Cross-Talk of Receptor Activator of Nuclear Factor-κB Ligand Signaling With Renin–Angiotensin System in Vascular Calcification

Osako, Mariana Kiomy; Nakagami, Hironori; Shimamura, Munehisa; Kuroda, Hiroshi; Nakagami, Futoshi; Shimizu, Hideo; Miyake, Takashi; Yoshizumi, Masao; Rakugi, Hiromi; Morishita, Ryuichi

doi:10.1161/atvbaha.112.301099

Cited by 57 publications

(34 citation statements)

References 32 publications

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“…Previous reports showed an inconsistent expression level of RANK and RANKL in OPG −/− mice compared with WT mice: increased mRNA levels of RANK and RANKL in the aorta (21); the same expression level of RANKL mRNA expression in osteoblasts (26,27); and a decreased expression level of RANK mRNA in osteoclasts in 12-wk-old mice followed by an increased level at 20 and 28 wk (28). From this viewpoint, the expression level of RANK and RANKL in OPG −/− might be dependent in cells or tissue.…”

Section: Discussionmentioning

confidence: 85%

OPG/RANKL/RANK axis is a critical inflammatory signaling system in ischemic brain in mice

Shimamura

Nakagami

Osako

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Osteoprotegerin (OPG) is a soluble secreted protein and a decoy receptor, which inhibits a receptor activator of nuclear factor κB (NF-κB) ligand (RANKL)/the receptor activator of NF-κB (RANK) signaling. Recent clinical studies have shown that a high-serum-OPG level is associated with unfavorable outcome in ischemic stroke, but it is unclear whether OPG is a culprit or an innocent bystander. Here we demonstrate that enhanced RANKL/RANK signaling in OPG −/− mice or recombinant RANKL-treated mice contributed to the reduction of infarct volume and brain edema via reduced postischemic inflammation. On the contrary, infarct volume was increased by reduced RANKL/RANK signaling in OPG −/− mice and WT mice treated with anti-RANKL neutralizing antibody. OPG, RANKL, and RANK mRNA were increased in the acute stage and were expressed in activated microglia and macrophages. Although enhanced RANKL/RANK signaling had no effects in glutamate, CoCl 2 , or H 2 O 2 -stimulated neuronal culture, enhanced RANKL/RANK signaling showed neuroprotective effects with reduced expression in inflammatory cytokines in LPS-stimulated neuron-glia mixed culture, suggesting that RANKL/RANK signaling can attenuate inflammation through a Toll-like receptor signaling pathway in microglia. Our findings propose that increased OPG could be a causal factor of reducing RANKL/RANK signaling and increasing postischemic inflammation. Thus, the OPG/RANKL/RANK axis plays critical roles in controlling inflammation in ischemic brains.cerebral ischemia | neuroprotection | immune cells

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Section: Discussionmentioning

confidence: 85%

OPG/RANKL/RANK axis is a critical inflammatory signaling system in ischemic brain in mice

Shimamura

Nakagami

Osako

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…There is evidence that NFkB signaling pathway is required to trigger and propagate osteogenic program and vascular calcification [24][25][26]. Further studies point to involvement of the NFkB transcriptional activity and the Erk (Extracellularsignal Regulated Kinase) pathway for C5aR-related functional responses [2,27].…”

Section: Upar-c5ar Axis Activates Erk and Nfjb Upon Msc Osteogenic DImentioning

confidence: 97%

Urokinase Receptor Mediates Osteogenic Differentiation of Mesenchymal Stem Cells and Vascular Calcification via the Complement C5a Receptor

Anaraki

Patecki²,

Larmann³

et al. 2014

Stem Cells and Development

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Vascular calcification is a severe consequence of several pathological processes with a lack of effective therapy. Recent studies suggest that circulating and resident mesenchymal stem cells (MSC) contribute to the osteogenic program of vascular calcification. Molecular mechanisms underlying MSC osteogenic potential and differentiation remain, however, sparsely explored. We investigated a role for the complement receptor C5aR in these processes. We found that expression of C5aR was upregulated upon differentiation of human MSC to osteoblasts. C5aR inhibition by silencing and specific antagonist impaired osteogenic differentiation. We demonstrate that C5aR expression upon MSC differentiation was regulated by the multifunctional urokinase receptor (uPAR). uPAR targeting by siRNA resulted in complete abrogation of C5aR expression and consequently in the inhibition of MSC-osteoblast differentiation. We elucidated the NFkB pathway as the mechanism utilized by the uPAR-C5aR axis. MSC treatment with the NFkB inhibitor completely blocked the differentiation process. Nuclear translocation of the p65 RelA component of the NFkB complex was induced under osteogenic conditions and impaired by the inhibition of uPAR or C5aR. Dual-luciferase reporter assays demonstrated enhanced NFkB signaling upon MSC differentiation, whereas uPAR and C5aR downregulation lead to inhibition of the NFkB activity. We show involvement of the Erk1/2 kinase in this cascade. In vivo studies in a uPAR/LDLR double knockout mouse model of diet-induced atherosclerosis revealed impaired C5aR expression and calcification in aortic sinus plaques in uPAR -/ -/LDLR -/ -versus uPAR + / + /LDLR -/ -control animals. These results suggest that uPAR-C5aR axis via the underlying NFkB transcriptional program controls osteogenic differentiation with functional impact on vascular calcification in vivo.

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“…Osteoblasts express OPG and RANKL, which regulate osteoclast differentiation through the activation of RANK [40]. The present study showed that exenatide could decrease the expression of RANKL and inhibit the expression of ALP, OC, and Runx2 in human CVSMCs.…”

Section: Discussionmentioning

confidence: 60%

Exenatide can inhibit calcification of human VSMCs through the NF-kappaB/RANKL signaling pathway

Zhan

Tan

Wang

et al. 2014

Cardiovasc Diabetol

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BackgroundArterial calcification is an important pathological change of diabetic vascular complication. Osteoblastic differentiation of vascular smooth muscle cells (VSMCs) plays an important cytopathologic role in arterial calcification. The glucagon-like peptide-1 receptor agonists (GLP-1RA), a novel type of antidiabetic drugs, exert cardioprotective effects through the GLP-1 receptor (GLP-1R). However, the question of whether or not GLP-1RA regulates osteoblastic differentiation and calcification of VSMCs has not been answered, and the associated molecular mechanisms have not been examined.MethodsCalcifying VSMCs (CVSMCs) were isolated from cultured human arterial smooth muscle cells through limiting dilution and cloning. The extent of matrix mineralization was measured by Alizarin Red S staining. Protein expression and phosphorylation were detected by Western blot. Gene expression of receptor activator of nuclear factor-κB ligand (RANKL) was silenced by small interference RNA (siRNA).ResultsExenatide, an agonist of GLP-1 receptor, attenuated β-glycerol phosphate (β-GP) induced osteoblastic differentiation and calcification of human CVSMCs in a dose- and time-dependent manner. RANKL siRNA also inhibited osteoblastic differentiation and calcification. Exenatide decreased the expression of RANKL in a dose-dependent manner. 1,25 vitD3 (an activator of RANKL) upregulated, whereas BAY11-7082 (an inhibitor of NF-κB) downregulated RANKL, alkaline phosphatase (ALP), osteocalcin (OC), and core binding factor α1 (Runx2) protein levels and reduced mineralization in human CVSMCs. Exenatide decreased p-NF-κB and increased p-AMPKα levels in human CVSMCs 48 h after treatment. Significant decrease in p-NF-κB (p-Ser276, p-Ser536) level was observed in cells treated with exenatide or exenatide + BAY11-7082.ConclusionGLP-1RA exenatide can inhibit human VSMCs calcification through NF-κB/RANKL signaling.

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Cross-Talk of Receptor Activator of Nuclear Factor-κB Ligand Signaling With Renin–Angiotensin System in Vascular Calcification

Cited by 57 publications

References 32 publications

OPG/RANKL/RANK axis is a critical inflammatory signaling system in ischemic brain in mice

OPG/RANKL/RANK axis is a critical inflammatory signaling system in ischemic brain in mice

Urokinase Receptor Mediates Osteogenic Differentiation of Mesenchymal Stem Cells and Vascular Calcification via the Complement C5a Receptor

Exenatide can inhibit calcification of human VSMCs through the NF-kappaB/RANKL signaling pathway

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