RANKL inhibition reduces lesional cellularity, Gαs variant expression and enables osteogenic maturation in fibrous dysplasia

Abstract

Abstract Fibrous dysplasia (FD) is a rare, disabling skeletal disease with no established treatments. Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear Kappa-B ligand (RANKL) as a potential treatment strategy. In this study, we investigated mechanisms underlying RANKL neutralization with the monoclonal antibody denosumab on FD osteoprogenitors, by evaluating human FD tissue pre- and post-treatment, and in murine in vivo and ex vivo pre-clinical models. Histological analysis of human and mouse tissue demonstrated increased osteogenic maturation, reduced cellularity, and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL neutralization. RNA sequencing of human and mouse tissue supported these findings. Interplay between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model, indicating that the proliferation of abnormal FD osteoprogenitors was dependent on osteoclastogenesis. Results from this study demonstrate that, beyond its expected anti-osteoclastic effects, denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation, leading to increased lesional bone formation. These findings highlight an unappreciated role for cellular crosstalk between osteoclasts and pre-osteoblast/osteoblasts as a driver of FD pathology, and demonstrate a novel mechanism of denosumab action in the treatment of bone disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT03571191