Alcohol inhibits osteopontin-dependent transforming growth factor-β1 expression in human mesenchymal stem cells

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

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)9959-9973
Number of pages15
JournalJournal of Biological Chemistry
Volume290
Issue number16
DOIs
StatePublished - Apr 17 2015
Externally publishedYes

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Osteopontin
Transforming Growth Factors
Stem cells
Mesenchymal Stromal Cells
Fracture Healing
Alcohols
Zinc Fingers
Zinc
Bone
Bone Fractures
Bony Callus
Transcription
Alcoholic Intoxication
Phosphorylation
Bone Remodeling
Animals
Proteins
Transcription Factors
Animal Models
Morbidity

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Driver, J., Weber, C. E., Callaci, J. J., Kothari, A. N., Zapf, M. A., Roper, P. M., ... Mi, Z. (2015). Alcohol inhibits osteopontin-dependent transforming growth factor-β1 expression in human mesenchymal stem cells. Journal of Biological Chemistry, 290(16), 9959-9973. https://doi.org/10.1074/jbc.M114.616888

Alcohol inhibits osteopontin-dependent transforming growth factor-β1 expression in human mesenchymal stem cells. / 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.

In: Journal of Biological Chemistry, Vol. 290, No. 16, 17.04.2015, p. 9959-9973.

Research output: Contribution to journalArticle

Driver, J, Weber, CE, Callaci, JJ, Kothari, AN, Zapf, MA, Roper, PM, Borys, D, Franzen, CA, Gupta, GN, Wai, PY, Zhang, J, Denning, MF, Kuo, PC & Mi, Z 2015, 'Alcohol inhibits osteopontin-dependent transforming growth factor-β1 expression in human mesenchymal stem cells', Journal of Biological Chemistry, vol. 290, no. 16, pp. 9959-9973. https://doi.org/10.1074/jbc.M114.616888
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. / Alcohol inhibits osteopontin-dependent transforming growth factor-β1 expression in human mesenchymal stem cells. In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 16. pp. 9959-9973.
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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.",
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AU - Weber, Cynthia E.

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AU - Kothari, Anai N.

AU - Zapf, Matthew A.

AU - Roper, Philip M.

AU - Borys, Dariusz

AU - Franzen, Carrie A.

AU - Gupta, Gopal N.

AU - Wai, Philip Y.

AU - Zhang, Jiwang

AU - Denning, Mitchell F.

AU - Kuo, Paul C.

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