Age-Dependent Demise of GNAS-Mutated Skeletal Stem Cells and Normalization of Fibrous Dysplasia of Bone

We Studied the role of somatic mosaicism in fibrous dysplasia of bone (FD) within the context of skeletal (mesenchymal) stern cells by assessing the frequency of mutated colony forming unit-fibroblasts (CFU-Fs) from FD lesions. and in some cases, from unaffected sites, in a series of patients. There was a tight inverse correlation between the percentage mutant CFU-F versus age, suggesting demise of mutant stem cells caused by exuberant apoptosis noted in samples from young patients. In older patients. either partially or completely normal bone/marrow histology was observed. On in vivo transplantation. FD ossicles were generated only by cell strains in which mutant CFU-Fs were identified. strains that lacked mutant CFU-F (but were mutation positive) failed to regenerate an FD ossicle. These data indicate that GNAS Mutations are only Pathogenic when in clonogenic skeletal stern cells. From these data, we have evolved the novel concept of normalization of FD. As a lesion ages, mutant stern cells fail to self-renew, and their progeny are consumed by apoptosis. whereas residual normal stern cells survive, self-renew. and enable formation of a normal Structure. This suggests that activating GNAS Mutations disrupt a pathway that is required for skeletal stern cell self-renewal.