: The unifying hypothesis of this Program Project is that Pb exposure causes osteoporosis, which at the cellular level is known to be the result of an imbalance between bone resorption and bone formation. This condition is also associated with defective skeletal repair, which represents a significant component of the disease, as it has been shown that ~24% of osteoporosis patients that sustain a hip fracture die from associated complications. Critical data in support of this theory are that animals feed Pb in their diet become osteoporotic. At present the mechanism of this Pb-induced osteoporosis and the effects of Pb on fracture healing are unknown. This project will test the hypotheses that 1) Pb-induced osteoporosis is caused by preferential inhibitory effects on bone stem cells (osteoblast >>osteoclast progenitors) and 2) this inhibition has significant effects on skeletal repair (fracture healing). To test this the investigators will utilize two different Pb exposure regimens: Chronic Pb exposure (adult mice continually fed Pb in their drinking water) and osteoporosis-induced exposure (adolescent mice are exposed to Pb during development to incorporate Pb into their bones following 2 month of a Pb free diet, to clear the systemic Pb, the mice are overiectomized to commence the osteoporosis-induced exposure). Utilizing these exposures regimens with the dosing of 0,200 or 500ppm of Pb in their drinking water, to achieve a blood Pb concentration of (<5, 15, and 40ug/dl respectively), the investigators will evaluate the effects of Pb on bone stem cells (Aim 1) and fracture healing (Aim 2). The effects of Pb exposure on osteoblast progenitor cells will be analyzed in nodule formation, alkaline phosphatase, and gene expression assays on primary bone marrow cells from mice. Effects on osteoclast progenitor cells will be evaluated in splenocyte CFU-M colony and osteoclastogenesis (TRAP) assays to determine osteoclast precursor frequency; and bone wafer resorption assays to evaluate effects on osteoclast activity. The effects of Pb exposure on fracture healing will be evaluated utilizing a stabilized tibia fracture model with quantitative radiology and histomorphometry at various time points after fracture.
Showing the most recent 10 out of 17 publications
