scholarly journals Pro-calcifying analysis of uraemic serum from patients treated with medium cut-off membrane in a prospective, cross-over study

2020 ◽  
Author(s):  
Paola Ciceri ◽  
Giorgia Tettamanti ◽  
Andrea Galassi ◽  
Lorenza Magagnoli ◽  
Nicolas Fabresse ◽  
...  
Keyword(s):  
Osteoblastic Differentiation ◽  
Water Soluble ◽  
Matrix Gla Protein ◽  
Bone Morphogenetic Protein 2 ◽  
Calcium Deposition ◽  
Open Label ◽  
Small Water ◽  
Middle Molecules ◽  
Related Transcription Factor ◽  
The Difference

Abstract Background The retention of a large number of solutes that are normally excreted or metabolized by the kidney is responsible for the symptoms typical in uraemic patients. These molecules are defined as uraemic toxins and can be classified into three groups: small water-soluble molecules, middle molecules and protein-bound toxins. Recently, efforts were put towards developing dialysis membranes that allow the removal of large middle molecules without clinically relevant albumin loss. These membranes are the medium cut-off (MCO) membranes that allow the removal of middle molecules up to ∼50 000 Da. Methods We performed a prospective, open-label, controlled, cross-over pilot study comparing expanded haemodialysis (HDx) (novel MCO membrane Theranova 400) and conventional haemodialysis (HD) in 20 prevalent HD patients. Ten patients used conventional HD high-flux dialyser and 10 patients used HDx for 3 months; later the patients switched and received the other treatment for a further 3 months. We then analysed the pro-calcifying effect of uraemic serum in a model of high phosphate(Pi)–induced calcification in vascular smooth muscle cells (VSMCs). Results In this study, every patient was the control of himself and, interestingly, we found a tendency of less pro-calcifying potential from HDx-treated patients’ serum compared with HD. Studying pathogenetic processes involved in high Pi–induced calcium deposition, we found that uraemic serum of HDx-treated patients induced less VSMC necrosis compared with uraemic serum of HD patients. Nevertheless, no differences were found between the different dialytic treatments in the serum potential to induce apoptosis and to modulate the expression of a panel of genes involved in VSMC simil-osteoblastic differentiation such as bone morphogenetic protein 2, runt-related transcription factor 2, osteocalcin, matrix Gla protein, osteopontin, elastin and collagen I α1. In an effort to characterize the difference in uraemic toxin profile during the two different dialytic treatments, we measured a panel of 10 uraemic toxins and 3 precursors, finding a significant increased removal during HDx of 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, tryptophane and some of its metabolites, such as 3-indoxyl sulphate, indole 3-acetic acid and kynurenine. Conclusions These preliminary data are promising, although larger patients’ groups are needed to better understand the effects of HDx on vascular calcification.

P1392ANALYSIS OF CALCIFYING POTENTIAL OF UREMIC SERUM FROM HAEMODIALYSIS PATIENTS TREATED WITH A MEDIUM CUT-OFF (THERANOVA) DIALYSER: A PROSPECTIVE, CROSS-OVER STUDY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Paola Ciceri ◽  
Andrea Galassi ◽  
Nicolas Fabresse ◽  
Jean-Claude Alvarez ◽  
Ziad Massy ◽  
...  
Keyword(s):  
Osteoblastic Differentiation ◽  
Uremic Toxins ◽  
Water Soluble ◽  
Calcium Deposition ◽  
Uremic Toxin ◽  
Open Label ◽  
Small Water ◽  
Uremic Serum ◽  
Middle Molecules ◽  
The Difference

Abstract Background and Aims The retention of a large number of solutes that are normally excreted or metabolized by the kidney is responsible for the classical symptoms of haemodialysis (HD) patients. These molecules are defined as uremic toxins and can be classified into three groups: small water-soluble molecules, middle molecules and protein-bound toxins. Recently, efforts were put in order to develop dialysis membranes that allow the removal of large-middle molecules without clinically relevant albumin loss. These dialysers are the medium cut-off (MCO) membranes, which allow the removal of middle molecules up to approximately 50,000 Da. We performed a prospective, open-label, controlled, cross-over pilot study comparing expanded HD (HDx) with MCO membrane Theranova and conventional HD in 20 patients. Method Ten patients underwent conventional HD high-flux dialyser and 10 patients underwent HDx for 3 months, later the patients switched and received the other treatment for a further 3 months. We then analyzed the pro-calcifying effect of patient uremic serum in a model of high-phosphate (Pi) induced calcification in vascular smooth muscle cells (VSMCs). Results In this study each patient was the control of himself and, interestingly, we found a tendency of less pro-calcifying potential of serum from patients when treated with HDx, in comparison with HD (6.6±1.1, 5.6±0.6 and 6.7±1.0, OD/mg protein, baseline HD, 0-3 HDx and 3-6 HD, months, respectively; and 4.7±0.7 vs 3.2±0.2, OD/mg protein, 0-3 HD vs 3-6 HDx, months, respectively) (Figure). Investigating the major mechanisms involved in high-Pi induced calcium deposition, we found that serum from patients when treated with HDx induced less necrosis in VSMCs, compared with HD (3.2±0.8 vs. 0.9±0.1, necrosis enrichment factor, 0-3 HD vs. 3-6 HDx, months, respectively). Nevertheless, no differences were found between the different dialysis treatment in the serum potential to induce apoptosis and to modulate the expression of a panel of genes involved in VSMC osteoblastic-differentiation such as BMP2, RUNX2, osteocalcin, MGP, OPN, and elastin. In the effort to characterize the difference in uremic toxin profile during the two different dialysis treatments, we measured a panel of protein-bound uremic toxins which have been shown to promote vascular calcification and /or bone loss and shown a significant increased removal by HDx of 3-indoxyl sulfate (30.6±13.2 vs -17.1±10.2 Δ%; 0-3 HD vs 3-6 HDx, months; p<0.05; and -21.1±11.4 vs 54.4±33.2 Δ%; 0-3 HDx vs 3-6 HD, months; p<0.05), indole 3-acetic acid (43.1±16.9 vs -2.3±10.9 Δ%; 0-3 HD vs 3-6 HDx, months; p<0.05), CMPF (61.8±27.6 vs -16.1±9.6 Δ%; 0-3 HD vs 3-6 HDx, months; p<0.05), and kynurenine (44.2±12.9 vs -0.2±6.8 Δ%; 0-3 HD vs 3-6 HDx, months; p<0.05). Conclusion These preliminary data suggest a role for HDx in reducing the calcifying potential of uremic serum. Our findings are promising and they need to be confirmed in larger studies.

Protein-bound toxins: has the Cinderella of uraemic toxins turned into a princess?

2016 ◽  
Vol 130 (23) ◽  
pp. 2209-2216 ◽  
Author(s):  
Sophie Liabeuf ◽  
Cédric Villain ◽  
Ziad A. Massy
Keyword(s):  
Kidney Disease ◽  
Public Health Problem ◽  
Neurological Complications ◽  
Water Soluble ◽  
Global Public Health ◽  
Bone Disorders ◽  
Small Water ◽  
Middle Molecules ◽  
Cv Disease ◽  
Stage Renal Disease

Chronic kidney disease (CKD) has emerged as a global public health problem. Although the incidence and prevalence of CKD vary from one country to another, the estimated worldwide prevalence is 8–16%. The complications associated with CKD include progression to end-stage renal disease (ESRD), mineral and bone disorders, anaemia, cognitive decline and elevated all-cause and cardiovascular (CV) mortality. As a result of progressive nephron loss, patients with late-stage CKD are permanently exposed to uraemic toxins. These toxins have been classified into three groups as a function of the molecular mass: small water-soluble molecules, middle molecules and protein-bound uraemic toxins. The compounds can also be classified according to their origin (i.e. microbial or not) or their protein-binding ability. The present review will focus on the best-characterized protein-bound uraemic toxins, namely indoxylsulfate (IS), indole acetic acid (IAA) and p-cresylsulfate (PCS, a cresol metabolite). Recent research suggests that these toxins accelerate the progression of CV disease, kidney disease, bone disorders and neurological complications. Lastly, we review therapeutic approaches that can be used to decrease toxin levels.

Osteogenic regulation of vascular calcification: an early perspective

2004 ◽  
Vol 286 (5) ◽  
pp. E686-E696 ◽  
Author(s):  
Radhika Vattikuti ◽  
Dwight A. Towler
Keyword(s):  
Parathyroid Hormone ◽  
Vascular Calcification ◽  
Current Data ◽  
Fracture Repair ◽  
Matrix Gla Protein ◽  
Bone Morphogenetic Protein 2 ◽  
Calcium Deposition ◽  
Variable Degree ◽  
Clinical Consequences ◽  
Stage Renal Disease

Cardiovascular calcification is a common consequence of aging, diabetes, hypercholesterolemia, mechanically abnormal valve function, and chronic renal insufficiency. Although vascular calcification may appear to be a uniform response to vascular insult, it is a heterogenous disorder, with overlapping yet distinct mechanisms of initiation and progression. A minimum of four histoanatomic variants—atherosclerotic (fibrotic) calcification, cardiac valve calcification, medial artery calcification, and vascular calciphylaxis—arise in response to metabolic, mechanical, infectious, and inflammatory injuries. Common to the first three variants is a variable degree of vascular infiltration by T cells and macrophages. Once thought benign, the deleterious clinical consequences of calcific vasculopathy are now becoming clear; stroke, amputation, ischemic heart disease, and increased mortality are portended by the anatomy and extent of calcific vasculopathy. Along with dystrophic calcium deposition in dying cells and lipoprotein deposits, active endochondral and intramembranous (nonendochondral) ossification processes contribute to vascular calcium load. Thus vascular calcification is subject to regulation by osteotropic hormones and skeletal morphogens in addition to key inhibitors of passive tissue mineralization. In response to oxidized lipids, inflammation, and mechanical injury, the microvascular smooth muscle cell becomes activated. Orthotopically, proliferating stromal myofibroblasts provide osteoprogenitors for skeletal growth and fracture repair; however, in valves and arteries, vascular myofibroblasts contribute to cardiovascular ossification. Current data suggest that paracrine signals are provided by bone morphogenetic protein-2, Wnts, parathyroid hormone-related polypeptide, osteopontin, osteoprotegerin, and matrix Gla protein, all entrained to endocrine, metabolic, inflammatory, and mechanical cues. In end-stage renal disease, a “perfect storm” of vascular calcification often occurs, with hyperglycemia, hyperphosphatemia, hypercholesterolemia, hypertension, parathyroid hormone resistance, and iatrogenic calcitriol excess contributing to severe calcific vasculopathy. This brief review recounts emerging themes in the pathobiology of vascular calcification and highlights some fundamental deficiencies in our understanding of vascular endocrinology and metabolism that are immediately relevant to human health and health care.

scholarly journals Randomised controlled trial of the impact of haemodiafiltration on uraemic neuropathy: FINESSE study protocol

BMJ Open ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. e023736
Author(s):  
Brendan Smyth ◽  
Arun V Krishnan ◽  
Martin Gallagher ◽  
Matthew Kiernan ◽  
Paul Snelling ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Randomised Trial ◽  
Cumulative Exposure ◽  
Open Label ◽  
Middle Molecules ◽  
Show Evidence ◽  
The Difference ◽  
Randomised Controlled ◽  
End Stage ◽  
The Impact

IntroductionThe majority of patients undergoing haemodialysis (HD) show evidence of uraemic neuropathy, a condition with no known disease-modifying treatments. The pathogenesis of uraemic neuropathy is poorly understood, but may be related to cumulative exposure to middle molecules or other solutes such as potassium. It is not known whether haemodiafiltration (HDF) reduces the progression of uraemic neuropathy.Methods and analysisFiltration In the Neuropathy of End-Stage kidney disease Symptom Evolution (FINESSE) is a multicentre, randomised, open-label, blinded endpoint assessment, controlled trial designed to assess the impact of HDF versus HD on uraemic neuropathy. Maintenance HD patients will be randomised in a 1:1 ratio to receive HDF or HD with high-flux membranes for 4 years. The primary endpoint is the difference in the mean change in Total Neuropathy Score (TNS)—a measure of peripheral neuropathy combining symptoms, signs and nerve conduction velocity—over the study period. Secondary outcomes include change at annual timepoints in the TNS and the Neuropathy Symptom Score; and in morbidity, mortality and safety events.Ethics and disseminationThe FINESSE trial has been approved by the Ethics Review Committee of the Sydney South West Area Health Service (HREC/09/RPAH/268) and of Adventist HealthCare Limited (2012–027). When published in a peer-reviewed journal, it will be the largest and longest reported randomised trial aimed at reducing the incidence and severity of uraemic neuropathy. It will advance the understanding of the natural history of uraemic neuropathy and the influence of convective therapies on both neurophysiological and clinical outcomes. It will also allow refinement of current hypotheses surrounding the pathogenesis of uraemic neuropathy and, most importantly, may lead to improvements in the lives of the many patients affected by this debilitating condition.Trial registration numberACTRN12609000615280.

scholarly journals CBX4-dependent regulation of HDAC3 nuclear translocation reduces Bmp2-induced osteoblastic differentiation and calcification in adamantinomatous craniopharyngioma

2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Xiaorong Yan ◽  
Dezhi Kang ◽  
Yuanxiang Lin ◽  
Songtao Qi ◽  
Changzhen Jiang
Keyword(s):  
Nuclear Localization ◽  
Nuclear Translocation ◽  
Tumor Resection ◽  
Osteoblastic Differentiation ◽  
Therapeutic Interventions ◽  
Bone Morphogenetic Protein 2 ◽  
Luciferase Reporter ◽  
Calcium Deposition ◽  
Alizarin Red ◽  
Adamantinomatous Craniopharyngioma

Abstract Background Calcification of adamantinomatous craniopharyngioma (ACP) often causes problems with tumor resection, leading to a high incidence of deadly complications and tumor recurrence. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) are 2 key enzymes that regulate histone acetylation and play important roles in tumor development. However, the roles of HAT and HDAC in the calcification and osteoblastic differentiation of ACP are not known. Methods In this study, primary cells were isolated from ACP tissues, and calcification was induced with bone morphogenetic protein 2 (Bmp2). HDAC3 expression was assessed in 12 tissue samples by Western blotting and immunohistochemistry. ACP calcification was assessed by Alizarin red staining. A luciferase reporter assay was performed to examine the interaction between miR-181b and the 3’-untranslated region of the polycomb chromobox 4 (CBX4) gene. Results Our results showed that the expression of HDAC3 was increased in the calcified ACP samples, but inhibition of HDAC3 promoted ACP cell calcification and osteoblastic differentiation. Mechanistically, HDAC3 nuclear translocation was suppressed by Bmp2, leading to Runx2 protein expression and Osterix, osteocalcin (OCN), osteopontin (OPN), and alkaline phosphatase (ALP) mRNA expression. In addition, this process was suppressed by CBX4, which stabilized the nuclear localization of HDAC3. miR-181b, the expression of which was increased in Bmp2-induced ACP cells, directly targeted and decreased CBX4 expression and inhibited the nuclear localization of HDAC3. Conclusions Our results demonstrate that Bmp2 increases miR-181b levels to directly target and inhibit CBX4 expression, leading to a reduction in the CBX4-dependent regulation of HDAC3 nuclear translocation, which results in Runx2 activation/osteoblastic differentiation and calcium deposition in ACP. Further studies targeting these cascades may contribute to therapeutic interventions used for recurrent ACP.

ANALISA KANDUNGAN BETA-GLUKAN LARUT AIR DAN LARUT ALKALI DARI TUBUH BUAH JAMUR TIRAM (Pleurotus ostreatus) DAN SHIITAKE (Lentinus edodes)

2013 ◽  
Vol 13 (3) ◽  
Author(s):  
Netty Widyastuti ◽  
Teguh Baruji ◽  
Henky Isnawan ◽  
Priyo Wahyudi ◽  
Donowati Donowati
Keyword(s):  
Molecular Structure ◽  
Molecular Weight ◽  
Immune System ◽  
Pleurotus Ostreatus ◽  
Water Soluble ◽  
Low Molecular Weight ◽  
Lentinus Edodes ◽  
Beta Glucan ◽  
Oyster Mushrooms ◽  
The Difference

Beta glucan is a polysaccharide compound, generally not soluble inwater and resistant to acid. Beta glucan is used as an immunomodulator (enhancing the immune system) in mammals is usually a beta-glucan soluble in water, easily absorbed and has a low molecular weight. Several example of beta-glucan such as cellulose (β-1 ,4-glucan), lentinan (β-1 0.6-glucan) and (β-1 ,3-glucan), pleuran (β-1, 6 and β-1 ,3-glucan) are isolated from species of fungi Basidiomycota include mushrooms (Pleurotus ostreatus) and shiitake (Lentinus edodes).The purpose of thisresearch activity is to obtain beta-glucan compound that can be dissolved in water and in alkali derived from fungi Basidiomycota, i.e, Oyster mushrooms (Pleurotus ostreatus) and shiitake (Lentinus edodes). The result of beta-glucan compared to characterize the resulting beta glucan that is molecular structure . The difference of beta glucan extraction is based on the differences in solubility of beta-glucan. Beta glucan could be water soluble and insoluble water.

scholarly journals Procyanidin B2 Reduces Vascular Calcification through Inactivation of ERK1/2-RUNX2 Pathway

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 916
Author(s):  
Yingquan Liang ◽  
Guilan Chen ◽  
Feng Zhang ◽  
Xiaoxiao Yang ◽  
Yuanli Chen ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Calcification ◽  
Aortic Root ◽  
Smooth Muscle Actin ◽  
Bone Morphogenetic Protein 2 ◽  
Plaque Burden ◽  
Runx2 Expression ◽  
Plaque Instability ◽  
Related Transcription Factor

Vascular calcification is strongly associated with atherosclerotic plaque burden and plaque instability. The activation of extracellular signal-regulated kinase 1/2 (ERK1/2) increases runt related transcription factor 2 (RUNX2) expression to promote vascular calcification. Procyanidin B2 (PB2), a potent antioxidant, can inhibit ERK1/2 activation in human aortic smooth muscle cells (HASMCs). However, the effects and involved mechanisms of PB2 on atherosclerotic calcification remain unknown. In current study, we fed apoE-deficient (apoE−/−) mice a high-fat diet (HFD) while treating the animals with PB2 for 18 weeks. At the end of the study, we collected blood and aorta samples to determine atherosclerosis and vascular calcification. We found PB2 treatment decreased lesions in en face aorta, thoracic, and abdominal aortas by 21.4, 24.6, and 33.5%, respectively, and reduced sinus lesions in the aortic root by 17.1%. PB2 also increased α-smooth muscle actin expression and collagen content in lesion areas. In the aortic root, PB2 reduced atherosclerotic calcification areas by 75.8%. In vitro, PB2 inhibited inorganic phosphate-induced osteogenesis in HASMCs and aortic rings. Mechanistically, the expression of bone morphogenetic protein 2 and RUNX2 were markedly downregulated by PB2 treatment. Additionally, PB2 inhibited ERK1/2 phosphorylation in the aortic root plaques of apoE−/− mice and calcified HASMCs. Reciprocally, the activation of ERK1/2 phosphorylation by C2-MEK1-mut or epidermal growth factor can partially restore the PB2-inhibited RUNX2 expression or HASMC calcification. In conclusion, our study demonstrates that PB2 inhibits vascular calcification through the inactivation of the ERK1/2-RUNX2 pathway. Our study also suggests that PB2 can be a potential option for vascular calcification treatment.

Periostin promotes arterial calcification through PPARγ-related glucose metabolism reprogramming

2021 ◽  
Author(s):  
Yi Zhu ◽  
Jing-Jing Ji ◽  
Xiao-Dong Wang ◽  
Xue-Jiao Sun ◽  
Min Li ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Ex Vivo ◽  
Matrix Gla Protein ◽  
Calcium Deposition ◽  
Arterial Calcification ◽  
Agatston Score ◽  
Respiratory Chain Complexes ◽  
Ecm Remodeling ◽  
Pparγ Agonist ◽  
Lactate Levels

Extracellular matrix (ECM) exerts a list of biological functions, contributing to almost 30% of the osteogenic process. Periostin is a secreted protein that can alter ECM remodeling in response to vascular injury. However, the functional role of periostin in vascular calcification has yet to be fully described. Ex vivo, recombinant periostin accelerated thoracic aortas calcification, increased the expression of glycolysis key enzymes, and disturbed the normal oxidative phosphorylation (OXPHOS), which could be alleviated by the peroxisome proliferation-activated receptor γ (PPARγ) agonist pioglitazone. In vascular smooth muscle cells (VSMCs), recombinant periostin promoted VSMC-osteoblastic phenotype transition and calcium deposition, and suppressed PPARγ expression. Mechanistically, recombinant periostin caused over-activation of glycolysis and mitochondrial dysfunction in VSMCs, as assessed by extracellular acidification rate (ECAR), oxygen consumption rate, and mitochondrial respiratory chain complexes activities. Targeted glycolysis inhibitors reduced mitochondrial calcium overload, apoptosis, and periostin-induced VSMCs calcification. PPARγ agonists preserved glycolysis and OXPHOS in the stimulated microenvironment, and reversed periostin-promoted VSMC calcification. Furthermore, plasma periostin, lactate, and matrix Gla protein levels were measured in 274 patients who underwent computed tomography to determine coronary artery calcium score (Agatston score). Plasma periostin and lactate levels were both linked to an Agatston score of more than zero in patients with coronary artery calcification. There is also a positive correlation between plasma periostin and lactate levels. This study suggests that downregulation of PPARγ is involved in the mechanism by which periostin accelerates arterial calcification, partly through excessive glycolysis activation and unbalanced mitochondrial homeostasis.

scholarly journals A NOTCH1/LSD1/BMP2 co-regulatory network mediated by miR-137 negatively regulates osteogenesis of human adipose-derived stem cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Cong Fan ◽  
Xiaohan Ma ◽  
Yuejun Wang ◽  
Longwei Lv ◽  
Yuan Zhu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Osteoblastic Differentiation ◽  
Negative Control ◽  
Bone Morphogenetic Protein 2 ◽  
Luciferase Reporter ◽  
Adipose Derived Stem Cells ◽  
Differentiation Potential ◽  
Lineage Differentiation ◽  
Morphogenetic Protein ◽  
Genes Expression

Abstract Background MicroRNAs have been recognized as critical regulators for the osteoblastic lineage differentiation of human adipose-derived stem cells (hASCs). Previously, we have displayed that silencing of miR-137 enhances the osteoblastic differentiation potential of hASCs partly through the coordination of lysine-specific histone demethylase 1 (LSD1), bone morphogenetic protein 2 (BMP2), and mothers against decapentaplegic homolog 4 (SMAD4). However, still numerous molecules involved in the osteogenic regulation of miR-137 remain unknown. This study aimed to further elucidate the epigenetic mechanisms of miR-137 on the osteogenic differentiation of hASCs. Methods Dual-luciferase reporter assay was performed to validate the binding to the 3′ untranslated region (3′ UTR) of NOTCH1 by miR-137. To further identify the role of NOTCH1 in miR-137-modulated osteogenesis, tangeretin (an inhibitor of NOTCH1) was applied to treat hASCs which were transfected with miR-137 knockdown lentiviruses, then together with negative control (NC), miR-137 overexpression and miR-137 knockdown groups, the osteogenic capacity and possible downstream signals were examined. Interrelationships between signaling pathways of NOTCH1-hairy and enhancer of split 1 (HES1), LSD1 and BMP2-SMADs were thoroughly investigated with separate knockdown of NOTCH1, LSD1, BMP2, and HES1. Results We confirmed that miR-137 directly targeted the 3′ UTR of NOTCH1 while positively regulated HES1. Tangeretin reversed the effects of miR-137 knockdown on osteogenic promotion and downstream genes expression. After knocking down NOTCH1 or BMP2 individually, we found that these two signals formed a positive feedback loop as well as activated LSD1 and HES1. In addition, LSD1 knockdown induced NOTCH1 expression while suppressed HES1. Conclusions Collectively, we proposed a NOTCH1/LSD1/BMP2 co-regulatory signaling network to elucidate the modulation of miR-137 on the osteoblastic differentiation of hASCs, thus providing mechanism-based rationale for miRNA-targeted therapy of bone defect.

Targeting EZH2 Ameliorates the LPS-Inhibited PDLSC Osteogenesis via Wnt/β-Catenin Pathway

2021 ◽  
pp. 1-9
Author(s):  
Mosha Cheng ◽  
Qing Zhou
Keyword(s):  
Bone Morphogenetic Protein 2 ◽  
Periodontal Ligament Stem Cells ◽  
Alizarin Red ◽  
Protein Levels ◽  
Inflammatory Conditions ◽  
Morphogenetic Protein ◽  
Related Transcription Factor ◽  
Underlying Mechanisms ◽  
Factor Α ◽  
Osteoblast Maturation

As a histone methyltransferase, enhancer of zeste homolog 2 (EZH2), suppresses osteoblast maturation and is involved in inflammation. However, the role of EZH2 in human periodontal ligament stem cells (PDLSCs) under inflammation still needs to be further investigated. This study aimed to identify the underlying mechanisms and explore the function of EZH2 in PDLSC osteogenesis under inflammation. PDLSCs were treated with sh-EZH2, DZNep or DKK1 under inflammation. The alkaline phosphatase (ALP) activity, alizarin red staining, and osteogenesis-related protein levels were analyzed. Lipopolysaccharide (LPS)-induced inflammation restrained osteogenic differentiation. Under inflammation, the upregulation of EZH2 suppressed the expression of osteogenic markers, including osteocalcin, runt-related transcription factor 2, and bone morphogenetic protein-2, the activity of ALP, and the accumulation of mineralization through the Wnt/β-catenin pathway. EZH2 knockdown inhibited the levels of proinflammatory cytokines such as interleukin-6 and tumor necrosis factor-α. These results suggested that LPS-induced overexpression of EZH2 suppressed PDLSC osteogenesis under inflammatory conditions through the Wnt/β-catenin pathway. These findings give new insights into the physiological differentiation and pathological inflammation of PDLSC osteogenesis, and provide an underlying therapeutic target for periodontitis.

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