Elevated Gα<sub>11</sub>expression in osteoblast lineage cells promotes osteoclastogenesis and leads to enhanced trabecular bone accrual in response to pamidronate

Cruz, Ariana Dela; Grynpas, Marc D.; Mitchell, Jane

doi:10.1152/ajpendo.00049.2016

Cited by 3 publications

(2 citation statements)

References 52 publications

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“…However, their data compared mRNA levels but not cellular Gq activity, which for GTPases is a more relevant readout. In support of our findings, other scientists suggest that activation of G proteins by AlF4 treatment activates osteoclast differentiation ( 60 ) and that elevated expression of Gq in osteoblasts increases osteoclastogenesis in a transgenic mouse model ( 61 ). New therapeutic tools to inhibit G protein signaling are currently being characterized, and it remains to be seen whether they will provide helpful tools in the treatment of auto-inflammatory diseases such as RA as well ( 62 ).…”

Section: Discussionsupporting

confidence: 90%

Pasteurella multocida Toxin Triggers RANKL-Independent Osteoclastogenesis

et al. 2017

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Bone remodeling is a continuous process to retain the structural integrity and function of the skeleton. A tight coupling is maintained between osteoclast-mediated resorption of old or damaged bones and osteoblast-mediated formation of new bones for bone homeostasis. While osteoblasts differentiate from mesenchymal stem cells, osteoclasts are hematopoietic in origin and derived from myeloid precursor cells. Osteoclast differentiation is driven by two cytokines, cytokine receptor activator of NF-κB ligand (RANKL), and macrophage colony-stimulating factor. Imbalances in the activity of osteoblasts and osteoclasts result in the development of bone disorders. Bacterially caused porcine atrophic rhinitis is characterized by a loss of nasal ventral conche bones and a distortion of the snout. While Bordetella bronchiseptica strains cause mild and reversible symptoms, infection of pigs with toxigenic Pasteurella multocida strains causes a severe and irreversible decay. The responsible virulence factor Pasteurella multocida toxin (PMT) contains a deamidase activity in its catalytical domain that constitutively activates specific heterotrimeric G proteins to induce downstream signaling cascades. While osteoblasts are inhibited by the toxin, osteoclasts are activated, thus skewing bone remodeling toward excessive bone degradation. Still, the mechanism by which PMT interferes with bone homeostasis, and the reason for this unusual target tissue is not yet well understood. Here, we show that PMT has the potential to differentiate bone marrow-derived macrophages into functional osteoclasts. This toxin-mediated differentiation process is independent of RANKL, a cytokine believed to be indispensable for triggering osteoclastogenesis, as addition of osteoprotegerin to PMT-treated macrophages does not show any effect on PMT-induced osteoclast formation. Although RANKL is not a prerequisite, toxin-primed macrophages show enhanced responsiveness to low concentrations of RANKL, suggesting that the PMT-generated microenvironment offers conditions where low concentrations of RANKL lead to an increase in the number of osteoclasts resulting in increased resorption. PMT-mediated release of the osteoclastogenic cytokines such as IL-6 and TNF-α, but not IL-1, supports the differentiation process. Although the production of cytokines and the subsequent activation of signaling cascades are necessary for PMT-mediated differentiation into osteoclasts, they are not sufficient and PMT-induced activation of G protein signaling is essential for efficient osteoclastogenesis.

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Section: Discussionsupporting

confidence: 90%

Pasteurella multocida Toxin Triggers RANKL-Independent Osteoclastogenesis

et al. 2017

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“…It was found that 10-week -old DSEL mice predominantly developed trabecular alterations and only minor cortical changes [ 28 , 33 ]. PKC activation in osteoblasts had been shown to decrease trabecular and cortical bone volume [ 25 , 26 , 34 ]. Intermittent administration of a PTH analog, which was recently identified to selectively activate PKC, led to an osteoanabolic effect [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Inactivation of Osteoblast PKC Signaling Reduces Cortical Bone Mass and Density and Aggravates Renal Osteodystrophy in Mice with Chronic Kidney Disease on High Phosphate Diet

Zaloszyc

Choquet

Sayeh

et al. 2022

IJMS

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Chronic kidney disease (CKD) frequently leads to hyperphosphatemia and hyperparathyroidism, mineral bone disorder (CKD-MBD), ectopic calcifications and cardiovascular mortality. PTH activates the osteoanabolic Gαs/PKA and the Gαq/11/PKC pathways in osteoblasts, the specific impact of the latter in CKD-MBD is unknown. We generated osteoblast specific Gαq/11 knockout (KO) mice and established CKD-MBD by subtotal nephrectomy and dietary phosphate load. Bone morphology was assessed by micro-CT, osteoblast function by bone planar scintigraphy at week 10 and 22 and by histomorphometry. Osteoblasts isolated from Gαq/11 KO mice increased cAMP but not IP3 in response to PTH 1-34, demonstrating the specific KO of the PKC signaling pathway. Osteoblast specific Gαq/11 KO mice exhibited increased serum calcium and reduced bone cortical thickness and mineral density at 24 weeks. CKD Gαq/11 KO mice had similar bone morphology compared to WT, while CKD Gαq/11-KO on high phosphate diet developed decreased metaphyseal and diaphyseal cortical thickness and area, as well as a reduction in trabecular number. Gαq/11-KO increased bone scintigraphic tracer uptake at week 10 and mitigated tracer uptake in CKD mice at week 22. Histological bone parameters indicated similar trends. Gαq/11-KO in osteoblast modulates calcium homeostasis, bone formation rate, bone morphometry, and bone mineral density. In CKD and high dietary phosphate intake, osteoblast Gαq/11/PKC KO further aggravates mineral bone disease.

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Overexpression of Gα11 in Osteoblast Lineage Cells Suppresses the Osteoanabolic Response to Intermittent PTH and Exercise

2016

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Intermittent parathyroid hormone (iPTH) treatment and mechanical loading are osteoanabolic stimuli that are partially mediated through actions on G protein-coupled receptors (GPCRs). GPCR signaling can be altered by heterotrimeric G protein Gα subunits levels, which can therefore lead to altered responses to such stimuli. Previous studies have suggested that enhanced signaling through the Gαq/11 pathway inhibits the osteoanabolic actions of PTH. The influence of Gαq/11 signaling on mechanotransduction, however, has not been reported in vivo. Using transgenic mice that specifically overexpress Gα11 in osteoblast lineage cells (G11-Tg mice), we investigated the skeletal effects of elevated Gα11 levels on iPTH and mechanical loading by treadmill exercise. Both regimens increased trabecular and cortical bone in Wild-Type (WT) mice as a result of increased bone formation. In G11-Tg mice, there was no change in trabecular or cortical bone and no increase in bone formation in response to iPTH or exercise. While exercise reduced osteoclast parameters in WT mice, these changes were diminished in G11-Tg mice as expression of M-csf and Trap remained increased. Collectively, our results suggest that osteoblastic upregulation of Gα11 is inhibitory to osteoanabolic actions of both PTH and exercise, and that its suppression may be a promising target for treating bone loss.

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Elevated Gα₁₁expression in osteoblast lineage cells promotes osteoclastogenesis and leads to enhanced trabecular bone accrual in response to pamidronate

Cited by 3 publications

References 52 publications

Pasteurella multocida Toxin Triggers RANKL-Independent Osteoclastogenesis

Pasteurella multocida Toxin Triggers RANKL-Independent Osteoclastogenesis

Inactivation of Osteoblast PKC Signaling Reduces Cortical Bone Mass and Density and Aggravates Renal Osteodystrophy in Mice with Chronic Kidney Disease on High Phosphate Diet

Overexpression of Gα11 in Osteoblast Lineage Cells Suppresses the Osteoanabolic Response to Intermittent PTH and Exercise

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Elevated Gα11expression in osteoblast lineage cells promotes osteoclastogenesis and leads to enhanced trabecular bone accrual in response to pamidronate

Cited by 3 publications

References 52 publications

Pasteurella multocida Toxin Triggers RANKL-Independent Osteoclastogenesis

Pasteurella multocida Toxin Triggers RANKL-Independent Osteoclastogenesis

Inactivation of Osteoblast PKC Signaling Reduces Cortical Bone Mass and Density and Aggravates Renal Osteodystrophy in Mice with Chronic Kidney Disease on High Phosphate Diet

Overexpression of Gα11 in Osteoblast Lineage Cells Suppresses the Osteoanabolic Response to Intermittent PTH and Exercise

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Elevated Gα₁₁expression in osteoblast lineage cells promotes osteoclastogenesis and leads to enhanced trabecular bone accrual in response to pamidronate