title: Heavy Metal Ion Regulation of Gene Expression: MECHANISMS BY WHICH LEAD INHIBITS OSTEOBLASTIC BONE-FORMING ACTIVITY THROUGH MODULATION OF THE Wnt/β-CATENIN SIGNALING PATHWAY.
abstract: Exposure to lead (Pb) from environmental sources remains an overlooked and serious public health risk. Starting in childhood, Pb in the skeleton can disrupt epiphyseal plate function, constrain the growth of long bones, and prevent attainment of a high peak bone mass, all of which will increase susceptibility to osteoporosis later in life. We hypothesize that the effects of Pb on bone mass, in part, come from depression of Wnt/β-catenin signaling, a critical anabolic pathway for osteoblastic bone formation. In this study, we show that depression of Wnt signaling by Pb is due to increased sclerostin levels in vitro and in vivo. Downstream activation of the β-catenin pathway using a pharmacological inhibitor of GSK-3β ameliorates the Pb inhibition of Wnt signaling activity in the TOPGAL reporter mouse. The effect of Pb was determined to be dependent on sclerostin expression through use of the SOST gene knock-out mice, which are resistant to Pb-induced trabecular bone loss and maintain their mechanical bone strength. Moreover, isolated bone marrow cells from the sclerostin null mice show improved bone formation potential even after exposure to Pb. Also, our data suggest that the TGFβ canonical signaling pathway is the mechanism by which Pb controls sclerostin production. Taken together these results support our hypothesis that the osteoporotic-like phenotype observed after Pb exposure is, in part, regulated through modulation of the Wnt/β-catenin pathway.
authors.affiliation: Center for Musculoskeletal Research, University of Rochester, School of Medicine and Dentistry, Rochester, New York, 14624; Department of Environmental Medicine, University of Rochester, School of Medicine and Dentistry, Rochester, New York, 14624.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Beier
authors.affiliation: Center for Musculoskeletal Research, University of Rochester, School of Medicine and Dentistry, Rochester, New York, 14624.
authors.forename: Tzong-Jen
authors.initials: TJ
authors.lastname: Sheu
authors.affiliation: Center for Musculoskeletal Research, University of Rochester, School of Medicine and Dentistry, Rochester, New York, 14624.
authors.forename: Deborah
authors.initials: D
authors.lastname: Dang
authors.affiliation: Center for Musculoskeletal Research, University of Rochester, School of Medicine and Dentistry, Rochester, New York, 14624; Department of Environmental Medicine, University of Rochester, School of Medicine and Dentistry, Rochester, New York, 14624.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Holz
authors.affiliation: Center for Musculoskeletal Research, University of Rochester, School of Medicine and Dentistry, Rochester, New York, 14624.
authors.forename: Resika
authors.initials: R
authors.lastname: Ubayawardena
authors.affiliation: Department of Metabolic Disorders, Amgen, Inc., Thousand Oaks, California 91320-1799.
authors.forename: Philip
authors.initials: P
authors.lastname: Babij
authors.affiliation: Center for Musculoskeletal Research, University of Rochester, School of Medicine and Dentistry, Rochester, New York, 14624; Department of Environmental Medicine, University of Rochester, School of Medicine and Dentistry, Rochester, New York, 14624. Electronic address: edward_puzas@urmc.rochester.edu.
authors.forename: J Edward
authors.initials: JE
authors.lastname: Puzas
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001842:Bone and Bones / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004781:Environmental Exposure / Q000009:adverse effects; D004785:Environmental Pollutants / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006023:Glycoproteins / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D007854:Lead / Q000633:toxicity*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004785:Environmental Pollutants; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D051900:Smad3 Protein; C486030:Sost protein, mouse; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D007854:Lead; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: TGF-β signaling; Wnt signaling; bone; gene expression; lead toxicity; osteoblast; osteoporosis; sclerostin