Heavy Metal Lead Exposure, Osteoporotic-like Phenotype in an Animal Model, and Depression of Wnt Signaling
Eric E. Beier,1,2 Jason R. Maher,3 Tzong-Jen Sheu,1 Deborah A. Cory-Slechta,2 Andrew J. Berger,3 Michael J. Zuscik,1 and J. Edward Puzas1,2
1Center for Musculoskeletal Research, and 2Department of Environmental Medicine, University of Rochester, School of Medicine and Dentistry, Rochester, New York, USA; 3The Institute of Optics, University of Rochester, Rochester, New York, USA
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.
Objectives: 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.
Key words: bone mineral density, lead, mesenchymal stem cells, rat, Wnt signaling.
Environ Health Perspect 121:97–104 (2013). http://dx.doi.org/10.1289/ehp.1205374 [Online 19 October 2012]
Address correspondence to J.E. Puzas, 601 Elmwood Ave., Rochester, NY 14642 USA. Telephone: (585) 275-3664. Fax: (585) 756-4727. E-mail: email@example.com
Supplemental Material is available online (http://dx.doi.org/10.1289/ehp.1205374).
We thank R. Tierney and S. Mack for assistance with histology, R. Gelein for bone lead measurements, M. Thullen for CT (computed tomography) imaging and analysis, E. Resseguie for gathering adipocyte metrics, and C. Muzytchuk for dual-energy X‑ray absorptiometry measurements. Biomechanical testing was performed with assistance from H. Awad and T. Chen in the Biomechanics and Multimodal Tissue Imaging Core laboratory, established by grant P30AR061307 from the National Institutes of Health (NIH).
This work was supported by Public Health Service grants NIH T32 ES07026 and R01 ES012712, T32 AR053459, P01 ES011854, and P30 ES301247.
The authors declare they have no actual or potential competing financial interests.
Received 21 April 2012; Accepted 19 October 2012; Online 19 October 2012.
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