Grant: Operating Grant: Fall 2008 Priority Announcement (IMHA)

Vitamin-A and its metabolites, the retinoids, play important roles in the development and maintenance of the skeleton. Excess intake of retinoids has been associated with congenital defects of the skeleton and more recently it has been linked to osteoporosis and an increased incidence of bone fracture. The retinoids function through the retinoic acid receptors (RARs), to regulate the expression of genes. In a series of studies we have shown that the RA pathway regulates the formation of bone and cartilage. However, the mechanisms through which this pathway influences these cellular programs has been unclear. More recently, we have discovered several genes that the retinoids regulate and in this application we will focus on one particular RAR target gene named Hypermethylated in cancer 1 or Hic1. This gene was originally identified in humans because it is down-regulated in a variety of tumors. Using gain- and loss-of-function approaches in mouse models we will define the function of this gene in cartilage and bone formation. Information from this research will provide greater insight into these processes and the identification of potentially useful clinical targets for the treatment of diseases of the skeleton such as arthritis and osteoporosis. Further, these studies will also aid our basic understanding of Hic1 action in cell differentiation and how loss of Hic1 may contribute to the tumorgenic process.