Chronic ethanol exposure inhibits distraction osteogenesis in a mouse model: Role of the TNF signaling axis

Aronson, James; Liu, Lichu; Liu, Zhendong; Perrien, Daniel S.; Skinner, Robert A.; Badger, Thomas M.; Ronis, Martin J. J.; Lumpkin, Charles K.

doi:10.1016/j.taap.2007.02.011

Cited by 29 publications

(41 citation statements)

References 29 publications

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“…Chronic alcohol feeding is known to enhanced expression of pro-inflammatory cytokines including TNFα (Leudemann et al, 2005;Wahl et al, 2007). TNFα on the other hand exerts similar inhibitory effect on the expression of GLUT4 (Rotter et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Chronic ethanol feeding impairs AMPK and MEF2 expression and is associated with GLUT4 decrease in rat myocardium

et al. 2010

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Abbreviations: AICAR, 5-amino-4-imidazolecarboxamide ribonucleotide; AMPK, AMP-activated protein kinase; GLUT4, glucose transporter 4; MEF2, myocyte enhancer factor 2 AbstractChronic and heavy alcohol consumption is one of the causes of heart diseases. However, the effects of ethanol on insulin sensitivity in myocardium has been unclear. To investigate the effects of ethanol on the expression of AMP-activated protein kinase (AMPK), myocyte enhancer factor 2 (MEF2) and glucose transporter 4 (GLUT4), all of which are involved in the regulation of insulin sensitivity, in the myocardium, we performed three parts of experiments in vivo and in vitro. ) of ethanol for 22-week. III: Primary neonatal rat cardiomyocytes were isolated and treated with or without 100 mM ethanol or 1 mM AICAR for 4 h. The cardiac protein and mRNA expression of AMPKα subunits, MEF2 and GLUT4 were observed by western-blotting and RT-PCR, respectively. Serum TNFα levels were assessed by ELISA. The results showed chronic ethanol exposure induced insulin resistance. Ethanol decreased the mRNA levels of AMPKα1 and α2, the protein levels of total-and phospho-AMPKα in cardiomyocytes. Similarly, ethanol showed inhibitory effects on both the mRNA and protein levels of MEF2A and 2D, and GLUT4 in a dose-response-like fashion. Correlation analysis implied an association between phospho-AMPKα and MEF2A or MEF2D, and between the levels of MEF2 protein and GLUT4 transcription. In addition, ethanol elevated serum TNFα level. Taken together, chronic ethanol exposure decreases the expression of AMPKα and MEF2, and is associated with GLUT4 decline in rat myocardium.

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Section: Discussionmentioning

confidence: 99%

Chronic ethanol feeding impairs AMPK and MEF2 expression and is associated with GLUT4 decrease in rat myocardium

et al. 2010

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“…A time course study of the serum TNF-a level (Fig. 3A) suggested that high levels of serum TNF-a would persist during the period (days 0-14) after tooth extraction, whereas the TNF-a level might be decreasing to a level <50 pg/ml during the late period after tooth extraction (days [14][15][16][17][18][19][20][21]. The significant reduction of serum osteocalcin level by LPS injection in WT mice appeared on day 7 not on day 21 after tooth extraction (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…(10,17,18) However, there are few reports showing an inhibitory role for TNF-a in vivo or in clinical studies. A recent report showed that chronic ethanol exposure inhibited osteogenesis through the TNF signaling axis in a murine tibia distraction model, (19) but the mechanism by which TNF-a inhibits in vivo osteogenesis remains unclear. Clinical reports show that anti-TNF-a therapy increases BMD and plasma levels of osteocalcin in patients with rheumatoid arthritis, (20,21) but direct evidence proving the ability of TNF-a to inhibit osteogenesis is lacking.…”

Section: Introductionmentioning

confidence: 99%

LPS-Induced Inhibition of Osteogenesis Is TNF-α Dependent in a Murine Tooth Extraction Model

Tomomatsu

Aoki

Alles

et al. 2009

Journal of Bone and Mineral Research

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TNF-a is a major etiologic factor of inflammatory bone diseases such as periodontitis and rheumatoid arthritis. In addition, patients with metabolic diseases such as chronic heart disease and diabetes have significantly increased plasma levels of TNF-a. Several lines of evidence show inhibition of osteoblastogenesis by TNF-a in vitro. Therefore, bone formation and osteogenesis in these patients might be inhibited because of TNF-a. However, little is known about the inhibitory role of TNF-a in bone formation/ osteogenesis in vivo. The purpose of this study was to investigate the role of TNF-a in osteogenesis using a murine tooth extraction model. Lipopolysaccharide (LPS) was injected subcutaneously into the calvariae of either wildtype (WT) or TNF-a-deficient (KO) mice. The left incisor was extracted 4 days after LPS injection. The measuring area was established as the tooth socket under the mesial root of the first molar. A significant increase in serum TNF-a levels after LPS injection was observed in WT mice. The BMD of the tooth socket was significantly decreased by LPS injection 21 days after extraction in WT but not in KO mice. Histomorphometric analysis showed a significant decrease in the mineral apposition rate after LPS injection, which appeared at an early stage in WT but not in KO mice. Injection of a peptide that blocked the TNF-a signaling pathway by preventing transmission of the NF-kB signal recovered the inhibition of osteogenesis observed after LPS injection. In conclusion, TNF-a might play a major role in LPS-induced inhibition of osteogenesis under inflammatory conditions.

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“…While it has long been known that excessive alcohol consumption promotes adipogenesis and inhibits osteogenesis [5,6,7,8,9] and induces ER stress [11,12,13] that mediates alcoholic damages to many organs, the relationship between ER stress and osteogenesis disruption in BMSCs remained unknown. The present study provides evidence for the role of ER stress in mediating osteogenesis disruption after chronic alcohol exposure.…”

Section: Discussionmentioning

confidence: 99%

“…Excessive alcohol consumption substantially promotes adipogenesis and inhibits osteogenesis [5,6,7,8,9]. Moreover, both chronic and binge consumptions of ethanol are known to cause suppression of bone formation and enhancement of bone resorption.…”

Section: Introductionmentioning

confidence: 99%

ER Stress Activating ATF4/CHOP-TNF-α Signaling Pathway Contributes to Alcohol-Induced Disruption of Osteogenic Lineage of Multipotential Mesenchymal Stem Cell

Chen¹,

Gao

Yin

et al. 2013

Cell Physiol Biochem

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Background/Aims: Studies have provided substantial evidence that osteoblasts and adipocytes share common progenitor‒multipotential mesenchymal stem cells in bone marrow (BMSCs), and excessive alcohol consumption shifts away from osteogenic to adipogenic lineage. However, how exactly alcohol impairs osteogenesis is still incompletely understood. This study was designed to shed light on this issue. Methods: We treated primary BMSCs from human subjects with alcohol for 24 days. We measured changes of genes related to endoplasmic reticulum (ER) stress, adipogenic markers and osteogenic markers using quantitative real-time RT-PCR and Western blot analysis. We performed Oil red O staining and quantification of adipogenesis. We also conducted caspase 3 activity assay to assess BMSC apoptosis. Results: We showed here that chronic exposure of BMSCs to alcohol induced adipogenesis and disrupted osteogenesis as indicated by upregulation of adipogenic markers (PPARγ2 and aP2), downregulation of osteogenic markers (Osf2/Cbfa1), and accumulation of lipid droplets. Alcohol induced ER stress, as reflected by increased expression of glucose-regulated proteins GRP78 and GRP94, and by increased expression of transcription factors activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), and enhanced caspase 3 activity. Additionally, ER stress also upregulated tumor necrosis factor-alpha (TNF-α). Simultaneous silencing of ATF4 and CHOP prevented upregulation of TNF-α. Knockdown of either ATF4 and CHOP or TNF-α by their siRNAs was able to reverse the ethanol-induced adipogenesis. Conclusion: Our data therefore revealed a role of ER stress and ATF4/CHOP in the ethanol-induced inhibition of osteogenesis, and activation of TNF-α signaling by ATF4/CHOP linking ER stress to adipogenic lineage in response to alcohol stimulation. This work should establish a new signaling pathway linking alcohol, ER stress, and TNF-α to loss of bone formation: Ethanol → ER stress↑↑↑ → ATF4 & CHOP↑↑↑ → TNF-α↑↑↑ → Osteoblasts↓↓↓.

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Chronic ethanol exposure inhibits distraction osteogenesis in a mouse model: Role of the TNF signaling axis

Cited by 29 publications

References 29 publications

Chronic ethanol feeding impairs AMPK and MEF2 expression and is associated with GLUT4 decrease in rat myocardium

Chronic ethanol feeding impairs AMPK and MEF2 expression and is associated with GLUT4 decrease in rat myocardium

LPS-Induced Inhibition of Osteogenesis Is TNF-α Dependent in a Murine Tooth Extraction Model

ER Stress Activating ATF4/CHOP-TNF-α Signaling Pathway Contributes to Alcohol-Induced Disruption of Osteogenic Lineage of Multipotential Mesenchymal Stem Cell

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