RANKL Inhibition in Fibrous Dysplasia of Bone: A Preclinical Study in a Mouse Model of the Human Disease

Abstract

Fibrous dysplasia of bone/McCune‐Albright syndrome (Polyostotic FD/MAS; OMIM#174800) is a crippling skeletal disease caused by gain‐of‐function mutations of Gsα. Enhanced bone resorption is a recurrent histological feature of FD and a major cause of fragility of affected bones. Previous work suggests that increased bone resorption in FD is driven by RANKL and some studies have shown that the anti‐RANKL monoclonal antibody, denosumab, reduces bone turnover and bone pain in FD patients. However, the effect of RANKL inhibition on the histopathology of FD and its impact on the natural history of the disease remain to be assessed. In this study, we treated the EF1α‐GsαR201C mice, which develop an FD‐like phenotype, with an anti‐mouse RANKL monoclonal antibody. We found that the treatment induced marked radiographic and microscopic changes at affected skeletal sites in 2‐month‐old mice. The involved skeletal segments became sclerotic due to the deposition of new, highly mineralized bone within developing FD lesions and showed a higher mechanical resistance compared to affected segments from untreated transgenic mice. Similar changes were also detected in older mice with a full‐blown skeletal phenotype. The administration of anti‐mouse RANKL antibody arrested the growth of established lesions and, in young mice, prevented the appearance of new ones. However, after drug withdrawal, the newly formed bone was remodelled into FD tissue and the disease progression resumed in young mice. Taken together, our results show that the anti‐RANKL antibody significantly affected the bone pathology and natural history of FD in the mouse. Pending further work on the prevention and management of relapse after treatment discontinuation, our preclinical study suggests that RANKL inhibition may be an effective therapeutic option for FD patients. © 2019 American Society for Bone and Mineral Research.

Zoledronic Acid in a Mouse Model of Human Fibrous Dysplasia: Ineffectiveness on Tissue Pathology, Formation of “Giant Osteoclasts” and Pathogenetic Implications

“…We demonstrated that the administration of ZA alone had no significant effect on the tissue changes of FD and was associated with the persistence of intra-lesional osteoclasts and with the appearance of "giant osteoclasts". We also confirmed that the anti-mRANKL Ab leads to the formation of mineralized bone in the setting of FD lesions [17]. Overall, our results support the hypothesis that osteoclasts per se, independently of their resorptive activity, are essential for development and expansion of FD lesions.…”

“…In contrast, sporadic clinical studies performed with denosumab, a humanized antibody against the central osteoclastogenic factor RANKL, showed that RANKL inhibition may effectively reduce the growth rate of FD lesions, besides reducing pain and bone turn-over markers (for review see [5]). Using the transgenic EF1α-Gsα R201C mouse model of FD [16] and a murine analog of denosumab anti-mouse RANKL antibody (anti-mRANKL Ab), we recently demonstrated that the beneficial effect of RANKL inhibition in FD is underlaid by critical changes in the histopathology of the disease [17]. Indeed, in transgenic FD mice the anti-mRANKL Ab completely suppressed osteoclastogenesis and led to the replacement of the pre-existing FD tissue with a highly mineralized and mechanically sound bone.…”

Advances in Models of Fibrous Dysplasia/McCune-Albright Syndrome

“…Palmisano et al tested the effect of RANKL (receptor activator of nuclear factor kappa-B ligand) inhibition by treating the mice with an anti-RANKL antibody (30). They found that new and highly mineralized bone replaced the FD-like lesions in 2-month old mice, and the bone density increased.…”

Changes in gene expression in human skeletal stem cells transduced with constitutively active Gsα correlates with hallmark histopathological changes seen in fibrous dysplastic bone

“…There is a tight connection between cells in the hematopoietic lineage and bone remodeling, and many chemokines involved in inflammatory responses are also responsible for the regulation of osteoclastogenesis. C-X-C Ligands (CXCLs) such as CXCL1, CXCL13 and CXCL2 are highly over expressed in Gsα R201C mutant hBMSCs (Fig 5B), are able to attract osteoclast precursors to the bone environment [62], to enhance the proliferation of osteoclast precursor cells of bone marrow-derived macrophages [63] and to stimulate Tumor Necrosis Factor Ligand Superfamily member 11 (TNFSF11, also known as RANKL) expression [64], which has recently been shown to be over-expressed in human FD and in transgenic models of the disease [20,65]. Prostaglandin E2 (PGE2) produced by osteoblasts is also a potent stimulator of bone resorption, and Phospholipase A2 Group IVA (PLA2G4A), highly expressed in our system, plays a key role in PGE2 production [66].…”