Matrix metalloproteinase inhibitor reduces apoptosis induction of bone marrow cells in MDS-RA.

Background And Objectives: We examined the involvement of apoptosis with myelodysplastic syndrome (MDS) accompanied by peripheral cytopenias despite normo-hypercellular bone marrow.

Materials And 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.