The Gsalpha/cAMP signaling pathway mediates the effect of a variety of hormones and factors that regulate the homeostasis of the post-natal skeleton. Hence, the dysregulated activity of Gsalpha due to gain-of-function mutations (R201C/R201H) results in severe architectural and functional derangements of the entire bone/bone marrow organ. While the consequences of gain-of-function mutations of Gsalpha have been extensively investigated in osteoblasts and in bone marrow osteoprogenitor cells at various differentiation stages, their effect in adipogenically-committed bone marrow stromal cells has remained unaddressed. We generated a mouse model with expression of Gsalpha R201C driven by the Adiponectin (Adq) promoter. AdqGsalpha R201C mice developed a complex combination of metaphyseal, diaphyseal and cortical bone changes. In the metaphysis, Gsalpha R201C caused an early phase of bone resorption followed by bone deposition. Metaphyseal bone formation was sustained by cells that were traced by Adq-Cre and eventually resulted in a high trabecular bone mass phenotype. In the diaphysis, Gsalpha R201C, in combination with estrogen, triggered the osteogenic activity of Adq-Cre-targeted perivascular bone marrow stromal cells leading to intramedullary bone formation. Finally, consistent with the previously unnoticed presence of Adq-Cre-marked pericytes in intraosseous blood vessels, Gsalpha R201C caused the development of a lytic phenotype that affected both cortical (increased porosity) and trabecular (tunneling resorption) bone. These results provide the first evidence that the Adq-cell network in the skeleton not only regulates bone resorption but also contributes to bone formation, and that the Gsalpha/cAMP pathway is a major modulator of both functions.

Gsaplha R201C and estrogen reveal different subsets of bone marrow adiponectin expressing osteogenic cells / Palmisano, Biagio; Labella1, Rossella; Donsante, Samantha; Remoli, Cristina; Spica, Emanuela; Coletta, Ilenia; Farinacci, Giorgia; Dello Spedale Venti, Michele; Saggio, Isabella; Serafini, Marta; Gehron Robey, Pamela; Corsi, Alessandro; Riminucci, Mara. - In: BONE RESEARCH. - ISSN 2095-4700. - (2022).

GsαR201C and estrogen reveal different subsets of bone marrow adiponectin expressing osteogenic cells

Biagio Palmisano
Co-primo
;
Samantha Donsante;Cristina Remoli;Emanuela Spica;Ilenia Coletta;Giorgia Farinacci;Michele Dello Spedale Venti;Isabella Saggio;Alessandro Corsi
Penultimo
;
Mara Riminucci
Ultimo
2022

Abstract

The Gsalpha/cAMP signaling pathway mediates the effect of a variety of hormones and factors that regulate the homeostasis of the post-natal skeleton. Hence, the dysregulated activity of Gsalpha due to gain-of-function mutations (R201C/R201H) results in severe architectural and functional derangements of the entire bone/bone marrow organ. While the consequences of gain-of-function mutations of Gsalpha have been extensively investigated in osteoblasts and in bone marrow osteoprogenitor cells at various differentiation stages, their effect in adipogenically-committed bone marrow stromal cells has remained unaddressed. We generated a mouse model with expression of Gsalpha R201C driven by the Adiponectin (Adq) promoter. AdqGsalpha R201C mice developed a complex combination of metaphyseal, diaphyseal and cortical bone changes. In the metaphysis, Gsalpha R201C caused an early phase of bone resorption followed by bone deposition. Metaphyseal bone formation was sustained by cells that were traced by Adq-Cre and eventually resulted in a high trabecular bone mass phenotype. In the diaphysis, Gsalpha R201C, in combination with estrogen, triggered the osteogenic activity of Adq-Cre-targeted perivascular bone marrow stromal cells leading to intramedullary bone formation. Finally, consistent with the previously unnoticed presence of Adq-Cre-marked pericytes in intraosseous blood vessels, Gsalpha R201C caused the development of a lytic phenotype that affected both cortical (increased porosity) and trabecular (tunneling resorption) bone. These results provide the first evidence that the Adq-cell network in the skeleton not only regulates bone resorption but also contributes to bone formation, and that the Gsalpha/cAMP pathway is a major modulator of both functions.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11573/1642770
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