Lead inhibits osteoblastic bone formation and osteoclastic bone resorption. Their data suggest that the effect is more pronounced in osteoblasts than in osteoclasts, thus leading to a negative bone balance. However, the mechanism by which Pb has its effects on these cell types is not fully understood. They have at their disposal the appropriate cell and animal models and molecular reagents to uncover how Pb interferes with normal bone cell processes. n the case of bone formation, they focus on a newly discovered osteoblast regulatory protein, TRIP. TRIP modulates TGF signaling and thus could be a key factor in osteoblast differentiation and activity. TRIP expression is markedly blunted by exposure to Pb. n the case of bone resorption they will focus their investigations on RANK ligand, OPG and the transcription factor, NFkappaB. Their preliminary data indicate that Pb depresses RANK ligand synthesis and up regulates OPG synthesis. Both of these effects contribute to a decrease in osteoclastic bone resorption. Moreover, as NFkappaB is central to osteoclast function it is an important target to investigate. Again, their preliminary data show that Pb depresses NFkappaB signaling. In parallel with the in vitro studies, they will examine their hypothesis in an in vivo animal model. Utilizing sophisticated in situ hybridization techniques and immunohistochemical methods developed specifically for bone they can determine if Pb exposure in a whole animal regulates bone resorption and bone formation by affecting TRIP, RAND ligand, OPG and NFkappaB expression.

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Beier, Eric E; Holz, Jonathan D; Sheu, Tzong-Jen et al. (2016) Elevated Lifetime Lead Exposure Impedes Osteoclast Activity and Produces an Increase in Bone Mass in Adolescent Mice. Toxicol Sci 149:277-88
Shu, Lei; Beier, Eric; Sheu, Tzong et al. (2015) High-fat diet causes bone loss in young mice by promoting osteoclastogenesis through alteration of the bone marrow environment. Calcif Tissue Int 96:313-23
Beier, Eric E; Inzana, Jason A; Sheu, Tzong-Jen et al. (2015) Effects of Combined Exposure to Lead and High-Fat Diet on Bone Quality in Juvenile Male Mice. Environ Health Perspect 123:935-43
Beier, Eric E; Sheu, Tzong-Jen; Dang, Deborah et al. (2015) Heavy Metal Ion Regulation of Gene Expression: MECHANISMS BY WHICH LEAD INHIBITS OSTEOBLASTIC BONE-FORMING ACTIVITY THROUGH MODULATION OF THE Wnt/?-CATENIN SIGNALING PATHWAY. J Biol Chem 290:18216-26
Beier, Eric E; Sheu, Tzong-Jen; Buckley, Taylor et al. (2014) Inhibition of beta-catenin signaling by Pb leads to incomplete fracture healing. J Orthop Res 32:1397-405
Beier, Eric E; Maher, Jason R; Sheu, Tzong-Jen et al. (2013) Heavy metal lead exposure, osteoporotic-like phenotype in an animal model, and depression of Wnt signaling. Environ Health Perspect 121:97-104
Holz, Jonathan D; Beier, Eric; Sheu, Tzong-Jen et al. (2012) Lead induces an osteoarthritis-like phenotype in articular chondrocytes through disruption of TGF-? signaling. J Orthop Res 30:1760-6
van Wijngaarden, Edwin; Campbell, James R; Cory-Slechta, Deborah A (2009) Bone lead levels are associated with measures of memory impairment in older adults. Neurotoxicology 30:572-80
Zuscik, Michael J; Ma, Lin; Buckley, Taylor et al. (2007) Lead induces chondrogenesis and alters transforming growth factor-beta and bone morphogenetic protein signaling in mesenchymal cell populations. Environ Health Perspect 115:1276-82
Awad, Hani A; Zhang, Xinping; Reynolds, David G et al. (2007) Recent advances in gene delivery for structural bone allografts. Tissue Eng 13:1973-85

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