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.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.

Bone lead (Pb) content at the tibia is associated with thinner distal tibia cortices and lower volumetric bone density in postmenopausal women

“…Put into context, the larger amount of bone lead at the tibia observed in the present study, being associated with smaller cortical thickness and lower integral vBMD after adjusting for age and antiresorptives, was consistent with the hypothesis that bone lead stored for long periods may have a negative effect on bone integrity. Mechanistic evidence to support this association was presented by Beier et al who saw that lead caused a decrease in osteoblast cell number, leading to reduced bone formation, corresponding to elevated levels of sclerostin and reduced β-catenin and Runx2 signaling in bone precursors [26]. The loss of bone structural integrity could also be explained by lead's activation of the peroxisome proliferator-activated receptor (PPAR)-γ pathway, leading to preferential differentiation of mesenchymal stem cells to adipocytes rather than to osteocytes [26].…”

“…Mechanistic evidence to support this association was presented by Beier et al who saw that lead caused a decrease in osteoblast cell number, leading to reduced bone formation, corresponding to elevated levels of sclerostin and reduced β-catenin and Runx2 signaling in bone precursors [26]. The loss of bone structural integrity could also be explained by lead's activation of the peroxisome proliferator-activated receptor (PPAR)-γ pathway, leading to preferential differentiation of mesenchymal stem cells to adipocytes rather than to osteocytes [26]. Cortical thickness was the primary variable that showed any effect due to bone lead, and is also one of the most clinically impacted structural outcomes previously reported to relate directly to fracture risk [27,28].…”

Allogeneic and Autogenous Bone Grafts Are Affected by Historical Donor Environmental Exposure

“…In children, exposure results in impairment in skeletal development, reduced chest circumference, diminished stature, and can be assessed with blood tests for markers of bone turnover in this population [5,6,[10][11][12]. The mechanism and toxicology of lead in bone formation, resorption, and healingis well known being mediated by impairment of the cellular pathways regulating osteoblast and osteoclast function [3,4,6,8,15,16,18,20,22]. Presumably the levels of lead in allografts mirror the level of lead in bone in the general population; however, the degree to which processing might decrease this and the frequency with which potentially osteotoxic levels appear in bone grafts have not been studied.…”

“…In animal models and clinical studies, lead has specifically been shown to be a source of adverse cellular effects resulting in skeletal disease [3,5,20,22]. The number of specimens falling within this range was determined for each of the study groups as well as for cortical and cancellous bone specimens.…”

“…The lead content of bone from humans exposed to environmental sources ranges from 2 to 20 ppm [20]. In animal models and clinical studies, lead has specifically been shown to be a source of adverse cellular effects resulting in skeletal disease [3,5,20,22]. The mechanism for the skeletal effects is thought to be related to release of lead from the bone compartment with subsequent molecular consequences on key signaling pathways in the osteoblasts [6].…”