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.
Highlights
Alcohol (EtOH) exposure has detrimental effects on fracture healing
Resident Mesenchymal stem cells (MSC) are critical for fracture healing and function as a source of Transforming growth factor 1 (TGF-1) induced by local OPN, which acts through the transcription factor myeloid zinc finger 1 (MZF1)
We further demonstrated that EtOH inhibits RNA polymerase II and MZF1 binding to the transforming growth factor- (TGF-)1 promoter, pointing to an explanation for decreased TGF-1 protein levels
Summary
Alcohol (EtOH) exposure has detrimental effects on fracture healing. Results: EtOH inhibits TGF-1 protein expression via interference with the transcription factor myeloid zinc finger 1. Alcohol (EtOH) intoxication is a risk factor for increased morbidity and mortality with traumatic injuries, in part through inhibition of bone fracture healing. Resident MSC are critical for fracture healing and function as a source of TGF-1 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-1 expression in MSC. Alcohol intoxication is a significant risk factor associated with traumatic injury. Patients who abuse alcohol have prolonged healing time following transverse tibial fractures (3)
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