Exp Mol Med.  2017 Nov;49(11):e398. 10.1038/emm.2017.182.

Participation of GATA-3 in regulation of bone healing through transcriptional upregulation of bcl-x(L) expression

• Liao MH
• Lin PI
• Ho WP
• Chan WP
• Chen TL
• Chen RM

• KMID: 2396803
• DOI: http://doi.org/10.1038/emm.2017.182

Abstract

We have previously demonstrated the expression of GATA-DNA-binding protein (GATA)-3, a transcription factor, in osteoblasts and have verified its function in transducing cell survival signaling. This translational study was further designed to evaluate the roles of GATA-3 in regulating bone healing and to explore its possible mechanisms. A metaphyseal bone defect was created in the left femurs of male ICR mice. Analysis by micro-computed topography showed that the bone volume, trabecular bone number and trabecular thickness were augmented and that the trabecular pattern factor decreased. Interestingly, immunohistological analyses showed specific expression of GATA-3 in the defect area. In addition, colocalized expression of GATA-3 and alkaline phosphatase was observed at the wound site. As the fracture healed, the amounts of phosphorylated and non-phosphorylated GATA-3 concurrently increased. Separately, GATA-3 mRNA was induced during bone healing, and, levels of Runx2 mRNA and protein were also increased. The results of confocal microscopy and co-immunoprecipitation showed an association between nuclear GATA-3 and Runx2 in the area of insult. In parallel with fracture healing, Bcl-XL mRNA was significantly triggered. A bioinformatic search revealed the existence of a GATA-3-specific DNA-binding element in the promoter region of the bcl-x(L) gene. Analysis by chromatin immunoprecipitation assays further demonstrated transactivation activity by which GATA-3 regulated bcl-x(L) gene expression. Therefore, this study shows that GATA-3 participates in the healing of bone fractures via regulating bcl-xL gene expression, owing to its association with Runx2. In the clinic, GATA-3 may be used as a biomarker for diagnoses/prognoses or as a therapeutic target for bone diseases, such as bone fractures.

MeSH Terms

Alkaline Phosphatase
Animals
Bone Diseases
Cell Survival
Chromatin Immunoprecipitation
Computational Biology
Femur
Fracture Healing
Fractures, Bone
Gene Expression
Humans
Immunoprecipitation
Male
Mice
Mice, Inbred ICR
Microscopy, Confocal
Osteoblasts
Promoter Regions, Genetic
RNA, Messenger
Transcription Factors
Transcriptional Activation
Up-Regulation*
Wounds and Injuries
Alkaline Phosphatase
RNA, Messenger
Transcription Factors