title: Alcohol inhibits osteopontin-dependent transforming growth factor-β1 expression in human mesenchymal stem cells.
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.
authors.affiliation: From the Departments of Surgery.
authors.forename: Joseph
authors.initials: J
authors.lastname: Driver
authors.affiliation: From the Departments of Surgery.
authors.forename: Cynthia E
authors.initials: CE
authors.lastname: Weber
authors.affiliation: Orthopaedic Surgery.
authors.forename: John J
authors.initials: JJ
authors.lastname: Callaci
authors.affiliation: From the Departments of Surgery.
authors.forename: Anai N
authors.initials: AN
authors.lastname: Kothari
authors.affiliation: From the Departments of Surgery.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Zapf
authors.affiliation: Orthopaedic Surgery.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Roper
authors.affiliation: Pathology, and.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Borys
authors.affiliation: Urology, Loyola University Medical Center, Maywood, Illinois 60130.
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Franzen
authors.affiliation: Urology, Loyola University Medical Center, Maywood, Illinois 60130.
authors.forename: Gopal N
authors.initials: GN
authors.lastname: Gupta
authors.affiliation: From the Departments of Surgery.
authors.forename: Philip Y
authors.initials: PY
authors.lastname: Wai
authors.affiliation: Pathology, and.
authors.forename: Jiwang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Pathology, and.
authors.forename: Mitchell F
authors.initials: MF
authors.lastname: Denning
authors.affiliation: From the Departments of Surgery, pkuo@lumc.edu.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Kuo
authors.affiliation: From the Departments of Surgery.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Mi
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D000431:Ethanol / Q000009:adverse effects*; D017102:Fracture Healing / Q000187:drug effects; D005786:Gene Expression Regulation; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D053495:Osteopontin / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation; D015398:Signal Transduction; D013977:Tibia / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D013978:Tibial Fractures / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D052157:Aptamers, Nucleotide; D051741:Kruppel-Like Transcription Factors; C085969:MZF1 protein, human; C490095:Mzf1 protein, mouse; D053773:Transforming Growth Factor beta1; D053495:Osteopontin; D000431:Ethanol; D008156:Luciferases
keywords: Alcohol (EtOH); Gene Expression; Gene Transcription; Mesenchymal Stem Cells (MSCs); Osteopontin; Promoter; Protein Kinase A (PKA); Transforming Growth Factor β (TGF-β); Zinc Finger