CHARACTERIZATION OF THE MOLECULAR BASIS OF OSTEOPETROSIS: THE OSTEOCLAST-POOR FORM

Our project is aimed at the study of a severe bone disease, autosomal recessive osteopetrosis, through the analysis of genes playing a pivotal role for proper osteoclast activity. The term “Osteopetrosis” defines a group of rare diseases, with a broad spectrum of presentations, from severe to mild. However, the clinical picture is due to a defect in bone resorption by osteoclasts, which are the cells deputated to this peculiar function. Among osteopetroses, the malignant infantile form, which has an autosomal recessive way of inheritance (for this reason it is called ARO, autosomal recessive osteopetrosis), affects children in their early life and leads to death, if not properly treated (bone marrow transplantation) thanks to an early diagnosis. In these cases, an early and precise diagnosis is required in order to start therapies able to prevent the formation of irreversible bone lesions. About the 70% of ARO patients bear mutations in one of three genes “effector” of osteoclast function: TCIRG1, ClCN7 or OSTM1; in all these cases, the patient’s osteoclasts can’t display their specific function in bone resorption, even though they are often present in high number. In the remaining 30% of cases the gene, or genes, responsible for the disease are unknown. In this project we aim to identify novel genes involved in the pathogenesis of osteopetrosis; in particular we plan to focus on the rare forms of human ARO in which osteoclasts are absent or in reduced number.This will allow the precise diagnosis of patients affected by osteopetrosis and to identify new therapeutic approaches.