Matrix metalloproteinase activity and osteoclasts in experimental prostate cancer bone metastasis tissue

Previously, we and others showed that broad spectrum pharmaceutical inhibition of matrix metalloproteinase (MMP) activity reduces intraosseous tumor bur den and bone degradation in annual models of bone metastasis. Herein, we used specific assays to measure net enzymatic activities of individual MMPs during colonization of bone by prostate cancer cells. PC3 cells were injected into the marrow of human fetal femurs previously implanted in SCED mice. Net MMP-9 activity in bone tissues peaked 2 weeks after injection, coincidmg with a wave of osteoclast recruitment in contrast, MMP-2 and MT1-MMP activity did not change. In vitro, co-culture of PQ cells with bone tissue led to activation of pro-MMP-9 and increases in secreted net MMP-9 activity Activation of pro-MMP-9 was prevented by metal loprotease inhibitors but not by inhibitors of other classes of proteases. Ribozyme suppression of MMP-9 expression in PC3 cells did not affect pro-MMP-9 activation or net MMP-9 activity and did not affect the phenotype of bone tumors. siRNA targeting of MMP-9 expression in preosteoclasts in vitro demonstrated that tumor-induced preosteoclast motility was dependent on MMP-9 expression. These data suggest that osteoclast-derived MMP-9 may represent a potential therapeutic target in bone metastasis and provide a rationale for the development of MMP-9-specific inhibitors.