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.
FD is therapeutically an orphan disease. The availability of a mouse model of the human FD of bone offers, for the first time, the opportunity to test a specific pharmacological treatment and the unique advantage of controlled studies in a sizable number of individuals homogenous for age and type of lesion.
Specifically this study will let to investigate the ability of a RANKL-inhibiting biologic molecule to interfere either with the progression of well established FD lesions or with the development of new FD lesions in FD-mice with either nascent (2-3 months old mice) or osteolytic (6-9 months old mice) or with full-blown lesions (~12 months old mice). In addition, this study will let a) to identify precisely the type of lesions to be targeted and the timing of intervention, b) to assess if any effect of treatment is influenced by the phase of the FD lesions, if multiple cycles of treatments are well tolerated and if and which adverse effects appear along with treatment and c) to correlate accurately the radiographic and histologic features of the FD-affected and unaffected skeletal segments of treated compared to those of untreated mice. Finally, the data from this study could be, in the case of beneficial therapeutic effects, significant to elaborate a schedule of treatment and, in principle, translatable to humans.