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

TY - JOUR

T1 - 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

AU - Remoli, Cristina

AU - Michienzi, Stefano

AU - Sacchetti, Benedetto

AU - Consiglio, Alberto Di

AU - Cersosimo, Stefania

AU - Spica, Emanuela

AU - Robey, Pamela G

AU - Holmbeck, Kenn

AU - Cumano, Ana

AU - Boyde, Alan

AU - Davis, Graham

AU - Saggio, Isabella

AU - Riminucci, Mara

AU - Bianco, Paolo

N1 - © 2014 American Society for Bone and Mineral Research.

PY - 2015/6/1

Y1 - 2015/6/1

N2 - 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.

AB - 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.

KW - Amino Acid Substitution

KW - Animals

KW - Bone and Bones/metabolism

KW - Chromogranins

KW - Disease Models, Animal

KW - Fibrous Dysplasia of Bone/genetics

KW - GTP-Binding Protein alpha Subunits, Gs/genetics

KW - Gene Expression Regulation

KW - Humans

KW - Mice

KW - Mice, Transgenic

KW - Mutation, Missense

KW - Organ Size

KW - Osteoblasts/metabolism

U2 - 10.1002/jbmr.2425

DO - 10.1002/jbmr.2425

M3 - Journal article

C2 - 25487351

SN - 0884-0431

VL - 30

SP - 1030

EP - 1043

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

IS - 6

ER -