Nalini Chandar, Ph.D.

Regulation of osteoblast function and differentiation by tumor suppressor genes

Our laboratory investigates the role of several tumor suppressor genes in osteoblast differentiation and in the genesis of osteosarcomas. P53 is a well- known tumor suppressor gene that is inactivated in a number of different cancers. We have found p53 inactivation in osteosarcomas to be unique in that loss of expression prevails more often than other forms of functional inactivation. In our work, we have identified several differentiation-related genes that are directly regulated by p53. More recently we have studied p53 regulated microRNAs during osteoblast differentiation. We have established p53 to be an important processor of cellular information from various pathways to determine the choice between proliferation, differentiation, cell cycle arrest and apoptosis. Current evidence suggests that p53 function is essential in bone remodeling without which normal regulation of bone differentiation is set out of balance. Retinoblastoma (Rb) is another tumor suppressor gene implicated in osteosarcomagenesis. It is well known that pediatric patients with primary retinoblastoma tumors usually have secondary tumors in bone during their growth spurt. More recent evidence suggests that Rb might play a role in osteoblast differentiation from mesenchymal stem cells. Menin is another tumor suppressor gene that functions in pathways where Rb is involved. Both Rb and Menin have been implicated in the chromatin-mediated regulation of gene expression.



Research projects

Project I: Understand the role of specific microRNAs in mesenchymal and osteoblast differentiation. Our initial analyses of 3000 different microRNAs have identified several microRNAs that might play a role in osteoblast cell fate determination. We have extended these studies to specific microRNAs regulated by menin, p53 and Rb. This project will further analyze specific microRNAs and their roles in aiding menin, p53 and Rb mediated differentiation of the bone phenotype.

Project II: Role of retinoblastoma in the regulation of osterix. Our preliminary data has identified osterix a bone specific transcription factor to be the target of retinoblastoma protein. This project will analyze the mechanism of action of retinoblastoma and its binding proteins in the regulation of osterix during osteoblast differentiation from stem cells. These studies will help identify mechanisms important for osteoblast differentiation from mesenchymal stem cells and aid in our understanding of why Rb function is critical for osteoblast fate determination.

Project III: Relationship between retinoblastoma and menin during osteoblast differentiation. Our preliminary studies and current evidence in the literature suggests that the relationship between the two tumor suppressors is important for cell fate determination and differentiation and is mediated through chromatin modifying proteins associated with Rb and Menin. These studies will attempt to dissect pathways and genes that are regulated by menin and Rb during stem cell differentiation.