Alcohol Inhibits Osteopontin-dependent Transforming Growth Factor-β1 Expression in Human Mesenchymal Stem Cells

Driver, Joseph; Weber, Cynthia E.; Callaci, John J.; Kothari, Anai N.; Zapf, Matthew; Roper, Philip M.; Borys, Dariusz; Franzen, Carrie A.; Gupta, Gopal N.; Wai, Philip Y.; Zhang, Jiwang; Denning, Mitchell F.; Kuo, Paul C.; Mi, Zhiyong

doi:10.1074/jbc.m114.616888

Cited by 28 publications

(27 citation statements)

References 33 publications

(37 reference statements)

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“…Animal studies also indicated decreased osteogenesis and bone volume after long-term alcohol consumption [9, 10]. Human bone mesenchymal stem cells (hBMSCs) are regarded as the main source of self-renewal and regeneration of bone tissue [11-13], whereas recent studies demonstrated that ethanol treatment could impair the osteogenic differentiation of hBMSCs [2, 14]. Meanwhile, suppressed osteogenic activity has been detected in ONFH patients [15].…”

Section: Introductionmentioning

confidence: 99%

The Protective Effect of Cordycepin On Alcohol-Induced Osteonecrosis of the Femoral Head

Chen¹,

Zhu²,

Xu³

et al. 2017

Cell Physiol Biochem

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Background: Alcohol abuse is known to be a leading risk factor for atraumatic osteonecrosis of the femoral head (ONFH), in which the suppression of osteogenesis plays a critical role. Cordycepin benefits bone metabolism; however, there has been no study to determine its effect on osteonecrosis. Methods: Human bone mesenchymal stem cells (hBMSCs) were identified by multi-lineage differentiation. Alkaline phosphatase (ALP) activity, RT-PCR, western blots, immunofluorescent assay and Alizarin red staining of BMSCs were evaluated. A rat model of alcohol-induced ONFH was established to investigate the protective role of cordycepin against ethanol. Hematoxylin & eosin (H&E) staining and micro-computerized tomography (micro-CT) were performed to observe ONFH. Apoptosis was assessed by TdT-mediated dUTP nick end labeling (TUNEL). Immunohistochemical staining was carried out to detect OCN and COL1. Results: Ethanol significantly suppressed ALP activity, decreased gene expression of OCN and BMP2, lowered levels of RUNX2 protein, and reduced immunofluorescence staining of OCN and COL1 and calcium formation of hBMSCs. However, these inhibitory effects were attenuated by cordycepin co-treatment at concentrations of 1 and 10 µg/mL Moreover, it was revealed that the osteo-protective effect of cordycepin was associated with modulation of the Wnt/β-catenin pathway. In vivo, by micro-CT, TUNEL and immunohistochemical staining of OCN and COL1, we found that cordycepin administration prevented alcohol-induced ONFH. Conclusion: Cordycepin treatment to enhance osteogenesis may be considered a potential therapeutic approach to prevent the development of alcohol-induced ONFH.

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Section: Introductionmentioning

confidence: 99%

The Protective Effect of Cordycepin On Alcohol-Induced Osteonecrosis of the Femoral Head

Chen¹,

Zhu²,

Xu³

et al. 2017

Cell Physiol Biochem

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“…Remarkably, the L/BD regional cluster analysis identified 9 DMRs, 4 of which mapped to genes with known links to alcohol use ( PDE10A, CCBE1, FZD5, MZF1 ) (Driver et al, 2015; Edenberg et al, 2010; Logrip, 2015; Wang et al, 2016). The other 5 DMRs map to 4 genes of relevance to synaptic signaling ( PKD2L2, FXDY5, TRAPPC9, MACROD1 ) (Fiederling et al, 2011; Georgolios et al, 2012; Hu et al, 2005; Spanagel et al, 2014; Wu et al, 2011) although this is the first report to specifically link them to sustained levels of voluntary alcohol drinking.…”

Section: Discussionmentioning

confidence: 99%

“…Others have shown that moderate alcohol consumption has a protective anti-inflammatory role by inhibiting NF-κβ activation (Mandrekar et al, 2007), however our studies hint that NF-κβ mediated mechanisms may also play a role in regulating alcohol consumption. A downstream target of the AC/cAMP/PKA pathway recently identified as a target of alcohol is the transcription factor of the Kruppel family of zinc finger proteins encoded by MZF1 (Driver et al, 2015; Luo et al, 2009). While the role of MZF1 in the brain is currently unknown, it was found that ethanol interfered with the phosphorylation and transcriptional activation of MZF1 in mesenchymal stem cells, ultimately impairing bone healing (Driver et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…A downstream target of the AC/cAMP/PKA pathway recently identified as a target of alcohol is the transcription factor of the Kruppel family of zinc finger proteins encoded by MZF1 (Driver et al, 2015; Luo et al, 2009). While the role of MZF1 in the brain is currently unknown, it was found that ethanol interfered with the phosphorylation and transcriptional activation of MZF1 in mesenchymal stem cells, ultimately impairing bone healing (Driver et al, 2015). Our study provides the first evidence suggesting a role of MZF1 in mediating the effects of alcohol in the NAcc, as well.…”

Section: Discussionmentioning

confidence: 99%

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Genome-wide analysis of the nucleus accumbens identifies DNA methylation signals differentiating low/binge from heavy alcohol drinking

Cervera-Juanes

Wilhelm

Park

et al. 2017

Alcohol

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Alcohol use disorders encompass a range of drinking levels and behaviors, including low, binge and heavy drinking. In this regard, investigating the neural state of individuals who chronically self-administer lower doses of alcohol may provide insight into mechanisms that prevent the escalation of alcohol use. DNA methylation is one of the epigenetic mechanisms that stabilizes adaptations in gene expression and has been associated with alcohol use. Thus, we investigated DNA methylation, gene expression and the predicted neural effects in the nucleus accumbens of male rhesus macaques categorized as “low” or “binge” drinkers, compared to “alcohol-naïve” and “heavy” drinkers based on drinking patterns during a 12 month alcohol self-administration protocol. Using genome-wide CpG-rich region enrichment and bisulfite sequencing, the methylation levels of 2.6 million CpGs were compared between alcohol naïve (AN), low/binge (L/BD) and heavy/very heavy (H/VHD) drinking subjects (n=24). Through regional clustering analysis, we identified nine significant differential methylation regions (DMRs) that specifically distinguished ANs and L/BDs, and then compared those DMRs among H/VHDs. The DMRs mapped to genes encoding ion channels, receptors, cell adhesion molecules and cAMP, NF-κβ and Wnt signaling pathway proteins. Two of the DMRs, linked to PDE10A and PKD2L2, were also differentially methylated in H/VHDs, suggesting an alcohol-dose independent effect. However two other DMRs, linked to the CCBE1 and FZD5 genes, had L/BD methylation levels that significantly differed from both ANs and H/VHDs. The remaining 5 DMRs also differentiated L/BDs and ANs, however H/VHDs methylation levels were not distinguishable from either of the two groups. Functional validation of two DMRs, linked to FZD5 and PDE10A, support their role in regulating gene expression and exon usage, respectively. In summary, the findings demonstrate that L/BD is associated with unique DNA methylation signatures in the primate NAcc, and identifies synaptic genes that may play a role in preventing the escalation of alcohol use.

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“…HCECs were treated with human osteopontin recombinant protein (rhOPN; R&D Systems) at a final concentration of 180 ng mL −1 ) or 4E1RC at 1 h after treatment with the OPN neutralizing antibody. After pretreatment, HCECs were treated with A. fumigatus conidia at an MOI of 1 for 0 and 16 h in 12‐well plates for qRT‐PCR and 0 and 16 h in 6‐well plates for western blotting.…”

Section: Methodsmentioning

confidence: 99%

Osteopontin contributes to effective neutrophil recruitment, IL‐1β production and apoptosis in Aspergillus fumigatus keratitis

Zhao

Cui

et al. 2018

Immunol Cell Biol

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Fungal keratitis is a major cause of corneal ulcers, resulting in significant visual impairment and blindness. A phosphorylated glycoprotein secreted by immunocompetent cells, osteopontin (OPN) mediates cluster formation of the host fungal receptors and enhances the phagocytosis and clearance of pathogenic fungi. However, whether OPN production and function occurs in fungal keratitis is unknown. OPN expression in Aspergillus fumigatus keratitis patient corneas was assessed by quantitative polymerase chain reaction (qRT-PCR) and immunofluorescence. Human neutrophils, THP-1 macrophages and corneal epithelial cells (HCECs) stimulated with A. fumigatus were utilized for in vitro experiments. Mouse models of A. fumigatus keratitis were developed by intrastromal injection for in vivo experiments. Using siRNAs, neutralizing antibodies, recombinant proteins and inhibitors, the production and role of OPN in A. fumigatus infection was assessed by clinical evaluation, qRT-PCR, immunofluorescence, western blotting and bioluminescence image acquisition. We observed increased corneal OPN expression in A. fumigatus keratitis patients and mouse models compared to controls. OPN production in response to A. fumigatus infection was dependent on LOX-1 and Erk1/2. Compared to controls, OPN knockdown impaired proinflammatory cytokine IL-1β production, which was dependent on 4E-BP1. OPN knockdown decreased myeloperoxidase levels, and resulted in decreased neutrophil recruitment, higher fungal load and increased apoptosis in mouse A. fumigatus keratitis. Our results indicate that OPN is a critical component of the antifungal immune response and is essential for effective neutrophil recruitment, inflammatory cytokine production and apoptosis in A. fumigatus keratitis.

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Alcohol Inhibits Osteopontin-dependent Transforming Growth Factor-β1 Expression in Human Mesenchymal Stem Cells

Cited by 28 publications

References 33 publications

The Protective Effect of Cordycepin On Alcohol-Induced Osteonecrosis of the Femoral Head

The Protective Effect of Cordycepin On Alcohol-Induced Osteonecrosis of the Femoral Head

Genome-wide analysis of the nucleus accumbens identifies DNA methylation signals differentiating low/binge from heavy alcohol drinking

Osteopontin contributes to effective neutrophil recruitment, IL‐1β production and apoptosis in Aspergillus fumigatus keratitis

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