GsαR201C 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 GsαR201C driven by the Adiponectin (Adq) promoter. Adq-GsαR201C mice developed a complex combination of metaphyseal, diaphyseal and cortical bone changes. In the metaphysis, GsαR201C 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, GsαR201C, 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, GsαR201C 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.

Schnurri-3 controls osteogenic fate of Adipoq-lineage progenitors in bone marrow

“…As a physiological source of adult bone stem/progenitor cells, bone marrow Adipoq-lineage progenitors play a crucial role in callus formation during bone fracture healing [ 35 , 36 ]. To investigate the impact of Shn3 in bone marrow Adipoq-lineage progenitors under pathological conditions, we conducted a femoral fracture model in Shn3 Adq and Shn3 f/f mice.…”

“…However, it is important to note that Adipoq-lineage progenitors also contribute to osteogenesis, despite not being prone to mineralization in in vitro assays. Studies using animal models lacking the α subunit of the stimulatory G protein (GSα) specifically under the control of Adipoq-Cre have revealed that Adipoq-derived stromal cells directly contribute to bone formation under both in vivo and in vitro conditions [ 36 ]. Furthermore, Adipoq-lineage progenitors give rise to matrix-embedded cells that contribute to skeletal regeneration in a drill-hole model [ 35 ].…”

An in vivo humanized model to study homing and sequestration of Plasmodium falciparum transmission stages in the bone marrow

“…Then ossicles and bone samples were decalcified in 10% EDTA for 2 weeks. For embedding, all samples were placed in 20% sucrose and 2% Polyvinylpyrrolidone (PVP) in PBS for 48 hr and embedded in an 8% porcine gelatin solution containing 20% sucrose and 2% PVP as previously reported ( Kusumbe et al., 2015 ; Palmisano et al., 2022 ). Five to 10 μm thick sections were cut with a cryostat and allowed to air-dry.…”

Angiotensin II Modulates Calcium/Phosphate Excretion in Experimental Model of Hypertension: Focus on Bone

“…Sections were stained with H&E and Sirius red and used to measure trabecular bone volume per tissue volume (BV/TV), osteoblast number per bone surface (N.Ob/BS) and osteoblast surface per bone surface (Ob.S/BS). Ten pictures at 20X were acquired with an optical microscope (Leica DMRB, Leica Biosystems, Muttenz, Switzerland) through a digital camera (Leica LAS EZ, Leica Biosystems, Switzerland) and all histomorphometric analyses were performed using Image J [ 31 ].…”