Changes in gene expression in human skeletal stem cells transduced with constitutively active Gsα correlates with hallmark histopathological changes seen in fibrous dysplastic bone

Fibrous dysplasia (FD) of bone is a complex disease of the skeleton caused by dominant activating mutations of the GNAS locus encoding for the α subunit of the G protein-coupled receptor complex (Gsα). The mutation involves a substitution of arginine at position 201 by histidine or cysteine (GsαR201...

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Main Authors: Raimondo, Domenico, Remoli, Cristina, Astrologo, Letizia, Burla, Romina, La Torre, Mattia, Vernì, Fiammetta, Tagliafico, Enrico, Corsi, Alessandro, Del Giudice, Simona, Persichetti, Agnese, Giannicola, Giuseppe, Robey, Pamela G., Riminucci, Mara, Saggio, Isabella
Other Authors: School of Biological Sciences
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Language:English
Published: 2021
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Online Access:https://hdl.handle.net/10356/147069
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spelling sg-ntu-dr.10356-1470692023-02-28T17:08:52Z Changes in gene expression in human skeletal stem cells transduced with constitutively active Gsα correlates with hallmark histopathological changes seen in fibrous dysplastic bone Raimondo, Domenico Remoli, Cristina Astrologo, Letizia Burla, Romina La Torre, Mattia Vernì, Fiammetta Tagliafico, Enrico Corsi, Alessandro Del Giudice, Simona Persichetti, Agnese Giannicola, Giuseppe Robey, Pamela G. Riminucci, Mara Saggio, Isabella School of Biological Sciences NTU Institute of Structural Biology Science::Biological sciences Gene Ontologies Gene Expression Fibrous dysplasia (FD) of bone is a complex disease of the skeleton caused by dominant activating mutations of the GNAS locus encoding for the α subunit of the G protein-coupled receptor complex (Gsα). The mutation involves a substitution of arginine at position 201 by histidine or cysteine (GsαR201H or R201C), which leads to overproduction of cAMP. Several signaling pathways are implicated downstream of excess cAMP in the manifestation of disease. However, the pathogenesis of FD remains largely unknown. The overall FD phenotype can be attributed to alterations of skeletal stem/progenitor cells which normally develop into osteogenic or adipogenic cells (in cis), and are also known to provide support to angiogenesis, hematopoiesis, and osteoclastogenesis (in trans). In order to dissect the molecular pathways rooted in skeletal stem/progenitor cells by FD mutations, we engineered human skeletal stem/progenitor cells with the GsαR201C mutation and performed transcriptomic analysis. Our data suggest that this FD mutation profoundly alters the properties of skeletal stem/progenitor cells by pushing them towards formation of disorganized bone with a concomitant alteration of adipogenic differentiation. In addition, the mutation creates an altered in trans environment that induces neovascularization, cytokine/chemokine changes and osteoclastogenesis. In silico comparison of our data with the signature of FD craniofacial samples highlighted common traits, such as the upregulation of ADAM (A Disintegrin and Metalloprotease) proteins and other matrix-related factors, and of PDE7B (Phosphodiesterase 7B), which can be considered as a buffering process, activated to compensate for excess cAMP. We also observed high levels of CEBPs (CCAAT-Enhancer Binding Proteins) in both data sets, factors related to browning of white fat. This is the first analysis of the reaction of human skeletal stem/progenitor cells to the introduction of the FD mutation and we believe it provides a useful background for further studies on the molecular basis of the disease and for the identification of novel potential therapeutic targets. Published version 2021-03-24T05:27:39Z 2021-03-24T05:27:39Z 2020 Journal Article Raimondo, D., Remoli, C., Astrologo, L., Burla, R., La Torre, M., Vernì, F., Tagliafico, E., Corsi, A., Del Giudice, S., Persichetti, A., Giannicola, G., Robey, P. G., Riminucci, M. & Saggio, I. (2020). Changes in gene expression in human skeletal stem cells transduced with constitutively active Gsα correlates with hallmark histopathological changes seen in fibrous dysplastic bone. PloS One, 15(1). https://dx.doi.org/10.1371/journal.pone.0227279 1932-6203 https://hdl.handle.net/10356/147069 10.1371/journal.pone.0227279 31999703 2-s2.0-85078709920 1 15 en PloS One © 2020 The Author(s). This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Biological sciences
Gene Ontologies
Gene Expression
spellingShingle Science::Biological sciences
Gene Ontologies
Gene Expression
Raimondo, Domenico
Remoli, Cristina
Astrologo, Letizia
Burla, Romina
La Torre, Mattia
Vernì, Fiammetta
Tagliafico, Enrico
Corsi, Alessandro
Del Giudice, Simona
Persichetti, Agnese
Giannicola, Giuseppe
Robey, Pamela G.
Riminucci, Mara
Saggio, Isabella
Changes in gene expression in human skeletal stem cells transduced with constitutively active Gsα correlates with hallmark histopathological changes seen in fibrous dysplastic bone
description Fibrous dysplasia (FD) of bone is a complex disease of the skeleton caused by dominant activating mutations of the GNAS locus encoding for the α subunit of the G protein-coupled receptor complex (Gsα). The mutation involves a substitution of arginine at position 201 by histidine or cysteine (GsαR201H or R201C), which leads to overproduction of cAMP. Several signaling pathways are implicated downstream of excess cAMP in the manifestation of disease. However, the pathogenesis of FD remains largely unknown. The overall FD phenotype can be attributed to alterations of skeletal stem/progenitor cells which normally develop into osteogenic or adipogenic cells (in cis), and are also known to provide support to angiogenesis, hematopoiesis, and osteoclastogenesis (in trans). In order to dissect the molecular pathways rooted in skeletal stem/progenitor cells by FD mutations, we engineered human skeletal stem/progenitor cells with the GsαR201C mutation and performed transcriptomic analysis. Our data suggest that this FD mutation profoundly alters the properties of skeletal stem/progenitor cells by pushing them towards formation of disorganized bone with a concomitant alteration of adipogenic differentiation. In addition, the mutation creates an altered in trans environment that induces neovascularization, cytokine/chemokine changes and osteoclastogenesis. In silico comparison of our data with the signature of FD craniofacial samples highlighted common traits, such as the upregulation of ADAM (A Disintegrin and Metalloprotease) proteins and other matrix-related factors, and of PDE7B (Phosphodiesterase 7B), which can be considered as a buffering process, activated to compensate for excess cAMP. We also observed high levels of CEBPs (CCAAT-Enhancer Binding Proteins) in both data sets, factors related to browning of white fat. This is the first analysis of the reaction of human skeletal stem/progenitor cells to the introduction of the FD mutation and we believe it provides a useful background for further studies on the molecular basis of the disease and for the identification of novel potential therapeutic targets.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Raimondo, Domenico
Remoli, Cristina
Astrologo, Letizia
Burla, Romina
La Torre, Mattia
Vernì, Fiammetta
Tagliafico, Enrico
Corsi, Alessandro
Del Giudice, Simona
Persichetti, Agnese
Giannicola, Giuseppe
Robey, Pamela G.
Riminucci, Mara
Saggio, Isabella
format Article
author Raimondo, Domenico
Remoli, Cristina
Astrologo, Letizia
Burla, Romina
La Torre, Mattia
Vernì, Fiammetta
Tagliafico, Enrico
Corsi, Alessandro
Del Giudice, Simona
Persichetti, Agnese
Giannicola, Giuseppe
Robey, Pamela G.
Riminucci, Mara
Saggio, Isabella
author_sort Raimondo, Domenico
title Changes in gene expression in human skeletal stem cells transduced with constitutively active Gsα correlates with hallmark histopathological changes seen in fibrous dysplastic bone
title_short Changes in gene expression in human skeletal stem cells transduced with constitutively active Gsα correlates with hallmark histopathological changes seen in fibrous dysplastic bone
title_full Changes in gene expression in human skeletal stem cells transduced with constitutively active Gsα correlates with hallmark histopathological changes seen in fibrous dysplastic bone
title_fullStr Changes in gene expression in human skeletal stem cells transduced with constitutively active Gsα correlates with hallmark histopathological changes seen in fibrous dysplastic bone
title_full_unstemmed Changes in gene expression in human skeletal stem cells transduced with constitutively active Gsα correlates with hallmark histopathological changes seen in fibrous dysplastic bone
title_sort changes in gene expression in human skeletal stem cells transduced with constitutively active gsα correlates with hallmark histopathological changes seen in fibrous dysplastic bone
publishDate 2021
url https://hdl.handle.net/10356/147069
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