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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
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.
October 2014 Issue of IMpact