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National Institute of Environmental Health Sciences

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Publication Detail

Title: Inhibition of beta-catenin signaling by Pb leads to incomplete fracture healing.

Authors: Beier, Eric E; Sheu, Tzong-Jen; Buckley, Taylor; Yukata, Kiminori; O'Keefe, Regis; Zuscik, Michael J; Puzas, J Edward

Published In J Orthop Res, (2014 Nov)

Abstract: There is strong evidence in the clinical literature to suggest that elevated lead (Pb) exposure impairs fracture healing. Since Pb has been demonstrated to inhibit bone formation, and Wnt signaling is an important anabolic pathway in chondrocyte maturation and endochondral ossification, we investigated the impact of Wnt therapy on Pb-exposed mice undergoing bone repair in a mouse tibial fracture model. We established that tibial fracture calluses from Pb-treated mice were smaller and contained less mineralized tissue than vehicle controls. This resulted in the persistence of immature cartilage in the callus and decreased β-catenin levels. Reduction of β-catenin protein was concurrent with systemic elevation of LRP5/6 antagonists DKK1 and sclerostin in Pb-exposed mice throughout fracture healing. β-catenin stimulation by the GSK3 inhibitor BIO reversed these molecular changes and restored the amount of mineralized callus. Overall, Pb is identified as a potent inhibitor of endochondral ossification in vivo with correlated effects on bone healing with noted deficits in β-catenin signaling, suggesting the Wnt/β-catenin as a pivotal pathway in the influence of Pb on fracture repair.

PubMed ID: 25044211 Exiting the NIEHS site

MeSH Terms: Adaptor Proteins, Signal Transducing; Animals; Female; Fracture Healing/drug effects*; Glycogen Synthase Kinase 3/antagonists & inhibitors; Glycoproteins/metabolism; Indoles/chemistry; Intercellular Signaling Peptides and Proteins; Lead/chemistry*; Male; Mesenchymal Stem Cells/cytology*; Mice; Mice, Inbred C57BL; Osteoblasts/drug effects; Osteogenesis; Oximes/chemistry; Signal Transduction; Tibial Fractures/metabolism; Tibial Fractures/physiopathology*; Time Factors; Wnt Proteins/metabolism; Wound Healing; X-Ray Microtomography; beta Catenin/antagonists & inhibitors*; beta Catenin/metabolism

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