Fibrous dysplasia of bone (FD) is a crippling skeletal disease caused by activating mutations (R201C, R201H) of the Gsα gene. We recently generated GsαR201C transgenic mice that develop a FD skeletal phenotype. The analyses of these mice demonstrated that increased bone resorption is one of the main morbidity factors in FD and that RANKL is the major molecular mediator of osteolysis at affected skeletal sites.
Objective: The aim of this study is to investigate the effect of RANKL-inhibition on the development and evolution of skeletal lesions in our mouse model of FD.
Methods: Twenty-four mice (2 months of age) with radiographically detectable lesions in the tail vertebrae were selected for the study. The mice were treated with either anti-RANKL antibody, or isotype rat IgG2a as a control (300 μg/mouse) by intraperitoneal injection, twice a week for 14 weeks. In each experimental group, half of the animals were euthanized at the end of the treatment, whereas the remaining half underwent a 3-month follow-up. The mice were radiographically monitored during treatment and follow up, at the end of which histological analysis was performed.
Results: The anti-RANKL antibody induced a progressive increase in bone density with disappearance of lytic areas in all treated mice. In addition, it prevented the development of new bone lesions and deformities. In contrast, the radiographic phenotype steadily progressed in control mice. Histological analysis performed at the end of the treatment confirmed a higher amount of bone in the tail vertebrae of the mice treated with anti-RANKL antibody compared to controls. The newly formed bone obliterated the medullary cavity and showed, at least in part, a lamellar structure. In contrast, radiographically non-affected vertebrae maintained a normal space. As expected, virtually no osteoclasts were identified by histological and cytochemical (TRAP) analysis. The discontinuation of the treatment was associated with a rebound of the disease. In both anti-RANKL treated and control mice, radiographs after 3 months of follow up were similar. The presence of fibro-osseous tissue along with clusters of TRAP-positive osteoclasts confirmed the relapse of the disease at histological level.
Conclusions: This preliminary study indicates that treatment with the anti-RANKL antibody is effective in preventing the progression of the disease. However, once treatment is discontinued, rebound of the disease occurs. Design of alternative therapeutic strategies are in progress.
This work was supported by grants from Telethon and Million Dollar Bike Ride.
Disclosure: The authors declared no competing interests.
10 - 13 Jun 2017