GENETIC DETERMINANTS OF BONE HOMEOSTASIS: A FUNCTIONAL STUDY OF DLX AND KROX GENES

Bone is formed and resorbed continuously, starting in the embryo and continuing throughout adult life. This process occurring in adult bone is called bone remodelling. Deregulation of bone remodelling leads to metabolic bone disease. For example osteoporosis, the most common disease in the Western Hemisphere, is characterised by reduced bone mass and is thought to result from an imbalance between bone formation and resorption. Osteopetrosis is also a bone remodelling disorder and is characterised by impaired osteoclast function, resulting in a net increase in skeletal mass. Predisposition to bone metabolic diseases is clearly genetic in nature. For example, from family histories, twin studies, and molecular genetics, it is clear that the predisposition for osteoporosis can be inherited. However, it is also clear that genetic control of bone homeostasis is polygenic. Studies of mouse targeted mutants are leading to the gradual elucidation of the genetic cascade which controls bone homeostasis, this conceptual model is, however, still incomplete. With this project we want to study the role of transcriptional regulators belonging to the Dlx and Krox families in the control of bone homeostasis. We will use an integrated set of experimental approaches ranging from targeted inactivation of genes, to microarray technology to in-vivo analysis of gene regulation in normal and pathological conditions. Our immediate objectives are: 1. To undestand the function of Dlx5/6 and Krox-20 in adult bone. 2. To identify the genes regulated by Dlx5/6 and Krox-20 in bone using microarray technologies. 3. To isolate and analyze the DNA elements which direct the expression of Dlx5/6 and Krox-20 in bone. To check if the regulatory elements identified in this study are involved in human bone genetic disorders such as osteoporosis we will genotype on DNA samples from osteoporotic patients allelic variants of genes affecting bone density in rodents.