Fibrous Dysplasia/McCune-Albright Syndrome (FD) is an invalidating disease of the skeleton caused by activating mutation of the GNAS gene. The result of the mutation in bone is the appearance of numerous osteoclasts with the deposition of a fibrotic tissue in the bone marrow. This causes fragility of the affected skeletal segments with spontaneous fractures and pain. Therapeutic options for FD are mainly surgical aiming to correct fractures and deformities. To date, two different anti-resorptive drugs have been used in FD patients: Bisphosphonates (BPs), the main medical option, and denosumab, a monoclonal antibody against RANKL, the most important factor for osteoclast differentiation and activity, which is highly expressed in FD lesions.
We recently showed in a mouse model of FD (EF1a-GsaR201C) that denosumab but not zoledronate, a potent BP, could be an effective therapy for FD. RANKL inhibition in EF1a-GsaR201C mice was able to arrest the growth of FD lesions, convert the fibrotic tissue into mineralized bone and prevent the appearance of new lesions by depleting osteoclastogenesis. However, RANKL inhibition prevents osteoclast formation in the entire skeleton and so may interfere with skeletal growth and regeneration. To overcome these problems, alternative strategies that inhibit osteoclast function are required.
Through a gene expression profiling of mouse FD lesions, we have observed that RANKL inhibition in EF1a-GsaR201C mice reduces the Matrix Metalloproteinase 9 (MMP9). MMP9 is secreted by osteoclasts and may be involved in the continuous remodeling of the fibro-osseous tissue of FD. This proposal aims to understand the role of MMP9 in mouse FD lesions and to assess the effect of its inhibition on the maturation and mineralization of the pathological fibrous tissue.
We hope that our results will advance the understanding of FD, leading to the development of specific treatments that target the disease without affecting the physiology of the skeleton.
As most skeletal diseases, FD is currently treated with Bisphosphonates (BPs) as a non-specific approach to inhibit bone resorption and to limit FD lesion growth and pain. However, to date BP administration has resulted in controversial effects on bone pain and no effect at all on the pathology and progression of the disease. By using our FD mouse model, we have demonstrated for the first time that osteoclastogenesis, and not bone resorption, may be an effective therapeutic target in FD. An antibody against the most important stimulator of osteoclast formation, RANKL (anti-RANKL antibody, denosumab) is already available and approved for therapy in other bone diseases. However, inhibition of RANKL prevents osteoclastogenesis in the entire skeleton and the complete absence of osteoclasts may severely compromise bone growth and remodeling, especially in young FD patients, and may have important undesired effects after treatment discontinuation. We will attempt the selective targeting of the osteoclast-derived factors that interfere with the osteogenic maturation and the mineralization of the FD tissue. This may represent a rational and valid alternative approach to reproduce the positive effects of denosumab without the clinical challenges posed by its inhibition. Of note, we will investigate a molecule, MMP9, that has been demonstrated to be involved in the development of pathological fibrosis and osteolytic lesions in several diseases. Accomplishing the aims of this project could pave the way for the development of therapeutic approaches that could have a major impact on quality of life of FD patients.