Role of Glucocorticoid-induced Leucine Zipper (GILZ) in Bone Acquisition

• Published in: The Journal of biological chemistry Vol. 289; no. 28; pp. 19373 - 19382
• Main Authors: Pan, Guodong, Cao, Jay, Yang, Nianlan, Ding, Kehong, Fan, Cheng, Xiong, Wen-Cheng, Hamrick, Mark, Isales, Carlos M., Shi, Xing-Ming
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.07.2014; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Arthritis; Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; Core Binding Factor Alpha 1 Subunit - biosynthesis; Core Binding Factor Alpha 1 Subunit - genetics; Gene Expression Regulation - physiology; Glucocorticoid; Inflammation; Male; Mice; Mice, Transgenic; Molecular Bases of Disease; Osteoblast; Osteoblasts - cytology; Osteoblasts - metabolism; Osteogenesis - physiology; Osteoporosis; PPAR gamma - genetics; PPAR gamma - metabolism; Promoter Regions, Genetic - physiology; Rats; Sp7 Transcription Factor; Stem Cells - cytology; Stem Cells - metabolism; Transcription Factors - biosynthesis; Transcription Factors - genetics; Transcription, Genetic - physiology; Osteoblast; Osteoporosis; Arthritis; Inflammation; Glucocorticoid
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.535237

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. Background: The in vivo role of GILZ, a glucocorticoid-indicible protein, in bone acquisition is unknown. Results: Overexpression of GILZ in osteoprogenitor cells increases bone acquisition in mice. Conclusion: GILZ enhances bone acquisition by promoting marrow mesenchymal stem/progenitor cell osteogenic differentiation. Significance: GILZ may represent the first GC-responsive gene mediating the positive effect of GCs in bone.