Activation of G Proteins by Aluminum Fluoride Enhances RANKL-Mediated Osteoclastogenesis

Park, Boryung; Yang, Young-Kyu; Choi, Byung Jai; Kim, Min Seuk; Shin, Dong Min

doi:10.4196/kjpp.2013.17.5.427

Cited by 10 publications

(4 citation statements)

References 35 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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“…Notably, the activity of NFATc1 are known to be regulated by Ca 2+ signaling relied on the tyrosine phosphorylation pathways. 4,25 In this study, vitamin K 1 treatment slightly enhanced the RANKL-induced Ca 2+ oscillation, whereas MK-4 and MK-7 reduced the frequency of Ca 2+ oscillations in BMMs (Fig. 5).…”

Section: Discussionsupporting

confidence: 48%

The inhibitory effect of vitamin K on RANKL-induced osteoclast differentiation and bone resorption

Kim

Ahn

2015

Food Funct.

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To further understand the correlation between vitamin K and bone metabolism, the effects of vitamins K1, menaquinone-4 (MK-4), and menaquinone-7 (MK-7) on RANKL-induced osteoclast differentiation and bone resorption were comparatively investigated. Vitamin K2 groups (MK-4 and MK-7) were found to significantly inhibit RANKL-medicated osteoclast cell formation of bone marrow macrophages (BMMs) in a dose-dependent manner, without any evidence of cytotoxicity. The mRNA expression of specific osteoclast differentiation markers, such as c-Fos, NFATc1, OSCAR, and TRAP, as well as NFATc1 protein expression and TRAP activity in RANKL-treated BMMs were inhibited by vitamin K2, although MK-4 exhibited a significantly greater efficiency compared to MK-7. In contrast, the same dose of vitamin K1 had no inhibitory effect on RANKL-induced osteoclast cell formation, but increased the expression of major osteoclastogenic genes. Interestingly, vitamins K1, MK-4 and MK-7 all strongly inhibited osteoclastic bone resorption (p < 0.01) in a dose dependent manner. These results suggest that vitamins K1, MK-4 and MK-7 have anti-osteoporotic properties, while their regulation effects on osteoclastogenesis are somewhat different.

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“…Accumulated evidence has revealed that RANKL-induced [Ca 2+ ] i oscillations require orchestration of Ca 2+ mobilization from internal and external Ca 2+ stores [ 7 , 11 – 13 ]. Especially, our previous work indicated that release of Ca 2+ from inositol 1,4,5-trisphosphate (IP 3 )-sensitive Ca 2+ stores and influx of extracellular Ca 2+ via store-operated Ca 2+ channels (SOCCs) are both essential for building up RANKL-induced [Ca 2+ ] i oscillations [ 7 ].…”

Section: Resultsmentioning

confidence: 99%

Attenuated RANKL-induced cytotoxicity by Portulaca oleracea ethanol extract enhances RANKL-mediated osteoclastogenesis

Erkhembaatar

Choi

Lee³

et al. 2015

BMC Complement Altern Med

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BackgroundPortulaca oleracea (PO) has been widely used as traditional medicine because of its pharmacological activities. However, the effects of PO on osteoclasts that modulate bone homeostasis are still elusive.MethodsIn this study, we examined the effects of PO ethanol extract (POEE) on receptor activator of nuclear factor-κB ligand (RANKL)-mediated Ca2+ mobilization, nuclear factor of activated T-cell c1 (NFATc1) amplification, tartrate-resistant acid phosphatase-positive (TRAP+) multinucleated cell (MNC) formation, and cytotoxicity.ResultsOur results demonstrated that POEE suppressed RANKL-induced Ca2+ oscillations by inhibition of Ca2+ release from internal Ca2+ stores, resulting in reduction of NFATc1 amplification. Notably, POEE attenuated RANKL-mediated cytotoxicity and cleavage of polyadenosine 5′-diphosphate-ribose polymerase (PARP), resulted in enhanced formation of TRAP+ MNCs.ConclusionsThese results present in vitro effects of POEE on RANKL-mediated osteoclastogenesis and suggest the possible use of PO in treating bone disorders, such as osteopetrosis.

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Activation of G Proteins by Aluminum Fluoride Enhances RANKL-Mediated Osteoclastogenesis

Cited by 10 publications

References 35 publications

Pasteurella multocida Toxin Triggers RANKL-Independent Osteoclastogenesis

Pasteurella multocida Toxin Triggers RANKL-Independent Osteoclastogenesis

The inhibitory effect of vitamin K on RANKL-induced osteoclast differentiation and bone resorption

Attenuated RANKL-induced cytotoxicity by Portulaca oleracea ethanol extract enhances RANKL-mediated osteoclastogenesis

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