Exploring bone formation mechanism and pattern during RANKL inhibition in a fibrous dysplasia mouse model

: Fibrous dysplasia (FD) of bone is a fibro-osseous disorder caused by GNAS mutations with defective osteogenic differentiation and increased bone remodeling activity. Inhibition of RANKL leads to the replacement of FD lesions with bone. However, the mechanism and pattern of deposition of the newly formed bone remain unclear. Here, we perform morphological and molecular analyses on EF1α-GsαR201C (FD) mice receiving an anti-mouse RANKL antibody. We show that, although the treatment reduces the expression of osteogenic genes, osteoblastic cells continue to produce bone matrix within FD lesions. However, bone formation does not occur in a diffuse or stochastic manner but follows an ordered spatial pattern that is restricted to the surfaces of the lesional bone. These results suggest that during RANKL inhibition the amount of intra-lesional bone trabecular surfaces is critical to the process of cell differentiation and to the skeletal improvement that FD patients may achieve during the treatment.