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Death effects of reveromycin A in normal and disease‐associated cells of the joint
Author(s) -
Svrcina Haley,
Greer Austin,
Baker Seth,
Smith Morgan,
Martinez Patricia,
Granger Nathan,
Thomas Natassja,
Miller Jaylin,
Steinke Ellen,
Davitt Kelsey,
Sloane Emily,
Nugent Lauren,
Sabo Ryan,
Williams Calli,
Lipton Mark A.,
Jones Daniel
Publication year - 2018
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.26463
Subject(s) - apoptosis , necrosis , programmed cell death , tumor necrosis factor alpha , rheumatoid arthritis , fibroblast , chemistry , arthritis , cytochrome c , cancer research , microbiology and biotechnology , immunology , pathology , biology , medicine , biochemistry , in vitro
Abstract Earlier work in our laboratory demonstrated that naturally occurring reveromycin A (Rev A) causes apoptosis in osteoclasts without accompanying necrosis. Rev A death effects in both normal and diseased joint cells were investigated in this study. A dose of 10 μM Rev A did not cause apoptosis nor necrosis in monolayer chondrocytes, even at pH 6.8, a pH mimicking that of an inflamed joint. In contrast, at the acidic pH Rev A did induce significant apoptosis (fourfold increase at 48 h of treatment, P < 0.005) in normal synoviocytes without accompanying necrosis. Western blot of the normal synoviocyte proteins revealed that cytochrome c levels were not significantly changed over the time course of treatment nor did caspase 8 activity increase; therefore, Rev A appears to exert this apoptotic effect through a mechanism independent of the classical intrinsic and extrinsic pathways. Fibroblast‐like synoviocytes isolated from rheumatoid arthritis patients (RAFLS) as well as normal human fibroblast‐like synoviocytes (NHFLS), cells known to play key roles in arthritic joint pathology, were also subjected to Rev A treatment at both physiologic and acidic pH's. Neither apoptosis nor necrosis was induced in either RAFLS or NHFLS. Parallel mitomycin C treatment of NHFLS induced both apoptosis and necrosis. Comparative structure‐activity analyses of Rev A and mitomycin C revealed that Rev A is less likely to cross the cell membrane at near neutral pH. Collectively the data reveal that a physiological dose of Rev A under acidic conditions induces normal synoviocytes to undergo apoptosis while pathologic fibroblast‐like synoviocytes are resistant to apoptosis and necrosis.