title: Osteoblast-specific expression of the fibrous dysplasia (FD)-causing mutation Gsα(R201C) produces a high bone mass phenotype but does not reproduce FD in the mouse.
abstract: We recently reported the generation and initial characterization of the first direct model of human fibrous dysplasia (FD; OMIM #174800), obtained through the constitutive systemic expression of one of the disease-causing mutations, Gsα(R201C) , in the mouse. To define the specific pathogenetic role(s) of individual cell types within the stromal/osteogenic system in FD, we generated mice expressing Gsα(R201C) selectively in mature osteoblasts using the 2.3kb Col1a1 promoter. We show here that this results in a striking high bone mass phenotype but not in a mimicry of human FD. The high bone mass phenotype involves specifically a deforming excess of cortical bone and prolonged and ectopic cortical bone remodeling. Expression of genes characteristic of late stages of bone cell differentiation/maturation is profoundly altered as a result of expression of Gsα(R201C) in osteoblasts, and expression of the Wnt inhibitor Sost is reduced. Although high bone mass is, in fact, a feature of some types/stages of FD lesions in humans, it is marrow fibrosis, localized loss of adipocytes and hematopoietic tissue, osteomalacia, and osteolytic changes that together represent the characteristic pathological profile of FD, as well as the sources of specific morbidity. None of these features are reproduced in mice with osteoblast-specific expression of Gsα(R201C) . We further show that hematopoietic progenitor/stem cells, as well as more mature cell compartments, and adipocyte development are normal in these mice. These data demonstrate that effects of Gsα mutations underpinning FD-defining tissue changes and morbidity do not reflect the effects of the mutations on osteoblasts proper.
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Remoli
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Michienzi
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Benedetto
authors.initials: B
authors.lastname: Sacchetti
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Alberto Di
authors.initials: AD
authors.lastname: Consiglio
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Cersosimo
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Spica
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, USA.
authors.forename: Pamela G
authors.initials: PG
authors.lastname: Robey
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, USA.
authors.forename: Kenn
authors.initials: K
authors.lastname: Holmbeck
authors.affiliation: Lymphopoiesis Unit, INSERM, Pasteur Institute, Paris, France.
authors.forename: Ana
authors.initials: A
authors.lastname: Cumano
authors.affiliation: Dental Physical Sciences, Queen Mary University of London, London, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Boyde
authors.affiliation: Dental Physical Sciences, Queen Mary University of London, London, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Davis
authors.affiliation: Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, and IBPM CNR, Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Saggio
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Riminucci
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bianco
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D002864:Chromogranins; D004195:Disease Models, Animal; D005357:Fibrous Dysplasia of Bone / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism / Q000502:physiology
chemical_list: D002864:Chromogranins; C406732:GNAS protein, human; C498642:Gnas protein, mouse; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: BONE MARROW; FIBROUS DYSPLASIA; GNAS; GSα; HEMATOPOIETIC NICHE; MOUSE MODELS; OSTEOBLASTS