A Translational Study to Confirm the Roles of Gata-DNA Binding Proteins in Bone Healing

Project: A - Government Institutionb - Ministry of Science and Technology

Project Details

Description

Bone structure is maintained by bone remodeling. Osteoblasts play critical roles in mediating bone formation. A complicated network of local or systemic mediators modulate osteoblast metabolism. Nitric oxide (NO) is one of such mediators to regulate osteoblast activity. Our previous projects (NSC90-2314-B-002-196, NSC91-2314-B-038-031, NSC92-2314-B-038-010, NSC94-2314-B-038- 013; NSC95-2314-B-038-029-MY3; NSC98-2314-B-038- 002-MY3) provided several lines of evidence to show that inflammation-induced overproduction of NO can induce osteoblast apoptosis, and its possible signal-transducing molecular mechanism had also been evaluated in our lab (Chen et al, 2002, Chen et al., 2005a, 2005b, Ho et al., 2005, 2009; Chen et al., 2010b; Hsu et al., 2011; Wei et al., 2011). Our recent study further demonstrated that NO at low concentrations can protect osteoblasts from oxidative stress-induced apoptotic insults via a mitochondrial dependent mechanism (Chang et al., 2006; Tai et al., 2007; Ho et al., 2009). Furthermore, the GATA-DNA binding family proteins (GATAs) have simultaneously been modulated in the process of osteoblast survival. Knockdown of GATA-3 expression in osteoblasts using RNAi technique inhibited Bcl-XL gene expression and simultaneously reduced cell survival. Our results have been published in Journal of Bone and Mineral Research (Chen et al., 2010a). Thus, GATAs seem to be involved in regulation of osteoblast survival. In addition, our preliminary results also showed that GATA-3 knockdown downregulated the levels of osteopontin (OPN) and osteocalcin (OCN) in osteoblasts and concurrently decreased cell viability. Therefore, GATAs may play crucial roles in regulating osteoblast survival and osteoblast differentiation. Based on our previous studies, this project is aimed to use the animal models of bone defect and bone fracture to confirm the roles of GATAs, especially in GATA-3, in bone healing and the possible mechanisms. This is a 3-year-period project. We hypothesized that GATAs, especially in GATA-3, can regulate bone healing through regulating osteoblast survival and differentiation (Fig. 5). In the 1st and 2nd years, we will use the animal model of bone defect to evaluate if GATAs could respectively regulate osteoblast survival and osteoblast differentiation and then promote bone healing. In the 3rd year, we will use the animal model of bone fracture to evaluate the roles of GATAs in healing of bone fracture. To validate the mechanisms, this project will also apply GATA siRNAs into the animals to evaluate the roles of GATAs in regulation of Bcl-XL, OPN, and OCN expressions as well as the relationship between GATA knockdown and bone healing (Fig. 5). This translational study is expected to understand if GATAs participate in bone healing and its possible mechanisms. In addition, GATAs will be evaluated in this project to determine if they can be used as de novo biomarkers for diagnosis and prognosis of related bone diseases. Finally, the data acquired from this study are very important to execute our subsequent clinical trial.
StatusFinished
Effective start/end date8/1/147/31/15

Keywords

  • Bone healing
  • GATA-DNA binding proteins
  • Translational medicine
  • Bone defect
  • Bone fracture
  • siRNAs