Alcohol Inhibits Osteopontin-dependent Transforming Growth Factor-beta 1 Expression in Human Mesenchymal Stem Cells

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

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2015, 290(16): 9959-9973.

DOI：10.1074/jbc.M114.616888

• Gene Expression
• Gene Transcription
• Mesenchymal Stem Cells (MSCs)
• Osteopontin
• Promoter
• Protein Kinase A (PKA)
• Transforming Growth Factor (TGF-)
• Zinc Finger
• Alcohol (EtOH)

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 1 (TGF-1) 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-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. We have demonstrated that EtOH inhibits OPN-induced TGF-1 protein expression, decreases MZF1-dependent TGF-1 transcription and MZF1 transcription, and blocks OPN-induced MZF1 phosphorylation. We also found that PKA signaling enhances OPN-induced TGF-1 expression. Last, we showed that EtOH exposure reduces the TGF-1 protein levels in mouse fracture callus. We conclude that EtOH acts in a novel mechanism by interfering directly with the OPN-MZF1-TGF-1 signaling pathway in MSC.

• 出版日期2015-4-17