Runx2 is a critical component of skeletal development. Global knock-out studies have proven the role of Runx2 as a regulator for skeletal and tooth development. Runx2-null mice are born with a complete lack of mineralization, and tooth germs that arrest at the late cap/early bell stage. Furthermore, it has been shown that Runx2 is required for commitment from mesenchymal progenitor cells to the osteoblast, chondrocyte, and odontoblast lineages. Mutations in Runx2 gene lead to skeletal abnormalities in humans, such as Cleidocranial Dysplasia, which arises from haploinsufficiency of Runx2. This disorder is characterized by skeletal and craniofacial anomalies. Thus, understanding the specific functions of Runx2 has immense potential for clinical applications. Attempts to study the cell and tissue specific functions of Runx2 and its role in postnatal development have been unsuccessful. Transgenic mouse models manifest significant variation in their phenotypes, by contradicting the basic understandings of the role of Runx2 in normal development. For example, transgenic studies overexpressing Runx2 after the osteoblast-commitment phase report osteopenia, suggesting that Runx2 acts as an inhibitor in late stages of osteogenesis. However, it is known that gene expression of Runx2 increases throughout embryonic development, and Runx2 maintains high expression in postnatal development. I propose to employ a novel Runx2 floxed mouse model to accomplish Runx2 deletion in a cell type specific manner. We have previously confirmed this as a valid model for Runx2 gene ablation. For cell-type specific gene deletion, I will use the 2.3kb Type I Collagen promoter to drive Cre expression. Using this model, I will determine the function of Runx2 specifically in osteoblasts for skeletogenesis, and identify its role in odontoblasts for tooth formation. Furthermore, the expected viability of this mouse model passed the major postnatal developmental age will permit invaluable advances in bone and dental research. Our hypothesis is that Runx2 is required for maintenance of mature osteoblast phenotype and postnatal bone acquisition, and that the function of Runx2 in odontoblasts is essential for odontoblast maturation, and proper dentin and tooth formation. I will address this hypothesis by in vivo and ex vivo approaches by two specific aims: 1) Osteoblast specific regulatory role of Runx2 for skeletogenesis; and 2) Requirement of Runx2 for odontoblast maturation and tooth formation. The information obtained from these studies will provide a foundation for understanding the molecular mechanisms involved in both normal and abnormal osteogenic and dental development. This research will elucidate the role of tooth/bone matrix material properties in oral and skeletal health and disease. Eventually, the proposed studies will facilitate the development of novel diagnostic tools and therapeutic treatments regarding dentin matrix malformations, skeletal abnormalities, and craniofacial dysplasias.

Public Health Relevance

These studies will contribute to our knowledge of how bone and tooth formation occurs normally, and also has the potential for development of novel therapeutics regarding dentin remodeling, and individuals with genetic or non-hereditary skeletal and craniofacial dysplasias.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30DE022693-04
Application #
9056648
Study Section
NIDR Special Grants Review Committee (DSR)
Program Officer
Frieden, Leslie A
Project Start
2012-07-01
Project End
2016-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Adhami, Mitra D; Rashid, Harunur; Chen, Haiyan et al. (2015) Loss of Runx2 in committed osteoblasts impairs postnatal skeletogenesis. J Bone Miner Res 30:71-82
Adhami, Mitra D; Rashid, Harunur; Chen, Haiyan et al. (2014) Runx2 activity in committed osteoblasts is not essential for embryonic skeletogenesis. Connect Tissue Res 55 Suppl 1:102-6