Winning Abstracts from the 2014 Medical Student Abstract Competition: Zoledronate Inhibits Cell Membrane Repair
First Author: Caroline M. Lewis, Georgia Regents University, Class of 2016
Bisphosphonates are a class of drugs that inhibit the resorption of bone by osteoclasts to increase bone mass. They are commonly prescribed to increase bone mass in patients with osteoporosis, cancerous tumors of bone, and other bone disorders. Unfortunately, bisphosphonates are associated with the poorly understood side effect of bisphosphonate related osteonecrosis of the jaw (BRONJ). This side effect is initiated by a traumatic injury to the jaw, such as a tooth extraction.
Traumatic tissue injury produces tears or disruptions in the plasma membranes of resident cells, and a previous study indicated that bisphosphonates interact with the protein machinery that mediates repair of this type of cell injury. Here we have tested whether the most commonly prescribed bisphosphonate with the highest incidence of the BRONJ side effect, zoledronate, inhibits the membrane repair process, and might thereby contribute to BRONJ
Monkey kidney epithelial cells (BSC1) and mouse myoblasts (C2C12) were treated with zoledronate and plasma membrane disruptions such as those that occur in traumatic injury. Membrane disruptions were created with a microscope laser in the presence of FM1-43, a fluorescent dye that rushes into the cell and brightly illuminates its interior when repair fails. When, however, the integrity of the boundary is restored by successful repair, FM1-43 dye entry into the cell interior is minimal: the cell interior remains dark except for a small, peripheral, spot-weld scar of fluorescence where the injury and subsequent repair occurred. This uptake of fluorescence can be quantitated by image analysis.
Both BSC1 and C2C12 cells incubated 24 hours with 1µM zoledronate in this laser assay exhibited significant ( p < 0.05, one way ANOVA Tukey post hoc comparison) increases in uptake of dye over time compared to untreated, control cells. Zoledronate-treated cells filled rapidly with dye, whereas controls did not. Thus, zoledronate strikingly inhibits cell membrane repair in two distinct cell types.
Zoledronate-induced inhibition of cell membrane repair and consequent cell death may be an important factor in BRONJ. Wound healing requires frequent membrane repairs since membranes are torn as cells glide past one another. Without proper cell membrane repair, these cells die, and complete wound healing cannot occur. Further study of BRONJ and the involvement of zoledronate-induced inhibition of cell membrane repair is warranted. Recently, a non-toxic compound, vitamin E, was found to promote membrane repair. The results of this study suggest a simple and inexpensive possible prophylactic treatment for BRONJ: administration of vitamin E supplements prior to dental work.