Matrix metalloproteinase inhibitors cause cell cycle arrest and apoptosis in glomerular mesangial cells

Inflammation is characterized by an excess of cell proliferation often lead ing to fibrosis and sclerosis with subsequent loss of organ function. We hy pothesized that these features may be ameliorated by induction of cell cycl e arrest and apoptosis as result of therapy with matrix metalloproteinase ( MMP) inhibitors. In our study, mesangial cells and experimental mesangial p roliferative glomerulonephritis provided the model of inflammation. First, we investigated the effect of the MMP inhibitor BB-1101 in anti-Thy1.1 neph ritis. The numbers of apoptotic glomerular cells in nephritic rats increase d about 4 and 6 times as a result of BB-1101 therapy, observed 11 and 14 da ys after induction of disease, respectively. Subsequently, rat mesangial ce lls were exposed to an MMP inhibitor in vitro. Fluorescence-activated cell sorter analyses of cells exposed to RO111-3456 demonstrated a dose-dependen t cell cycle arrest in the G(0)/G(1) phase associated with increased expres sion of statin. The cell cycle arrest was followed by apoptosis as investig ated by terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine t riphosphate (dUTP) biotin nick-end labeling (TUNEL) and acridine orange/eth idium 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 importa nt pathogenetic role. In summary, MMP inhibitors induce cell cycle arrest f ollowed by apoptosis in mesangial cells. These features help to explain the anti-inflammatory effects of these compounds, such as reduction of mesangi al cell proliferation and attenuation of extracellular matrix accumulation. In conclusion, induction of cell cycle arrest with subsequent apoptosis ma y offer new perspectives in the therapy of inflammation even beyond kidney diseases.