Fibrous Dysplasia (OMIM174800) is a human genetic disease of the skeleton caused by point mutations in the GNAS gene, encoding the alpha subunit of Gs-alpha. The mutations arise from methylation-deamination sequence of cytosine in a CpG dinucleotide at codon 201 in pluripotent cells in early embryos, and can be modeled by heterotopic transplantation in SCID/bg mice of skeletal progenitors from the bone marrow of affected postnatal bones. We generated mouse model of the human disease expressing the disease gene either constitutively or as targeted to specific cell types in the bone/bone marrow environment. Mice with constitutively expressed GsaR201C develop an exact replica of the human disease over time, while mice with osteoblast-targeted mutation develop a different phenotype phenocopying high bone mass disorders caused by dyregulated Wnt signaling in humans. A detailed analysis of the mode of development of FD lesions, in mice, which consist in the deposition of abnormally unmineralized and over-remodeled bone that deforms and fractures, revealed that bone lesions arise from a unique process of unstable brownization of marrow adipocytes triggered by overproduction of cAMP and characterized by morphological and molecular changes (UCP-1, PGC1a) defining BAT. This process is followed by reprogramming of newly brownize marrow adipocytes to aberrant osteoblasts, which ectoptically express adipocyte genes. Among these, the gla-containing protein, Matrix Gla Protein (MGP; expressed in adipocytes but not in mouse osteoblasts) is a potent local inhibitor of bone mineralization, explaining the characteristic mineralization defect of FD bone both in humans and in mice. Importantly, the reprogramming of marrow adipocytes to aberrant osteoblasts via BAT occurs in an obligate site and time specific pattern, which is directly dictated by the emergence of adipogenesis at specific times and sites in the mouse bone marrow. Sites of yellow marrow such as the tail vertebrae are the first sites to be affected, and onset of disease coincides with onset of marrow adipogenesis. Of note, adipogenesis is a postnatal event in mouse bone marrow, and the entire bone formation process that spans prenatal development is accordingly normal in FD mice. Mouse ES cells expressing the mutation could be directed to be directed to normal chondrogenesis in vitro, and normal endochondral ossification in a transplantation model. These data demonstrate the significance of site and time specific emergence of differentiation potential in bone marrow skeletal progenitors; reveal that bone marrow adipocytes can be brownized by excess cAMP, as predictable from its effect in extramedullary beige and brown fat; demonstrate a unique path to bone disease strictly dependent on the existence and properties of skeletal stem cells and its dependent system of time an dsite specific lineages

Site- and time-specific emergence of adipogenic competence in skeletal stem cells determines the natural history of Fibrous Dysplasia of bone

REMOLI, CRISTINA;SAGGIO, Isabella;LABELLA, ROSSELLA;PALMISANO, BIAGIO;SACCHETTI, Benedetto;RIMINUCCI, MARA;BIANCO, Paolo
2015

Abstract

Fibrous Dysplasia (OMIM174800) is a human genetic disease of the skeleton caused by point mutations in the GNAS gene, encoding the alpha subunit of Gs-alpha. The mutations arise from methylation-deamination sequence of cytosine in a CpG dinucleotide at codon 201 in pluripotent cells in early embryos, and can be modeled by heterotopic transplantation in SCID/bg mice of skeletal progenitors from the bone marrow of affected postnatal bones. We generated mouse model of the human disease expressing the disease gene either constitutively or as targeted to specific cell types in the bone/bone marrow environment. Mice with constitutively expressed GsaR201C develop an exact replica of the human disease over time, while mice with osteoblast-targeted mutation develop a different phenotype phenocopying high bone mass disorders caused by dyregulated Wnt signaling in humans. A detailed analysis of the mode of development of FD lesions, in mice, which consist in the deposition of abnormally unmineralized and over-remodeled bone that deforms and fractures, revealed that bone lesions arise from a unique process of unstable brownization of marrow adipocytes triggered by overproduction of cAMP and characterized by morphological and molecular changes (UCP-1, PGC1a) defining BAT. This process is followed by reprogramming of newly brownize marrow adipocytes to aberrant osteoblasts, which ectoptically express adipocyte genes. Among these, the gla-containing protein, Matrix Gla Protein (MGP; expressed in adipocytes but not in mouse osteoblasts) is a potent local inhibitor of bone mineralization, explaining the characteristic mineralization defect of FD bone both in humans and in mice. Importantly, the reprogramming of marrow adipocytes to aberrant osteoblasts via BAT occurs in an obligate site and time specific pattern, which is directly dictated by the emergence of adipogenesis at specific times and sites in the mouse bone marrow. Sites of yellow marrow such as the tail vertebrae are the first sites to be affected, and onset of disease coincides with onset of marrow adipogenesis. Of note, adipogenesis is a postnatal event in mouse bone marrow, and the entire bone formation process that spans prenatal development is accordingly normal in FD mice. Mouse ES cells expressing the mutation could be directed to be directed to normal chondrogenesis in vitro, and normal endochondral ossification in a transplantation model. These data demonstrate the significance of site and time specific emergence of differentiation potential in bone marrow skeletal progenitors; reveal that bone marrow adipocytes can be brownized by excess cAMP, as predictable from its effect in extramedullary beige and brown fat; demonstrate a unique path to bone disease strictly dependent on the existence and properties of skeletal stem cells and its dependent system of time an dsite specific lineages
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11573/935137
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