Document Detail

Matrix metalloproteinase 13 (MMP13) is a direct target of osteoblast-specific transcription factor osterix (Osx) in osteoblasts.
MedLine Citation:
PMID:  23185634     Owner:  NLM     Status:  MEDLINE    
Osterix (Osx) is an osteoblast-specific transcription factor required for bone formation and osteoblast differentiation from mesenchymal stem cells. In Osx-null mice, no bone formation occurs. Matrix metalloproteinase 13 (MMP13) is a member of the matrix metalloproteinase family and plays an important role in endochondral ossification and bone remodeling. Transcriptional regulation of MMP13 expression in osteoblasts is not well understood. Here, we provide several lines of evidence which show that MMP13 is a direct target of Osx in osteoblasts. Calvaria obtained from Osx-null embryos displayed dramatic reductions in MMP13 expression compared to wild-type calvaria. Stable overexpression of Osx stimulated MMP13 expression in C2C12 mesenchymal cells. Inhibition of Osx expression by siRNA led to downregulation of MMP13 expression. Mechanistic approaches using transient transfection assays showed that Osx directly activated a 1 kb fragment of the MMP13 promoter in a dose-dependent manner. To define the region of the MMP13 promoter that was responsive to Osx, a series of MMP13 promoter deletion mutants were examined and the minimal Osx-responsive region was refined to the proximal 80 bp of the MMP13 promoter. Additional point mutant analysis was used to identify one GC-rich region that was responsible for MMP13 promoter activation by Osx. Gel Shift Assay showed that Osx bound to MMP13 promoter sequence directly. Chromatin immunoprecipitation assays demonstrated that endogenous Osx was associated with the native MMP13 promoter in primary osteoblasts in vivo. Taken together, these data strongly support a direct regulatory role for Osx in MMP13 gene expression in osteoblasts. They further provide new insight into potential mechanisms and pathways that Osx controls bone formation.
Chi Zhang; Wanjin Tang; Yang Li
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-11-21
Journal Detail:
Title:  PloS one     Volume:  7     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2012  
Date Detail:
Created Date:  2012-11-27     Completed Date:  2013-05-13     Revised Date:  2014-09-10    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e50525     Citation Subset:  IM    
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MeSH Terms
Base Composition
Binding Sites
Cell Differentiation
Cell Line
Chromatin Immunoprecipitation
Electrophoretic Mobility Shift Assay
Embryo, Mammalian
Gene Deletion
Gene Expression Regulation, Developmental
Matrix Metalloproteinase 13 / genetics*,  metabolism
Mesenchymal Stromal Cells / cytology,  metabolism*
Osteoblasts / cytology,  metabolism*
Promoter Regions, Genetic
Protein Binding
RNA, Small Interfering / genetics
Skull / metabolism*,  pathology
Transcription Factors / genetics*,  metabolism
Transcription, Genetic
Reg. No./Substance:
0/RNA, Small Interfering; 0/Transcription Factors; 0/osterix protein, mouse; EC 3.4.24.-/Matrix Metalloproteinase 13; EC 3.4.24.-/Mmp13 protein, mouse
Erratum In:
PLoS One. 2013;8(8). doi:10.1371/annotation/a5ac9734-faa6-41d3-8ba2-6d0894f62db5

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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