title: Alcohol-related deficient fracture healing is associated with activation of FoxO transcription factors in mice.
abstract: The process of fracture healing is complex, and poor or incomplete healing remains a significant health problem. Proper fracture healing relies upon resident mesenchymal stem cell (MSC) differentiation into chondrocytes and osteoblasts, which are necessary for callus formation and ossification. Alcohol abuse is a leading contributor to poor fracture healing. Although the mechanism behind this action is unknown, excessive alcohol consumption is known to promote systemic oxidative stress. The family of FoxO transcription factors is activated by oxidative stress, and FoxO activation antagonizes Wnt signaling, which regulates mesenchymal stem cell differentiation. We hypothesize that alcohol exposure increases oxidative stress leading to deficient fracture repair by activating FoxO transcription factors within the fracture callus which disrupts chondrogenesis of mesenchymal stem cells. Our laboratory has developed an experimental model of delayed fracture union in mice using ethanol administration. We have found that ethanol administration significantly decreases external, cartilaginous callus formation, and hallmarks of endochondral ossification, and these changes are concomitant with increases in FoxO expression and markers of activation in fracture callus tissue of these mice. We were able to prevent these alcohol-induced effects with the administration of the antioxidant n-acetyl cysteine (NAC), suggesting that alcohol-induced oxidative stress produces the perturbed endochondral ossification and FoxO expression. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2106-2115, 2016.
authors.affiliation: Department of Orthopaedic Surgery and Rehabilitation, Loyola University Medical Center, Maywood, Illinois.|Integrative Cellular Biology Program, Health Sciences Campus, Loyola University Chicago, Building 110, Room 4244, 2160 S First Ave, Maywood, Illinois.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Roper
authors.affiliation: Department of Orthopaedic Surgery and Rehabilitation, Loyola University Medical Center, Maywood, Illinois.
authors.forename: Pegah
authors.initials: P
authors.lastname: Abbasnia
authors.affiliation: Integrative Cellular Biology Program, Health Sciences Campus, Loyola University Chicago, Building 110, Room 4244, 2160 S First Ave, Maywood, Illinois.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Vuchkovska
authors.affiliation: University of Maryland Shock Trauma Center, Baltimore, Maryland.
authors.forename: Roman M
authors.initials: RM
authors.lastname: Natoli
authors.affiliation: Department of Orthopaedic Surgery and Rehabilitation, Loyola University Medical Center, Maywood, Illinois.|Integrative Cellular Biology Program, Health Sciences Campus, Loyola University Chicago, Building 110, Room 4244, 2160 S First Ave, Maywood, Illinois.
authors.forename: John J
authors.initials: JJ
authors.lastname: Callaci
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002146:Bony Callus / Q000187:drug effects* / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000009:adverse effects*; D020219:Chondrogenesis / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D000431:Ethanol / Q000009:adverse effects*; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D017102:Fracture Healing / Q000187:drug effects*; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008810:Mice, Inbred C57BL; D011897:Random Allocation
chemical_list: D002492:Central Nervous System Depressants; D051858:Forkhead Transcription Factors; D016166:Free Radical Scavengers; D000431:Ethanol; D000111:Acetylcysteine
keywords: FoxO; Wnt; alcohol; fracture; oxidative stress