Constitutive expression of Gsα(R201C) in mice produces a heritable, direct replica of human fibrous dysplasia bone pathology and demonstrates its natural history

TY - JOUR

T1 - Constitutive expression of Gsα(R201C) in mice produces a heritable, direct replica of human fibrous dysplasia bone pathology and demonstrates its natural history

AU - Saggio, Isabella

AU - Remoli, Cristina

AU - Spica, Emanuela

AU - Cersosimo, Stefania

AU - Sacchetti, Benedetto

AU - Robey, Pamela G

AU - Holmbeck, Kenn

AU - Cumano, Ana

AU - Boyde, Alan

AU - Bianco, Paolo

AU - Riminucci, Mara

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

PY - 2014/2/1

Y1 - 2014/2/1

N2 - Fibrous dysplasia of bone (FD) is a crippling skeletal disease associated with postzygotic mutations (R201C, R201H) of the gene encoding the a subunit of the stimulatory G protein, Gs. By causing a characteristic structural subversion of bone and bone marrow, the disease results in deformity, hypomineralization, and fracture of the affected bones, with severe morbidity arising in childhood or adolescence. Lack of inheritance of the disease in humans is thought to reflect embryonic lethality of germline-transmitted activating Gsa mutations, which would only survive through somatic mosaicism. We have generated multiple lines of mice that express GsaR201C constitutively and develop an inherited, histopathologically exact replica of human FD. Robust transgene expression in neonatal and embryonic tissues and embryonic stem (ES) cells were associated with normal development of skeletal tissues and differentiation of skeletal cells. As in humans, FD lesions in mice developed only in the postnatal life; a defined spatial and temporal pattern characterized the onset and progression of lesions across the skeleton. In individual bones, lesions developed through a sequence of three distinct histopathological stages: a primary modeling phase defined by endosteal/medullary excess bone formation and normal resorption; a secondary phase, with excess, inappropriate remodeling; and a tertiary fibrous dysplastic phase, which reproduced a fullblown replica of the human bone pathology in mice of age ≥1 year. Gsa mutations are sufficient to cause FD, and are per se compatible with germline transmission and normal embryonic development in mice. Our novel murine lines constitute the first model of FD.

AB - Fibrous dysplasia of bone (FD) is a crippling skeletal disease associated with postzygotic mutations (R201C, R201H) of the gene encoding the a subunit of the stimulatory G protein, Gs. By causing a characteristic structural subversion of bone and bone marrow, the disease results in deformity, hypomineralization, and fracture of the affected bones, with severe morbidity arising in childhood or adolescence. Lack of inheritance of the disease in humans is thought to reflect embryonic lethality of germline-transmitted activating Gsa mutations, which would only survive through somatic mosaicism. We have generated multiple lines of mice that express GsaR201C constitutively and develop an inherited, histopathologically exact replica of human FD. Robust transgene expression in neonatal and embryonic tissues and embryonic stem (ES) cells were associated with normal development of skeletal tissues and differentiation of skeletal cells. As in humans, FD lesions in mice developed only in the postnatal life; a defined spatial and temporal pattern characterized the onset and progression of lesions across the skeleton. In individual bones, lesions developed through a sequence of three distinct histopathological stages: a primary modeling phase defined by endosteal/medullary excess bone formation and normal resorption; a secondary phase, with excess, inappropriate remodeling; and a tertiary fibrous dysplastic phase, which reproduced a fullblown replica of the human bone pathology in mice of age ≥1 year. Gsa mutations are sufficient to cause FD, and are per se compatible with germline transmission and normal embryonic development in mice. Our novel murine lines constitute the first model of FD.

KW - Age Factors

KW - Amino Acid Substitution

KW - Animals

KW - Bone Remodeling/genetics

KW - Disease Models, Animal

KW - Embryo, Mammalian/enzymology

KW - Fibrous Dysplasia of Bone/enzymology

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

KW - Gene Expression

KW - Humans

KW - Mice

KW - Mice, Transgenic

KW - Mutation, Missense

KW - Osteogenesis/genetics

U2 - 10.1002/jbmr.2267

DO - 10.1002/jbmr.2267

M3 - Journal article

C2 - 24764158

SN - 0884-0431

VL - 29

SP - 2357

EP - 2368

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

IS - 11

ER -