Scavenging Intracellular ROS Attenuates p-Cresyl Sulfate-Triggered Osteogenesis through MAPK Signaling Pathway and NF-κB Activation in Human Arterial Smooth Muscle Cells

Chang, Jichuan; Hsieh, Chih-Yu; Liou, Jian Chiun; Liu, Shih-Hao; Hung, Chi Feng; Lu, Kuo Cheng; Lin, Che‐Chern; Wu, Chang Chin; Ka, Shuk‐Man; Li, Wen; Wu, Mai Szu; Zheng, Cai Mei; Ko, Wen-Chin

doi:10.3390/toxins12080472

Cited by 17 publications

(18 citation statements)

References 28 publications

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“…Activation of the JNK (Suzuki et al, 2006;Wu et al, 2016) or of the NF-kB (Koumakis et al, 2019) pathway has been demonstrated to induce Pit1 expression and subsequent cell matrix mineralization or inflammation respectively. JNK and NF-kB activation were also associated to increased Alp expression and osteoblastic differentiation of arterial smooth muscle cells (Chang et al, 2020). As a second calcification mechanism, in our study we found that CD11b deficient chondrocytes secreted increased amounts of pro-inflammatory and pro-mineralizing IL-6 and MCP-1 when stimulated with CPP.…”

Section: Discussionsupporting

confidence: 59%

CD11b Signaling Prevents Chondrocyte Mineralization and Attenuates the Severity of Osteoarthritis

Ehirchiou¹,

Bernabei²,

Chobaz³

et al. 2020

Front. Cell Dev. Biol.

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Osteoarthritis (OA) is a progressive joint disease that is strongly associated with calcium-containing crystal formation (mineralization) by chondrocytes leading ultimately to cartilage calcification. However, this calcification process is poorly understood and treatments targeting the underlying disease mechanisms are lacking. The CD11b/CD18 integrin (Mac-1 or αMβ2), a member of the beta 2 integrin family of adhesion receptors, is critically involved in the development of several inflammatory diseases, including rheumatoid arthritis and systemic lupus erythematosus. We found that in a collagen-induced arthritis, CD11b-deficient mice exhibited increased cartilage degradation compared to WT control animals. However, the functional significance of CD11b integrin signaling in the pathophysiology of chondrocytes remains unknown. CD11b expression was found in the extracellular matrix and in chondrocytes in both healthy and damaged human and murine articular cartilage. Primary murine CD11b KO chondrocytes showed increased mineralization when induced in vitro by secondary calciprotein particles (CPP) and quantified by Alizarin Red staining. This increased propensity to mineralize was associated with an increased alkaline phosphatase (Alp) expression (measured by qRT-PCR and activity assay) and an enhanced secretion of the pro-mineralizing IL-6 cytokine compared to control wild-type cells (measured by ELISA). Accordingly, addition of an anti-IL-6 receptor antibody to CD11b KO chondrocytes reduced significantly the calcification and identified IL-6 as a pro-mineralizing factor in these cells. In the same conditions, the ratio of qRT-PCR expression of collagen X over collagen II, and that of Runx2 over Sox9 (both ratio being indexes of chondrocyte hypertrophy) were increased in CD11b-deficient cells. Conversely, the CD11b activator LA1 reduced chondrocyte mineralization, Alp expression, IL-6 production and collagen X expression. In the meniscectomy (MNX) model of murine knee osteoarthritis, deficiency of CD11b led to more severe OA (OARSI scoring of medial cartilage damage in CD11b: 5.6 ± 1.8, in WT: 1.2 ± 0.5, p < 0.05, inflammation in CD11b: 2.8 ± 0.2, in WT: 1.4 ± 0.5). In conclusion, these data demonstrate that CD11b signaling prevents chondrocyte hypertrophy and chondrocyte mineralization in vitro and has a protective role in models of OA in vivo.

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Section: Discussionsupporting

confidence: 59%

CD11b Signaling Prevents Chondrocyte Mineralization and Attenuates the Severity of Osteoarthritis

Ehirchiou¹,

Bernabei²,

Chobaz³

et al. 2020

Front. Cell Dev. Biol.

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“…pCS also increased mRNA levels of osteoblast-specific proteins in HASMCs, including alkaline phosphatase (ALP) and OPN, indicating a potential role of pCS in vascular calcification [ 56 ]. A recent study demonstrated pCS-induced ROS induces the phosphorylation of JNK, p38, and ERK, subsequently leading to increased NF-κB mediated expression of Runx2 and ALP [ 57 ]. pCS was also shown to increase the expression of adhesion molecules E-selectin, ICAM-1, and vascular cell adhesion molecule 1 (VCAM-1), promoting leukocyte-endothelium interaction in both endothelial cells and nephrectomised apoE-/- mice [ 54 ].…”

Section: Protein-bound Uremic Toxinsmentioning

confidence: 99%

Uremic Toxins in the Progression of Chronic Kidney Disease and Cardiovascular Disease: Mechanisms and Therapeutic Targets

Lim

Sidor

Tonial

et al. 2021

Toxins

126

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Chronic kidney disease (CKD) is a progressive loss of renal function. The gradual decline in kidney function leads to an accumulation of toxins normally cleared by the kidneys, resulting in uremia. Uremic toxins are classified into three categories: free water-soluble low-molecular-weight solutes, protein-bound solutes, and middle molecules. CKD patients have increased risk of developing cardiovascular disease (CVD), due to an assortment of CKD-specific risk factors. The accumulation of uremic toxins in the circulation and in tissues is associated with the progression of CKD and its co-morbidities, including CVD. Although numerous uremic toxins have been identified to date and many of them are believed to play a role in the progression of CKD and CVD, very few toxins have been extensively studied. The pathophysiological mechanisms of uremic toxins must be investigated further for a better understanding of their roles in disease progression and to develop therapeutic interventions against uremic toxicity. This review discusses the renal and cardiovascular toxicity of uremic toxins indoxyl sulfate, p-cresyl sulfate, hippuric acid, TMAO, ADMA, TNF-α, and IL-6. A focus is also placed on potential therapeutic targets against uremic toxicity.

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“…Mitogen-activated protein kinases (MAPKs), represented by p38, JNK, and ERK1/2, are a common signaling pathway cascades in responding to extracellular stimulation. Since previous studies have shown that JNK phosphorylation is related with calcification in SMC, 16,17 we examined if nHAp activated JNK signaling pathway in SMCs. Significantly more phosphorylated JNK was detected after VSMCs were treated with nHAp for 15 min (Figure 5A).…”

Section: Nano-hap Activated Jnk/c-jun Signaling Pathwaymentioning

confidence: 99%

“…Other reports also show that nHAp can activate other MAPK members, like p38 and ERK1/2 pathways. 16,17,53 Whether they are also involved in the process of calcification caused by nHAp remains to be proved.…”

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confidence: 99%

Nano-Sized Hydroxyapatite Induces Apoptosis and Osteogenic Differentiation of Vascular Smooth Muscle Cells via JNK/c-JUN Pathway

Liu¹,

Chen²,

Luo³

et al. 2021

IJN

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Purpose The deposition of hydroxyapatite (HAp) crystals plays an important role in the development of vascular calcification (VC). This study aimed to demonstrate the effects of nanosized HAp (nHAp) on vascular smooth muscle cells (VSMCs) and VC progression. Methods Transmission electron microscopy (TEM) was used to examine cellular uptake of nHAp. Cell viability was determined using CCK-8 assay kit. Mitochondrial impairment and reactive oxygen species were detected by TEM and fluorescence dye staining, respectively. Cell apoptosis was detected by Western blot analysis and Annexin V staining. Mouse model of VC was built via applying nHAp on the surface of abdominal aorta. Calcification was visualized by Alizarin red and von Kossa staining. Results We found that nHAp could promote osteogenic transformation of VSMCs by elevating expression of runt-related factor 2 (Runx2), osteopontin (OPN) and alkaline phosphatase (ALP), impairing function and morphology of mitochondria and inducing apoptosis of VSMCs. More phosphorylation of c-Jun N-terminal protein kinase/c-JUN (JNK/c-JUN) in VSMCs was detected after mixing nHAp with VSMCs. HAp-induced osteogenic transformation of VSMCs was blocked by JNK inhibitor SP600125, resulted in decreased ALP activity, less Runx2 and OPN expressions. SP600125 also inhibited apoptosis of VSMCs. Application of nHAp to outside of aorta induced osteogenic transformation and apoptosis of VSMCs, and significant deposition of calcium on the vessel walls of mice, which can be effectively attenuated by SP600125. Conclusion JNK/c-JUN signaling pathway is critical for nHAp-induced calcification, which could be a potential therapeutic target for controlling the progression of VC.

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Scavenging Intracellular ROS Attenuates p-Cresyl Sulfate-Triggered Osteogenesis through MAPK Signaling Pathway and NF-κB Activation in Human Arterial Smooth Muscle Cells

Cited by 17 publications

References 28 publications

CD11b Signaling Prevents Chondrocyte Mineralization and Attenuates the Severity of Osteoarthritis

CD11b Signaling Prevents Chondrocyte Mineralization and Attenuates the Severity of Osteoarthritis

Uremic Toxins in the Progression of Chronic Kidney Disease and Cardiovascular Disease: Mechanisms and Therapeutic Targets

Nano-Sized Hydroxyapatite Induces Apoptosis and Osteogenic Differentiation of Vascular Smooth Muscle Cells via JNK/c-JUN Pathway

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