Submitted to: Journal of Bone and Mineral Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/4/2014
Publication Date: N/A
Citation: Interpretive Summary: Glucocorticoids are potent anti-inflammatory and immunosuppressive agents for the management of chronic inflammatory diseases. Long-term pharmacological dosage of glucocorticoid therapy induced bone loss is a concern. However, the physiological concentrations of glucocorticoid are anabolic and required to normal osteoblast differentiation and bone acquisition. Here we show that glucocorticoid induced Leucine zipper, a member of the Leucine zipper protein family, is a glucocorticoid bone anabolic effect mediator and enhances bone formation by shifting bone marrow progenitor cell lineage commitment preferentially towards the osteoblast pathway.
Technical Abstract: Glucocorticoids (GCs) have both anabolic and catabolic effects on bone. However, no GC anabolic effect mediator has been identified to date. In this report, we provide the first evidence that glucocorticoid-induced leucine zipper (GILZ), a GC anti-inflammatory effect mediator, can enhance bone formation in mice. GILZ transgenic (Tg) mice, in which the expression of GILZ is under the control of a 3.6kb rat type I collagen promoter, exhibited a high bone mass phenotype with significantly increased bone mineral density (BMD) and bone mineral content (BMC) as assessed by bone densitometry analysis of femoral samples at 3 months of age. This bone phenotype was confirmed by u-CT analysis showing marked increases in bone volume (BV/TV), trabecular numbers (Tb.N), trabecular thickness (Tb.Th), connectivity density (Conn.D), and a significant decrease of trabecular spacing (Tb.Sp) in Tg mice. Dynamic analysis of calcein double-labeled bone tissues revealed remarkable increases in mineral apposition rate (MAR, 2.0-fold), mineralizing surface (MS/BS, 26%), and bone formation rate (BFR, 2.5-fold) in Tg mice. Histology and histomorphometry analyses showed significant increases in osteoblast numbers (N.Ob/B.Pm) and osteoblast surface (Ob.S/BS). No significant difference was detected between GILZ Tg and WT mice in osteoclast numbers. However, serum analysis showed a significant decrease in levels of RANKL, which resulted in a significantly decreased ratio of RANKL/OPG, although no difference between Tg and WT mice was detected in serum levels of OPG. In vitro cell culture studies showed that the osteogenic differentiation of GILZ Tg bone marrow cells was significantly increased and the adipogenic differentiation decreased. In line with the changes in cell differentiation capacity, the mRNA levels of key osteogenic regulators (Runx2 and Osx) increased and the levels of 3 adipogenic regulator PPAR'2 decreased significantly. In conclusion, our results have demonstrated that GILZ is a GC bone anabolic effect mediator and that GILZ enhances bone formation by shifting bone marrow MSC/progenitor cell lineage commitment preferentially towards the osteoblast pathway.