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J. Biol. Chem., Vol. 277, Issue 24, 21998-22009, June 14, 2002
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From the Cells in mechanically challenged
environments must cope with high amplitude forces to maintain cell
viability and tissue homeostasis. Currently, force-induced cell death
and the identity of mechanoprotective factors are not defined. We
examined death in cultured periodontal fibroblasts, connective tissue
cells that are exposed to heavy applied forces in vivo.
Static tensile forces (0.48 piconewtons/µm2 cell
area) were applied through magnetite beads coated with collagen or
bovine serum albumin. There was a time-dependent increase
of the percentage of propidium iodide-permeable cells in force-loaded cultures incubated with collagen but not bovine serum albumin beads,
indicating a role for integrins. Cells exhibited reduced mitochondrial
membrane potential, increased caspase-3 activation, nuclear
condensation, terminal deoxynucleotidyl transferase nick end labeling
staining, and detachment from the culture dish. The caspase-3 inhibitor
acetyl-Asp-Glu-Val-Asp-aldehyde reduced detachment 3-fold. There
was a rapid (<10-s) decrease in plasma membrane potential after force
application, which, in filamin A-deficient melanoma cells, contributed
to irreversible cell depolarization. In fibroblast cultures, cells with
increased permeability to propidium iodide exhibited ~2-fold less
filamin A content than impermeable cells. Fibroblasts transfected with
antisense filamin A constructs or with filamin A constructs without an
actin-binding domain exhibited 2-3-fold increased proportions of dead
cells relative to controls. We conclude that high amplitude forces
delivered through integrins can promote apoptosis in a proportion of
cells and that filamin A confers mechanoprotection by preventing
membrane depolarization.
Cell Death and Mechanoprotection by Filamin A
in Connective Tissues after Challenge by Applied Tensile Forces*
§¶,,
,, and§§
Canadian Institutes of Health Research Group
in Matrix Dynamics, University of Toronto, Toronto, Ontario M5S
3E2, Canada, § Department of Prosthetic Dentistry and
Stomatognathic Physiology, University of Oulu, Oulu,
Finland, ** Department of Neurology, Beth Israel Deaconess
Medical Center, Harvard University, Boston, Massachusetts 02115, and the Department of Preventive Dental Sciences,
Faculty of Dentistry, University of Manitoba, Winnipeg, Manitoba R3E
0W2, Canada
*
This work was supported by Canadian Institutes of Health
Research (CIHR) operating, maintenance, and group grants (to C. M.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by a CIHR fellowship.
§§
To whom correspondence should be addressed: Rm. 244, Fitzgerald Bldg., University of Toronto, 150 College St., Toronto,
Ontario M5S 3E2, Canada. Tel.: 416-978-1258; Fax: 416-978-5956; E-mail: christopher.mcculloch@utoronto.ca.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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