UNDERSTANDING AND TREATING OSTEOCLAST-POOR AUTOSOMAL RECESSIVE OSTEOPETROSIS: RANKL-RANK AXIS

“Osteopetroses” are genetic diseases whose clinical picture is caused by a defect in bone resorption by osteoclasts, the cells responsible for this activity. Among them, infantile malignant, autosomal recessive osteopetrosis (ARO) presents soon after birth and, even if treated properly (bone marrow transplantation is appropriate, but only in cases with a compatible donor), often leads to death or to irreversible bone and neurologic lesions. Our project aims to pursue three objectives: 1) to precisely diagnose patients referred to us with an ARO diagnosis, through sequencing of the genes (TCIRG1, ClCN7, OSTM1, PLEKHM1, RANKL) already involved in the disease; 2) to select patients without mutations in any of these genes and, through approaches of cellular biology, to verify the functionality of the various signaling pathways, both between osteoblast and osteoclast, and within the osteoclast, playing a critical role in the pathophysiology of bone. The identification of the step impaired in each case will allow us to address the analysis of hypothetical candidate genes in a rational way, in order to identify new disease-genes. 3) To verify the effects of recombinant RANKL administration in trance-/- mice, in order to evaluate the possibility of carrying out this kind of therapeutic approach in man. From this study we expect to add new knowledge in the field of bone physiology. From an applicative point of view, our research will allow us to precisely diagnose patients affected by osteopetrosis, to better understand their clinical characteristics on the basis of the molecular defect they bear, and to identify the best therapeutic approach which could positively affect prognosis. Moreover, from studies performed on trance-/- mice we expect to obtain suggestions on pros and cons of a pharmacological approach with recombinant RANKL in RANKL-deficient ARO patients, who might, theoretically, benefit from this kind of treatment.