Heavy metal lead exposure, osteoporotic-like phenotype in an animal model, and depression of Wnt signaling.
Heavy metal lead exposure, osteoporotic-like phenotype in an animal model, and depression of Wnt signaling.
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DOI：
10.1289/ehp.1205374
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发表时间：
2013-01
影响因子：
10.4
通讯作者：
Puzas JE
中科院分区：
文献类型：
--
作者：
Beier EE;Maher JR;Sheu TJ;Cory-Slechta DA;Berger AJ;Zuscik MJ;Puzas JE
背景：环境和工业来源的铅暴露仍然是一个被忽视的严重公共卫生风险。因此，阐明铅对骨细胞功能的影响对于了解其与低骨量疾病相关的风险至关重要。目的：我们测试的假设，铅对骨量有负面影响。我们还评估了铅对骨信号通路的潜在机制。方法：我们使用的模型，低水平铅暴露在啮齿动物开始前的概念，并持续超过18个月。我们使用双能X射线吸收法（DXA）、显微计算机断层扫描、拉曼光谱和组织学来表征铅对骨质量的影响。我们评估了铅对骨和脂肪细胞形成的矿物质沉积，脂滴形成，蛋白质印迹和RNA分析的影响。结果：铅暴露的动物骨量减少，导致骨骼更容易骨折。铅降低成骨细胞数量，导致骨形成的抑制。与此同时，铅暴露升高了骨骼中的sclerostin蛋白水平，并相应地降低了基质前体细胞中β-连环蛋白和Runx 2的水平。铅还增加了骨骼的过氧化物酶体增殖物激活受体-γ（PPAR-γ）的表达。这些结果表明间充质分化的转变，其中铅促进增强脂肪形成和减少成骨细胞。观察到骨髓组成的实质性差异，突出表现为脂肪细胞增加。结论：铅对骨量和骨稳态的破坏主要是通过抑制Wnt/β-连环蛋白途径来解释的，这可能为对抗铅诱导的骨病变的新治疗策略提供分子基础。
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.
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影响因子：
3.5
作者：
Maher, Jason R.;Takahata, Masahiko;Berger, Andrew J.
通讯作者：
Berger, Andrew J.
影响因子：
4.2
作者：
Escribano, A;Revilla, M;Rico, H
通讯作者：
Rico, H
影响因子：
6.2
作者：
Li, Xiaodong;Ominsky, Michael S.;Paszty, Chris
通讯作者：
Paszty, Chris
影响因子：
6.2
作者：
Khalil, Naila;Cauley, Jane A.;Cummings, Steven R.
通讯作者：
Cummings, Steven R.
影响因子：
4
作者：
Cho, YC;Jefcoate, CR
通讯作者：
Jefcoate, CR