Interleukin-18 Enhances Vascular Calcification and Osteogenic Differentiation of Vascular Smooth Muscle Cells Through TRPM7 Activation

Zhang, Kun; Zhang, Yinyin; Feng, Weijing; Chen, Renhua; Chen, Jie; Touyz, Rhian M.; Wang, Jingfeng; Huang, Hui

doi:10.1161/atvbaha.117.309161

Cited by 52 publications

(46 citation statements)

References 50 publications

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“…In addition, the RANKL/RANK system augments vascular calcification via NF-kB, which can be blocked by the inhibitory RANKL-decoy receptor osteoprotegerin [ 140 ]. Similarly, the SGK1/NF-kB osteoinductive pathway may be activated by IL-18 [ 133 ], resulting in aggravation of phosphate-induced VSMCs mineralization [ 133 , 141 ]. Furthermore, together with the NF-kB pathway, WNT/β-catenin signaling may modulate pro-inflammatory signaling cascades in VSMCs in response to hyperphosphatemia [ 127 , 142 , 143 ].…”

Section: Signaling Pathways Regulating Vsmcs Calcification During Higmentioning

confidence: 99%

Signaling pathways involved in vascular smooth muscle cell calcification during hyperphosphatemia

Voelkl

Läng

Eckardt

et al. 2019

Cell. Mol. Life Sci.

141

202

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Medial vascular calcification has emerged as a putative key factor contributing to the excessive cardiovascular mortality of patients with chronic kidney disease (CKD). Hyperphosphatemia is considered a decisive determinant of vascular calcification in CKD. A critical role in initiation and progression of vascular calcification during elevated phosphate conditions is attributed to vascular smooth muscle cells (VSMCs), which are able to change their phenotype into osteo-/chondroblasts-like cells. These transdifferentiated VSMCs actively promote calcification in the medial layer of the arteries by producing a local pro-calcifying environment as well as nidus sites for precipitation of calcium and phosphate and growth of calcium phosphate crystals. Elevated extracellular phosphate induces osteo-/chondrogenic transdifferentiation of VSMCs through complex intracellular signaling pathways, which are still incompletely understood. The present review addresses critical intracellular pathways controlling osteo-/chondrogenic transdifferentiation of VSMCs and, thus, vascular calcification during hyperphosphatemia. Elucidating these pathways holds a significant promise to open novel therapeutic opportunities counteracting the progression of vascular calcification in CKD.

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Section: Signaling Pathways Regulating Vsmcs Calcification During Higmentioning

confidence: 99%

Signaling pathways involved in vascular smooth muscle cell calcification during hyperphosphatemia

Voelkl

Läng

Eckardt

et al. 2019

Cell. Mol. Life Sci.

141

202

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“…In turn, strong inverse correlations were found between the mRNA expression level of IL-18 with that of ALPL (−0.79; p < 0.03; n = 7) and BMP6 (−0.82; p < 0.02; n = 7) and of BMP6 with those of the chemotaxis-related genes CXCL1 (−0.79; p < 0.04; n = 7) and CCL27 (−0.82; p < 0.02; n = 7) ( Figure 2 ). According to Cornish et al (2003), IL-18 plays a role as an autocrine/paracrine mitogen in both osteogenic and chondrogenic cells [ 62 ] and may be a trigger of osteogenic differentiation [ 63 ].…”

Section: Resultsmentioning

confidence: 99%

Gene Expression Regulation and Secretory Activity of Mesenchymal Stem Cells upon In Vitro Contact with Microarc Calcium Phosphate Coating

Litvinova

Yurova

Шуплецова

et al. 2020

IJMS

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The manufacture of biomaterial surfaces with desired physical and chemical properties that can directly induce osteogenic differentiation without the need for biochemical additives is an excellent strategy for controlling the behavior of mesenchymal stem cells (MSCs) in vivo. We studied the cellular and molecular reactions of MSCs to samples with a double-sided calcium phosphate (CaP) coating and an average roughness index (Ra) of 2.4–4.6 µm. The study aimed to evaluate the effect of a three-dimensional matrix on the relative mRNA expression levels of genes associated with the differentiation and maturation of MSCs toward osteogenesis (RUNX2, BMP2, BMP6, BGLAP, and ALPL) under conditions of distant interaction in vitro. Correlations were revealed between the mRNA expression of some osteogenic and cytokine/chemokine genes and the secretion of cytokines and chemokines that may potentiate the differentiation of cells into osteoblasts, which indicates the formation of humoral components of the extracellular matrix and the creation of conditions supporting the establishment of hematopoietic niches.

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“…Conversely, inflammatory processes upregulate IL-18 expression [ 14 ]. Increased plasma IL-18 levels are frequently observed in CKD patients [ 12 , 16 , 62 ]. IL-18 is involved in the progression of CKD [ 46 , 51 ] and its related complications including vascular calcification [ 46 , 62 ].…”

Section: Discussionmentioning

confidence: 99%

“…Increased plasma levels of interleukin-18 (IL-18), a pro-inflammatory cytokine [ 17 ], are frequently observed in CKD patients [ 12 , 16 ] and associated with medial vascular calcification [ 23 , 62 ]. Recent reports indicate that IL-18 enhances osteo-/chondrogenic transdifferentiation of VSMCs [ 62 ], but the intracellular signaling pathways contributing to these procalcific effects are still ill-defined.…”

Section: Introductionmentioning

confidence: 99%

SGK1-dependent stimulation of vascular smooth muscle cell osteo-/chondrogenic transdifferentiation by interleukin-18

Schelski

Luong

Läng

et al. 2019

Pflugers Arch - Eur J Physiol

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The serum- and glucocorticoid-inducible kinase 1 (SGK1) is a key regulator of osteo-/chondrogenic transdifferentiation and subsequent calcification of vascular smooth muscle cells (VSMCs). The phenotypical transdifferentiation of VSMCs is associated with increased interleukin-18 (IL-18) levels and generalized inflammation. Therefore, the present study investigated the possible involvement of SGK1 in IL-18-induced vascular calcification. Experiments were performed in primary human aortic smooth muscle cells (HAoSMCs) treated with recombinant human IL-18 protein in control or high phosphate conditions and following SGK1 knockdown by siRNA or pharmacological inhibition of SGK1, PI3K, and PDK1. As a result, IL-18 treatment increased SGK1 mRNA and protein expression in HAoSMCs. IL-18 upregulated SGK1 mRNA expression in a dose-dependent manner. This effect was paralleled by upregulation of the mRNA expression of MSX2 and CBFA1 , osteogenic transcription factors, and of tissue-nonspecific alkaline phosphatase ( ALPL ), an osteogenic enzyme, as markers of increased osteo-/chondrogenic transdifferentiation. Phosphate treatment increased SGK1 and osteogenic markers mRNA expression as well as ALPL activity and induced calcification of HAoSMCs, all effects significantly augmented by additional treatment with IL-18. Conversely, silencing of SGK1 or cotreatment with the SGK1 inhibitor EMD638683 blunted the effects of IL-18 on osteo-/chondrogenic transdifferentiation and calcification of HAoSMCs. The procalcific effects of IL-18 were similarly suppressed in the presence of PI3K or PDK1 inhibitors. In conclusion, SGK1 expression is upregulated by IL-18 in VSMCs and SGK1 participates in the intracellular signaling of IL-18-induced osteo-/chondrogenic transdifferentiation of VSMCs. Thus, SGK1 may serve as therapeutic target to limit the progression of medial vascular calcification during vascular inflammation.

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Interleukin-18 Enhances Vascular Calcification and Osteogenic Differentiation of Vascular Smooth Muscle Cells Through TRPM7 Activation

Cited by 52 publications

References 50 publications

Signaling pathways involved in vascular smooth muscle cell calcification during hyperphosphatemia

Signaling pathways involved in vascular smooth muscle cell calcification during hyperphosphatemia

Gene Expression Regulation and Secretory Activity of Mesenchymal Stem Cells upon In Vitro Contact with Microarc Calcium Phosphate Coating

SGK1-dependent stimulation of vascular smooth muscle cell osteo-/chondrogenic transdifferentiation by interleukin-18

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