The Journal of Bone and Joint Surgery (American) 83:1514-1523 (2001)
© 2001 The Journal of Bone and Joint Surgery, Inc.
Signal Transduction in Electrically Stimulated Bone Cells
Carl T. Brighton, MD, PhD,
Wei Wang, MD,
Richard Seldes, MD,
Guihong Zhang, PhD and
Solomon R. Pollack, PhD
Investigation performed at the Department of Orthopaedic Surgery,
University of Pennsylvania, Philadelphia, Pennsylvania
Carl T. Brighton, MD, PhD
Wei Wang, MD
Richard Seldes, MD
Guihong Zhang, PhD
Solomon R. Pollack, PhD
Departments of Orthopaedic Surgery (C.T.B., W.W., R.S., and G.Z.)
and Bioengineering (S.R.P.), University of Pennsylvania Medical
Center, 424 Stemmler Hall, 36th and Hamilton Walk, Philadelphia,
PA 19104-6081. E-mail address for C.T. Brighton: ctb{at}mail.med.upenn.edu
In support of their research or preparation of this manuscript, one
or more of the authors received grants or outside funding from NIH
Grant 5-T32-AR07132 and Biolectron, Incorporated. None of the authors
received payments or other benefits or a commitment or agreement
to provide such benefits from a commercial entity. No commercial
entity paid or directed, or agreed to pay or direct, any benefits
to any research fund, foundation, educational institution, or other
charitable or nonprofit organization with which the authors are
affiliated or associated.
A commentary is available with the electronic versions of this article,
on our web site (www.jbjs.org) and on our CD-ROM (call 781-449-9780,
ext. 140, to order).
Background: Electrical stimulation is used to
treat nonunions and to augment spinal fusions. We studied the biochemical
pathways that are activated in signal transduction when various
types of electrical stimulation are applied to bone cells.
Methods: Cultured MC3T3-E1 bone cells were exposed
to capacitive coupling, inductive coupling, or combined electromagnetic fields
at appropriate field strengths for thirty minutes and for two, six,
and twenty-four hours. The DNA content of each dish was determined.
Other cultures of MC3T3-E1 bone cells were exposed to capacitive
coupling, inductive coupling, or combined electromagnetic fields
for two hours in the presence of various inhibitors of signal transduction,
with or without electrical stimulation, and the DNA content of each
dish was determined.
Results: All three signals produced a significant
increase in DNA content per dish compared with that in the controls
at all time-points (p < 0.05), but only exposure to capacitive
coupling resulted in a significant, ever-increasing DNA production
at each time-period beyond thirty minutes. The use of specific metabolic
inhibitors indicated that, with capacitive coupling, signal transduction
was by means of influx of Ca2+ through
voltage-gated calcium channels leading to an increase in cytosolic
Ca2+ (blocked by verapamil),
cytoskeletal calmodulin (blocked by W-7), and prostaglandin E2 (blocked
by indomethacin). With inductive coupling and combined electromagnetic
fields, signal transduction was by means of intracellular release
of Ca2+ leading to an increase
in cytosolic Ca2+ (blocked by
TMB-8) and an increase in activated cytoskeletal calmodulin (blocked
by W-7).
Conclusions: The initial events in signal transduction
were found to be different when capacitive coupling was compared
with inductive coupling and with combined electromagnetic fields;
the initial event with capacitive coupling is Ca2+ ion
translocation through cell-membrane voltage-gated calcium channels,
whereas the initial event with inductive coupling and with combined
electromagnetic fields is the release of Ca2+ from
intracellular stores. The final pathway, however, is the same for
all three signals—that is, there is an increase in cytosolic
Ca2+ and an increase in activated
cytoskeletal calmodulin.
Clinical Relevance: Electrical stimulation in various
forms is currently being used to treat fracture nonunions and to
augment spinal fusions. Understanding the mechanisms of how bone
cells respond to electrical signals—that is, understanding
signal transduction and the metabolic pathways utilized in electrically
induced osteogenesis—will allow optimization of the effects
of the various bone-growth-stimulation signals.
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