Fibrous dysplasia (FD) is a crippling skeletal disease caused by post-zygotic activating mutations of the Gs-alpha gene. One or multiple bones can be affected. Marrow fibrosis, osteomalacia, and osteolysis, the elementary FD tissue changes, make the bone soft and fragile and prompt to fractures and deformities. Today, FD has no cure. Surgery is palliative and drugs in use cannot stop, slow or reverse the bone pathology.
Murine faithful replicas of human FD have been recently generated. In these mice, as in humans, FD lesions develop post-natally following a defined spatial and temporal pattern through discrete stages (non-lytic, 2-3 months; lytic, 6-9 months; full-blown, ~12 months) each with distinct radiographic and histologic features.
Since enhanced bone resorption is a significant morbidity factor in FD and RANKL the major molecular mediator of osteoclastogenesis, we ask if RANKL-inhibition can interfere with development and evolution of FD lesions. To this aim, we plan to treat FD mice with radiographically detectable lesions in the different stages with intraperitoneal injection of anti-RANKL antibody or rat IgG2a as control. At the end of treatment, half of the mice of each group will be euthanized for morphologic analysis; the other half will be euthanized after a 3-month follow-up to assess the effect of treatment discontinuation. During treatment and follow-up mice will be monitored by radiographs and serum biochemical assays. Qualitative and quantitative histology will be performed on FD-affected and unaffected bones. Additional studies, including microCT, BSE-SEM image, qBSE and biomechanical analysis are also planned.
The availability of a murine model of human FD offers, for the first time, the opportunity, to test a specific treatment for a disease for which a cure does not exist to date. In principle, data from this study could be translatable to humans.
