Matrix metalloproteinase inhibitor reduces apoptosis induction of bone marrow cells in MDS-RA.
OBJECTIVE
We examined the involvement of apoptosis with myelodysplastic syndrome (MDS) accompanied by peripheral cytopenias despite normo-hypercellular bone marrow.


METHODS
Bone marrow smears from 31 patients with MDS-refractory anemia (RA) and five normal controls were stained using the in situ end labeling (ISEL) method. Next, the inhibitory effects of a caspase-3 inhibitor, matrix metalloproteinase inhibitor (MMPI), anti-tumor necrosis factor (TNF)-alpha or anti-Fas antibody upon the apoptosis induction in overnight cultures of bone marrow cells from the patients were examined. Further, TNF-alpha, transforming growth factor (TGF)-beta and soluble Fas ligand (sFasL) concentrations in culture supernatants of the cells were assessed by enzyme-linked immunosorbent assay (ELISA).


RESULTS
The incidence of ISEL-positive cells among MDS patients was significantly higher than in normal controls (50.8 +/- 14.0% vs. 11.3 +/- 2.4%; P < 0.0001). A caspase-3 inhibitor reduced significantly the ISEL-positive rates (32.6 +/- 15.2% vs. 50.2 +/- 16.5%; P < 0.0001). Anti-TNF-alpha or anti-Fas antibody reduced the ISEL-positive rates significantly (28.2 +/- 6.0%, 29.2 +/- 5.8%, vs. 44.2 +/- 3.4%, P < 0.001, P = 0.001, respectively). KB-R7785 also significantly decreased the ISEL-positive rates (18.0 +/- 9.3% vs. 43.6 +/- 14.0%; P < 0.0001). The concentration of TNF-alpha was significantly reduced by KB-R7785 (P < 0.05), whereas that of TGF-beta was not. Concentration of sFasL was under detectable level in the present assay system. The derivatives of KB-R7785 that can be administrated orally showed inhibitory effect on apoptosis induction as well.


CONCLUSIONS
These findings suggest that MMPIs inhibits the apoptosis induction of MDS bone marrow cells via the inhibition of TNF-alpha and probably sFasL secretion, and that MMPIs can be used to control the abnormal induction of apoptosis in MDS.
Arimura
Kosei
K
Department of Haematology and Immunology, Kagoshima University Hospital, Sakuragaoka, Kagoshima, Japan.
Arima
Naomichi
N
Matsushita
Kakushi
K
Ohtsubo
Hideo
H
Fujiwara
Hiroshi
H
Kukita
Toshimasa
T
Ozaki
Atsuo
A
Hagiwara
Takafumi
T
Hamada
Heiichiro
H
Yoshino
Kohichiro
K
Tei
Chuwa
C
D000328:Adult; D000368:Aged; D000753:Anemia, Refractory / Q000473:pathology*; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D008562:Membrane Glycoproteins / Q000032:analysis; D008875:Middle Aged; D011480:Protease Inhibitors / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000276:immunology; D019014:fas Receptor / Q000276:immunology
D000906:Antibodies; D061945:Caspase Inhibitors; D016207:Cytokines; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D061965:Matrix Metalloproteinase Inhibitors; D008562:Membrane Glycoproteins; D011480:Protease Inhibitors; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C505407:CASP3 protein, human; D053148:Caspase 3