Glucocorticoid-Induced Leucine Zipper (GILZ) Antagonizes TNF-a Inhibition of Mesenchymal Stem Cell Osteogenic Differentiation

Hdl Handle:
http://hdl.handle.net/10675.2/783
Title:
Glucocorticoid-Induced Leucine Zipper (GILZ) Antagonizes TNF-a Inhibition of Mesenchymal Stem Cell Osteogenic Differentiation
Authors:
He, Linlin; Yang, Nianlan; Isales, Carlos M.; Shi, Xing-Ming
Abstract:
Tumor necrosis factor-alpha (TNF-a) is a potent proinflammatory cytokine that inhibits osteoblast differentiation while stimulating osteoclast differentiation and bone resorption. TNF-a activates MAP kinase pathway leading to inhibition of osterix (Osx) expression. TNF-a also induces the expression of E3 ubiquitin ligase protein Smurf1 and Smurf2 and promotes degradation of Runx2, another key transcription factor regulating osteoblast differentiation and bone formation. We showed previously that overexpression of glucocorticoid (GC)-induced leucine zipper (GILZ) enhances osteogenic differentiation of bone marrow mesenchymal stem cells (MSCs). We and others also showed that GILZ is a GC effecter and mediates GC anti-inflammatory activity. In this study, we asked the question whether GILZ retains its osteogenic activity while functioning as an anti-inflammatory mediator. To address this question, we infected mouse bone marrow MSCs with retroviruses expressing GILZ and induced them for osteogenic differentiation in the presence or absence of TNF-a. Our results show that overexpression of GILZ antagonized the inhibitory effects of TNF-a on MSC osteogenic differentiation and the mRNA and protein expression of Osx and Runx2, two pivotal osteogenic regulators. Further studies show that these antagonistic actions occur via mechanisms involving GILZ inhibition of TNF-a-induced ERK MAP kinase activation and protein degradation. These results suggest that GILZ may have therapeutic potential as a novel anti-inflammation therapy.
Citation:
PLoS One. 2012 Mar 2; 7(3):e31717
Issue Date:
2-Mar-2012
URI:
http://hdl.handle.net/10675.2/783
DOI:
10.1371/journal.pone.0031717
PubMed ID:
22396737
PubMed Central ID:
PMC3292550
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Institute of Molecular Medicine and Genetics: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorHe, Linlinen_US
dc.contributor.authorYang, Nianlanen_US
dc.contributor.authorIsales, Carlos M.en_US
dc.contributor.authorShi, Xing-Mingen_US
dc.date.accessioned2012-10-26T20:30:44Z-
dc.date.available2012-10-26T20:30:44Z-
dc.date.issued2012-03-2en_US
dc.identifier.citationPLoS One. 2012 Mar 2; 7(3):e31717en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid22396737en_US
dc.identifier.doi10.1371/journal.pone.0031717en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/783-
dc.description.abstractTumor necrosis factor-alpha (TNF-a) is a potent proinflammatory cytokine that inhibits osteoblast differentiation while stimulating osteoclast differentiation and bone resorption. TNF-a activates MAP kinase pathway leading to inhibition of osterix (Osx) expression. TNF-a also induces the expression of E3 ubiquitin ligase protein Smurf1 and Smurf2 and promotes degradation of Runx2, another key transcription factor regulating osteoblast differentiation and bone formation. We showed previously that overexpression of glucocorticoid (GC)-induced leucine zipper (GILZ) enhances osteogenic differentiation of bone marrow mesenchymal stem cells (MSCs). We and others also showed that GILZ is a GC effecter and mediates GC anti-inflammatory activity. In this study, we asked the question whether GILZ retains its osteogenic activity while functioning as an anti-inflammatory mediator. To address this question, we infected mouse bone marrow MSCs with retroviruses expressing GILZ and induced them for osteogenic differentiation in the presence or absence of TNF-a. Our results show that overexpression of GILZ antagonized the inhibitory effects of TNF-a on MSC osteogenic differentiation and the mRNA and protein expression of Osx and Runx2, two pivotal osteogenic regulators. Further studies show that these antagonistic actions occur via mechanisms involving GILZ inhibition of TNF-a-induced ERK MAP kinase activation and protein degradation. These results suggest that GILZ may have therapeutic potential as a novel anti-inflammation therapy.en_US
dc.rightsHe et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.subjectResearch Articleen_US
dc.subjectBiologyen_US
dc.subjectAnatomy and Physiologyen_US
dc.subjectImmune Physiologyen_US
dc.subjectMusculoskeletal Systemen_US
dc.subjectBiochemistryen_US
dc.subjectMetabolismen_US
dc.subjectDevelopmental Biologyen_US
dc.subjectMolecular Developmenten_US
dc.subjectStem Cellsen_US
dc.subjectImmunologyen_US
dc.subjectImmune Systemen_US
dc.subjectMolecular Cell Biologyen_US
dc.subjectCellular Typesen_US
dc.subjectStem Cellsen_US
dc.subjectMedicineen_US
dc.subjectAnatomy and Physiologyen_US
dc.subjectImmune Physiologyen_US
dc.subjectMusculoskeletal Systemen_US
dc.subjectClinical Immunologyen_US
dc.subjectImmune Systemen_US
dc.subjectRheumatologyen_US
dc.titleGlucocorticoid-Induced Leucine Zipper (GILZ) Antagonizes TNF-a Inhibition of Mesenchymal Stem Cell Osteogenic Differentiationen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3292550en_US
dc.contributor.corporatenameInstitute of Molecular Medicine and Genetics-
dc.contributor.corporatenameDepartment of Orthopaedic Surgery-
dc.contributor.corporatenameDepartment of Pathology-

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