Mesenchymal Stem Cell Transplantation as a therapeutic approach to RANKL-dependent Osteopetrosis

The "osteopetroses" are a heterogeneous group of rare bone diseases among which the autosomal recessive (ARO) form is the most severe as it presents soon after birth with increased bone density, reduced medullary space, pancytopenia, cranial nerves compression, blindness and/or deafness. Additional multi-systemic pathological changes, including severe neurological defects, may also occur in specific subsets of patients. The main cause of the disease is reduced bone resorption, due to either the presence of non-functional osteoclasts, the cells devoted to this function, or to their absence (in few cases). Untreated ARO is usually fatal. HSCT is the only therapeutic option and has the highest probability of success when an HLA-matched donor is available. However, the response to transplant is strongly affected by the specific molecular defect which leads to the disease. Indeed, the RANKL-deficient form is peculiar in that it does not benefit from HSCT and thus requires a different therapeutic approach. To this purpose, based on our experience with other murine models of bone diseases (Frattini et al, 2005; Panaroni et al, 2009; Tondelli et al, 2009), here we aim to evaluate the effects of Mesenchymal Stem Cell Transplantation (MSCT) in the mouse model rankl-/-, which recapitulates the most important aspects of the pathology in this subset of patients. The potentialities and applications of MSCs have come to the fore in the last years; with respect to RANKL-dependent ARO, there is a strong rationale in the application of MSCT since it could provide the patient with the specific precursor cells able to differentiate into normal osteoblasts and thus restore the originally defective RANKL production. Overall, the results of our project, if successful, will have a great clinical impact on the management of RANKL-dependent ARO patients, which are currently receiving only palliative care.