title: Heavy metal lead exposure, osteoporotic-like phenotype in an animal model, and depression of Wnt signaling.
abstract: BACKGROUND
  Exposure to lead (Pb) from environmental and industrial sources remains an overlooked serious public health risk. Elucidating the effect of Pb on bone cell function is therefore critical for understanding its risk associated with diseases of low bone mass.
  
  
  OBJECTIVE
  We tested the hypothesis that Pb negatively affects bone mass. We also assessed the underlying mechanisms of Pb on bone signaling pathways.
  
  
  METHODS
  We used a model of low-level Pb exposure in a rodent beginning before conception and continuing over 18 months. We characterized the effect of Pb on bone quality using dual-energy X-ray absorptiometry (DXA), micro-computed tomography, Raman spectroscopy, and histology. We assessed the effect of Pb on bone and adipocyte formation by mineral deposition, lipid droplet formation, and Western blot and RNA analysis.
  
  
  RESULTS
  Pb-exposed animals had decreased bone mass that resulted in bones that were more susceptible to fracture. Pb decreased osteoblastic cell number leading to a depression of bone formation. Accompanying this, Pb exposure elevated sclerostin protein levels in the skeleton, and correspondingly reduced levels of β-catenin and Runx2 in stromal precursor cells. Pb also increased skeletal expression of peroxisome proliferator-activated receptor-γ (PPAR-γ). These results indicate a shift in mesenchymal differentiation wherein Pb promoted enhanced adipogenesis and decreased osteoblastogenesis. Substantial differences in bone marrow composition were observed, highlighted by an increase in adipocytes.
  
  
  CONCLUSIONS
  The disruption Pb has on bone mass and bone homeostasis is principally explained by inhibition of the Wnt/β-catenin pathway, which may provide a molecular basis for novel therapeutic strategies to combat Pb-induced bone pathologies.
authors.affiliation: Center for Musculoskeletal Research, University of Rochester, School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Beier
authors.forename: Jason R
authors.initials: JR
authors.lastname: Maher
authors.forename: Tzong-Jen
authors.initials: TJ
authors.lastname: Sheu
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Cory-Slechta
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Berger
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Zuscik
authors.forename: J Edward
authors.initials: JE
authors.lastname: Puzas
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D007854:Lead / Q000633:toxicity*; D059630:Mesenchymal Stem Cells / Q000187:drug effects; D010024:Osteoporosis / Q000139:chemically induced* / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051153:Wnt Proteins; D007854:Lead