Inflammation is characterized by an excess of cell proliferation often leading to
fibrosis and
sclerosis with subsequent loss of organ function. We hypothesized that these features may be ameliorated by induction of cell cycle arrest and apoptosis as result of
therapy with
matrix metalloproteinase (
MMP) inhibitors. In our study, mesangial cells and experimental mesangial proliferative
glomerulonephritis provided the model of
inflammation. First, we investigated the effect of the
MMP inhibitor BB-1101 in anti-Thy1.1
nephritis. The numbers of apoptotic glomerular cells in nephritic rats increased about 4 and 6 times as a result of
BB-1101 therapy, observed 11 and 14 days after induction of disease, respectively. Subsequently, rat mesangial cells were exposed to an
MMP inhibitor in vitro. Fluorescence-activated cell sorter analyses of cells exposed to RO111-3456 demonstrated a dose-dependent cell cycle arrest in the G(0)/G(1) phase associated with increased expression of
statin. The cell cycle arrest was followed by apoptosis as investigated by
terminal deoxynucleotidyl transferase (TdT)-mediated
deoxyuridine triphosphate (dUTP)
biotin nick-end labeling (TUNEL) and
acridine orange/
ethidium bromide stainings, as well as by
annexin V binding. The induction of p53, p21, and bax, but not the Fas/FasL pathway appeared to play an important pathogenetic role. In summary,
MMP inhibitors induce cell cycle arrest followed by apoptosis in mesangial cells. These features help to explain the anti-inflammatory effects of these compounds, such as reduction of mesangial cell proliferation and attenuation of extracellular matrix accumulation. In conclusion, induction of cell cycle arrest with subsequent apoptosis may offer new perspectives in the
therapy of
inflammation even beyond
kidney diseases.