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

Cristina Remoli; Stefano Michienzi; Benedetto Sacchetti; Alberto Di Consiglio; Stefania Cersosimo; Emanuela Spica; Pamela G Robey; Kenn Holmbeck; Ana Cumano; Alan Boyde; Graham Davis; Isabella Saggio; Mara Riminucci; Paolo Bianco

doi:10.1002/jbmr.2425

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

Cristina Remoli, Stefano Michienzi, Benedetto Sacchetti, Alberto Di Consiglio, Stefania Cersosimo, Emanuela Spica, Pamela G Robey, Kenn Holmbeck, Ana Cumano, Alan Boyde, Graham Davis, Isabella Saggio, Mara Riminucci, Paolo Bianco

17 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Vol/bind	30
Udgave nummer	6
Sider (fra-til)	1030-43
Antal sider	14
ISSN	0884-0431
DOI	https://doi.org/10.1002/jbmr.2425
Status	Udgivet - 1 jun. 2015
Udgivet eksternt	Ja

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10.1002/jbmr.2425

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/jbmr.2425

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Remoli, C., Michienzi, S., Sacchetti, B., Consiglio, A. D., Cersosimo, S., Spica, E., Robey, P. G., Holmbeck, K., Cumano, A., Boyde, A., Davis, G., Saggio, I., Riminucci, M., & Bianco, P. (2015). 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. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 30(6), 1030-43. https://doi.org/10.1002/jbmr.2425

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. / Remoli, Cristina; Michienzi, Stefano; Sacchetti, Benedetto et al.

I: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, Bind 30, Nr. 6, 01.06.2015, s. 1030-43.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Remoli, C, Michienzi, S, Sacchetti, B, Consiglio, AD, Cersosimo, S, Spica, E, Robey, PG, Holmbeck, K, Cumano, A, Boyde, A, Davis, G, Saggio, I, Riminucci, M & Bianco, P 2015, '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', Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, bind 30, nr. 6, s. 1030-43. https://doi.org/10.1002/jbmr.2425

Remoli C, Michienzi S, Sacchetti B, Consiglio AD, Cersosimo S, Spica E et al. 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. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2015 jun. 1;30(6):1030-43. doi: 10.1002/jbmr.2425

Remoli, Cristina ; Michienzi, Stefano ; Sacchetti, Benedetto et al. / 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. I: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2015 ; Bind 30, Nr. 6. s. 1030-43.

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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.",

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author = "Cristina Remoli and Stefano Michienzi and Benedetto Sacchetti and Consiglio, {Alberto Di} and Stefania Cersosimo and Emanuela Spica and Robey, {Pamela G} and Kenn Holmbeck and Ana Cumano and Alan Boyde and Graham Davis and Isabella Saggio and Mara Riminucci and Paolo Bianco",

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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

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.

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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 -

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

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