Exogenous activation of Wnt/beta-catenin signaling attenuates binge alcohol-induced deficient bone fracture healing Journal Article

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Authors: Lauing, K. L.; Sundaramurthy, S.; Nauer, R. K.; Callaci, J. J.
Article Title: Exogenous activation of Wnt/beta-catenin signaling attenuates binge alcohol-induced deficient bone fracture healing
Abstract: AIMS: Excessive alcohol consumption is associated with fracture non-union. Canonical Wnt pathway signaling activity regulates normal fracture healing. We previously demonstrated that binge alcohol exposure modulates beta-catenin levels in the fracture callus of mice. Here, we sought to determine whether exogenous enhancement beta-catenin signaling activity could restore normal fracture healing to binge-exposed mice. METHODS: C57BL/6 male mice were exposed to episodic alcohol or saline for 6 total days of alcohol exposure over a 2-week period. Following alcohol exposure, mice were subjected to a stabilized mid-shaft tibia fracture. Beginning 4 days post-injury, mice received daily injections of either lithium chloride or saline subcutaneously. Protein levels of activated, inactivated, and total beta-catenin and GSK-3beta in fracture calluses were measured at post-injury day 9. Biomechanical strength testing and histology of callus tissue was assessed at post fracture day 14. RESULTS: Binge alcohol was associated with decreased callus biomechanical strength, and reduced cartilaginous callus formation. Alcohol decreased levels of callus-associated activated beta-catenin while concomitantly increasing the levels of inactive beta-catenin at post-injury day 9. Alcohol also increased callus associated activated GSK-3beta at post-injury day 9. Lithium chloride (an inhibitor of GSK-3beta) treatment increased activated beta-catenin protein levels, significantly decreased activated GSK-3beta and restored cartilaginous callus formation and endochondral ossification. CONCLUSION: These data link alcohol-impaired fracture healing with deregulation of Canonical Wnt signaling activity in the fracture callus. Exogenous activation of the Wnt pathway using LiCl attenuated the damaging effects of binge alcohol exposure on the fracture healing process by modulating canonical Wnt signaling activity.
Journal Title: Alcohol and Alcoholism (Oxford, Oxfordshire)
Volume: 49
Issue: 4
ISSN: 1464-3502; 0735-0414
Publisher: . Medical Council on Alcohol and Oxford University Press. All rights reserved  
Journal Place: England
Date Published: 2014
Start Page: 399
End Page: 408
Language: eng
DOI/URL:

10.1093/alcalc/agu006
Notes: LR: 20150701; CI: (c) The Author 2014; GR: F32 019613/PHS HHS/United States; GR: R01 AA016138/AA/NIAAA NIH HHS/United States; GR: R01 AA016138/AA/NIAAA NIH HHS/United States; GR: R21 AA021225/AA/NIAAA NIH HHS/United States; GR: R21 AA021225/AA/NIAAA NIH HHS/United States; GR: T32 013527/PHS HHS/United States; JID: 8310684; 0 (beta Catenin); EC 2.7.11.1 (glycogen synthase kinase 3 beta); EC 2.7.11.26 (Glycogen Synthase Kinase 3); G4962QA067 (Lithium Chloride); OID: NLM: PMC4060733; 2014/03/13 [aheadofprint]; ppublish