Gsα^R201C and estrogen reveal different subsets of bone marrow adiponectin expressing osteogenic cells

Abstract

The Gsα/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 Gsα 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 Gsα 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 Gsα ^R201C driven by the Adiponectin (Adq) promoter. Adq-Gsα ^R201C mice developed a complex combination of metaphyseal, diaphyseal and cortical bone changes. In the metaphysis, Gsα ^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, Gsα ^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, Gsα ^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 Gsα/cAMP pathway is a major modulator of both functions.

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Funding

University of Pennsylvania (Penn)(MDBR-22-101-FDMAS)

Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)(IG-24614)

U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research (NIDCR)(ZIA DE000380)

Sapienza Università di Roma (Sapienza University of Rome)(RM118164289636F0)