Alcohol inhibits osteopontin-dependent transforming growth factor-beta1 expression in human mesenchymal stem cells Journal Article


Authors: Driver, J.; Weber, C. E.; Callaci, J. J.; Kothari, A. N.; Zapf, M. A.; Roper, P. M.; Borys, D; Franzen, C. A.; Gupta, G. N.; Wai, P. Y.; Zhang, J; Denning, M. F.; Kuo, P. C.; Mi, Z.
Article Title: Alcohol inhibits osteopontin-dependent transforming growth factor-beta1 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 beta1 (TGF-beta1) 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-beta1 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-beta1 expression in MSC. We have demonstrated that EtOH inhibits OPN-induced TGF-beta1 protein expression, decreases MZF1-dependent TGF-beta1 transcription and MZF1 transcription, and blocks OPN-induced MZF1 phosphorylation. We also found that PKA signaling enhances OPN-induced TGF-beta1 expression. Last, we showed that EtOH exposure reduces the TGF-beta1 protein levels in mouse fracture callus. We conclude that EtOH acts in a novel mechanism by interfering directly with the OPN-MZF1-TGF-beta1 signaling pathway in MSC.
Journal Title: The Journal of biological chemistry
Volume: 290
Issue: 16
ISSN: 1083-351X; 0021-9258
Publisher: by The American Society for Biochemistry and Molecular Biology, Inc  
Journal Place: United States
Date Published: 2015
Start Page: 9959
End Page: 9973
Language: eng
DOI/URL:
Notes: LR: 20150427; CI: (c) 2015; JID: 2985121R; 0 (Aptamers, Nucleotide); 0 (Kruppel-Like Transcription Factors); 0 (MZF1 protein, human); 0 (Mzf1 protein, mouse); 0 (Transforming Growth Factor beta1); 106441-73-0 (Osteopontin); 3K9958V90M (Ethanol); EC 1.13.12.- (Luciferases); OID: NLM: PMC4400371 [Available on 04/17/16]; OTO: NOTNLM; PMCR: 2016/04/17 00:00; 2014/10/04 [received]; 2015/02/24 [aheadofprint]; ppublish