title: Inhibition of beta-catenin signaling by Pb leads to incomplete fracture healing.
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.
authors.affiliation: Center for Musculoskeletal Research, University of Rochester, School of Medicine and Dentistry, Rochester, New York, 14642; Department of Environmental Medicine, University of Rochester, School of Medicine and Dentistry, Rochester, New York, 14642.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Beier
authors.forename: Tzong-Jen
authors.initials: TJ
authors.lastname: Sheu
authors.forename: Taylor
authors.initials: T
authors.lastname: Buckley
authors.forename: Kiminori
authors.initials: K
authors.lastname: Yukata
authors.forename: Regis
authors.initials: R
authors.lastname: O'Keefe
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Zuscik
authors.forename: J Edward
authors.initials: JE
authors.lastname: Puzas
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D005260:Female; D017102:Fracture Healing / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D006023:Glycoproteins / Q000378:metabolism; D007211:Indoles / Q000737:chemistry; D036341:Intercellular Signaling Peptides and Proteins; D007854:Lead / Q000737:chemistry*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000187:drug effects; D010012:Osteogenesis; D010091:Oximes / Q000737:chemistry; D015398:Signal Transduction; D013978:Tibial Fractures / Q000378:metabolism / Q000503:physiopathology*; D013997:Time Factors; D051153:Wnt Proteins / Q000378:metabolism; D014945:Wound Healing; D055114:X-Ray Microtomography; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C483321:6-bromoindirubin-3'-oxime; D048868:Adaptor Proteins, Signal Transducing; C495267:CTNNB1 protein, mouse; D006023:Glycoproteins; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; D010091:Oximes; C486030:Sost protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin; D007854:Lead; D038362:Glycogen Synthase Kinase 3
keywords: Pb; Wnt signaling; fracture repair; mesenchymal stem cells; sclerostin