Apoptosis of human hepatic myofibroblasts promotes activation of matrix metalloproteinase‐2

Liver fibrosis is potentially reversible after removal of the injurious agent. Fibrosis resolution is characterized by apoptosis of hepatic myofibroblasts and degradation of extracellular matrix components. Matrix metalloproteinase‐2 (MMP‐2) is involved in matrix remodeling. In the liver, it is synthesized by myofibroblasts, secreted as a proenzyme, and activated by membrane type‐MMPs (MT‐MMP) such as MT1‐MMP. The goal of this work was to determine whether apoptosis induction in human hepatic myofibroblasts modulates the gene expression of MMP‐2 and/or its activation by MT1‐MMP. Induction of apoptosis by cytochalasin D or C2‐ceramide did not modulate MMP‐2 mRNA expression. In contrast, apoptosis was associated with marked activation of pro‐MMP‐2, as shown by gelatin zymography, which revealed the presence of the 59‐kd active form, whereas untreated cells only expressed the 66‐kd proform. SB‐203580, a specific inhibitor of p38 MAPK, selectively abrogated both C2‐ceramide–induced apoptosis and pro‐MMP‐2 activation. Apoptosis‐induced pro‐MMP‐2 activation was inhibited by the tissue inhibitors of metalloproteinases (TIMP)‐2 but not by TIMP‐1, implying involvement of an MT‐MMP–mediated process. Induction of apoptosis by cytochalasin D and C2‐ceramide upregulated MT1‐MMP protein expression and MT1‐MMP mRNA expression. In conclusion, apoptosis of hepatic myofibroblasts induces pro‐MMP‐2 activation through increased MT1‐MMP expression.