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Published on: May 4, 2018
Alcohol inhibits osteopontin-dependent transforming growth factor-β1 expression in human mesenchymal stem cells
Joseph Driver1, Cynthia E Weber1, John J Callaci2
1From the Departments of Surgery.
Abstract:
Alcohol (EtOH) intoxication is a risk factor for increased morbidity and mortality with traumatic injuries, in part through inhibition of bone fracture healing. Animal models have shown that EtOH decreases fracture callus volume, diameter, and biomechanical strength. Transforming growth factor β1 (TGF-β1) and osteopontin (OPN) play important roles in bone remodeling and fracture healing. Mesenchymal stem cells (MSC) reside in bone and are recruited to fracture sites for the healing process. Resident MSC are critical for fracture healing and function as a source of TGF-β1 induced by local OPN, which acts through the transcription factor myeloid zinc finger 1 (MZF1). The molecular mechanisms responsible for the effect of EtOH on fracture healing are still incompletely understood, and this study investigated the role of EtOH in affecting OPN-dependent TGF-β1 expression in MSC. We have demonstrated that EtOH inhibits OPN-induced TGF-β1 protein expression, decreases MZF1-dependent TGF-β1 transcription and MZF1 transcription, and blocks OPN-induced MZF1 phosphorylation. We also found that PKA signaling enhances OPN-induced TGF-β1 expression. Last, we showed that EtOH exposure reduces the TGF-β1 protein levels in mouse fracture callus. We conclude that EtOH acts in a novel mechanism by interfering directly with the OPN-MZF1-TGF-β1 signaling pathway in MSC.
Insights
Alcohol intoxication impairs bone fracture healing by disrupting the OPN-MZF1-TGF-β1 pathway in mesenchymal stem cells (MSC). This study reveals a novel mechanism where alcohol interferes with crucial signaling for bone repair.
Area of Science:
- Bone biology
- Traumatology
- Cell signaling
Background:
- Alcohol intoxication is a significant risk factor for poor outcomes in traumatic injuries, notably inhibiting bone fracture healing.
- Animal studies indicate alcohol reduces fracture callus volume, diameter, and biomechanical strength, highlighting its detrimental effects on bone repair.
- Transforming growth factor β1 (TGF-β1) and osteopontin (OPN) are critical for bone remodeling and fracture healing, with mesenchymal stem cells (MSCs) playing a central role.
Purpose of the Study:
- To investigate the molecular mechanisms by which alcohol (EtOH) affects osteopontin (OPN)-dependent transforming growth factor β1 (TGF-β1) expression in mesenchymal stem cells (MSCs).
- To elucidate the role of the OPN-MZF1-TGF-β1 signaling pathway in alcohol's impact on fracture healing.
Main Methods:
- Investigated the effect of EtOH on OPN-induced TGF-β1 protein expression in MSCs.
- Assessed EtOH's impact on MZF1-dependent TGF-β1 transcription and MZF1 transcription.
- Examined EtOH's effect on OPN-induced MZF1 phosphorylation.
- Measured TGF-β1 protein levels in mouse fracture callus following EtOH exposure.
Main Results:
- EtOH was found to inhibit OPN-induced TGF-β1 protein expression in MSCs.
- Alcohol exposure decreased MZF1-dependent TGF-β1 transcription and MZF1 transcription.
- EtOH blocked OPN-induced MZF1 phosphorylation, a key step in the signaling pathway.
- PKA signaling was identified as enhancing OPN-induced TGF-β1 expression.
- Reduced TGF-β1 protein levels were observed in mouse fracture callus after EtOH exposure.
Conclusions:
- Alcohol interferes with the OPN-MZF1-TGF-β1 signaling pathway in MSCs, representing a novel mechanism for its detrimental effects on bone fracture healing.
- Understanding this pathway provides new targets for therapeutic interventions aimed at improving fracture healing in individuals with alcohol intoxication.
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01:19Mesenchymal Stem Cells
01:16TGF - β Signaling Pathway