Low molecular weight inhibitors of matrix metalloproteinases can enhance the expression of matrix metalloproteinase-2 (gelatinase A) without inhibiting its activation

摘要

In the current study, the authors investigated the effects of synthetic low molecular weight inhibitors of matrix metalloproteinases (MMPs) on the expression and activation of MMP-2 in a three-dimensional tissue system. Rabbit periosteal explants were cultured with or without various concentrations of the MMP inhibitors CT1166, CT1399, or CT1746, and conditioned media and tissue extracts were analyzed for the expression and activity of MMP-2. The data showed that blocking the activity of all MMPs with relatively high inhibitor concentrations completely prevented the conversion of pro-MMP-2 into its active form and that the level of protein was decreased. Selective inhibition of the activity of gelatinases (MMP-2 and MMP-9) by using low inhibitor concentrations, however, induced a higher level of active MMP-2 and increased its expression significantly. The current observations indicate that selective inhibitors of MMPs affect the expression and activity of MMP-2, thus providing clues regarding the differing effects such inhibitors appear to have when applied in vivo