title: Age-dependent demise of GNAS-mutated skeletal stem cells and "normalization" of fibrous dysplasia of bone.
abstract: We studied the role of somatic mosaicism in fibrous dysplasia of bone (FD) within the context of skeletal ("mesenchymal") stem 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 stem cells. From these data, we have evolved the novel concept of "normalization" of FD. As a lesion ages, mutant stem cells fail to self-renew, and their progeny are consumed by apoptosis, whereas residual normal stem 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 stem cell self-renewal.
authors.affiliation: Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA.
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Kuznetsov
authors.forename: Natasha
authors.initials: N
authors.lastname: Cherman
authors.forename: Mara
authors.initials: M
authors.lastname: Riminucci
authors.forename: Michael T
authors.initials: MT
authors.lastname: Collins
authors.forename: Pamela Gehron
authors.initials: PG
authors.lastname: Robey
authors.forename: Paolo
authors.initials: P
authors.lastname: Bianco
mesh_terms: D000293:Adolescent; D000328:Adult; D000375:Aging / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000473:pathology; D002478:Cells, Cultured; D002648:Child; D002864:Chromogranins; D002999:Clone Cells; D003114:Colony-Forming Units Assay; D004252:DNA Mutational Analysis; D005260:Female; D005357:Fibrous Dysplasia of Bone / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000166:cytology*; D009154:Mutation / Q000235:genetics*; D020135:Peptide Nucleic Acids / Q000378:metabolism; D011877:Radionuclide Imaging; D013234:Stem Cells / Q000473:pathology*; D017154:Stromal Cells / Q000473:pathology / Q000637:transplantation
chemical_list: D002864:Chromogranins; D020135:Peptide Nucleic Acids; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs