vivo, and this action is mediated via a mechanism involving the inhibition of PPAR␥ gene transcription and shifting of bone marrow MSC/progenitor cell lineage commitment in favor of the osteoblast pathway. We have found previously that overexpression of glucocorticoid-induced leucine zipper (GILZ) [9, 10], known as a GC antiinflammatory effect mediator [11,12,13], can enhance osteogenic differentiation of bone marrow mesenchymal stem cells (MSCs) in vitro [14]. We found that overexpression of GILZ can antagonize the inhibitory effect of TNF-␣ on MSC osteogenic differentiation in vitro [15] It is not known whether or not GILZ is capable of enhancing bone formation in vivo and could serve as an endogenous GC anabolic effect mediator.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
