Grant: Operating Grant

Vitamin-A and its metabolites, the retinoids, play important roles in the development and maintenance of the skeleton. Excess intake of retinoids (typically through vitamin supplements) has been associated with congenital defects of the skeleton and more recently it has been linked to osteoporosis and an increased incidence in bone fracture. In some studies, vitamin A intake just above the recommended daily allowance (RDA) was associated with increased fracture risk and multiple groups have advocated that the RDA for vitamin A needs to be reevaluated and possibly reduced. Derivatives of retinoids have also long been used to treat various skin aliments and long-term increased intake has consistently been associated with decreased bone mass and aberrant bone formation at sites of tendon-bone attachment. 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 is unclear. More recently, we have discovered several genes that the retinoids regulate and herein we will focus on one particular RAR target gene named Hypermethylated in cancer 1 or Hic1. This gene was originally identified because it is silenced in a variety of tumors in humans. We have recently generated a mouse in which this gene can be removed in various tissues, and removal of this gene in the developing limb or skull leads to various skeletal defects. This proposal aims to define the function of Hic1 in the formation and maintenance of a functional skeleton. Information from this research will provide greater insight into these processes and the identification of potentially useful clinical targets for the treatment of diseases such as arthritis and osteoporosis, and strategies to promote skeletal repair following injury.