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

Abstract

BACKGROUNDIn 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.METHODSRabbit 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.RESULTSThe 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.CONCLUSIONSThe 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. Cancer 2003;97:1582–88. © 2003 American Cancer Society.DOI 10.1002/cncr.11193

Matrix metalloproteinase inhibitors reduce collagen gel contraction and α‐smooth muscle actin expression by periodontal ligament cells

“…In a previous study, we found an up‐regulation of MMP‐2 protein expression by several CMTs, including CMT‐3, in two‐dimensional cultures (18). An up‐regulation of MMP‐2 was also shown for periosteal cells incubated with other synthetic inhibitors (49). These data indicate that MMP inhibitors might have unexpected stimulatory effects on MMP production via positive feedback mechanisms.…”

Tissue inhibitor of metalloproteinases‐1 (TIMP‐1) modulates neuronal death, axonal plasticity, and learning and memory

“…In contrast, seizure‐mediated increases of gelatinase expression and activity in the WT, but not in the mutant mice, suggest paradoxically that TIMP‐1 increases gelatinase expression and/or activity in the brain. Analogous effects of TIMPs or MMPIs have been described in other tissues: TIMP‐1 induces gelatinase expression in hepatocytes (Roeb et al ., 1999); TIMP‐2 is involved in MMP‐2 activation by MT1‐MMP, both in vitro (Murphy et al ., 2003) and in vivo (Wang et al ., 2000), and synthetic MMPIs can enhance MMP‐2 expression without inhibiting its activation (Kerkvliet et al ., 2003).…”

Chemically modified tetracyclines stimulate matrix metalloproteinase‐2 production by periodontal ligament cells

“…An earlier study (27), on the other hand, described an inhibitory effect on MMP‐2 and ‐9 protein expression by porcine PDL epithelial cells at similar concentrations. Moreover, other synthetic MMP inhibitors have been shown to increase MMP‐2 mRNA and protein expression at low concentrations in rabbit periosteal cell cultures (42). The increase in MMP‐2 expression by PDL cells, as shown in our study, has not been previously reported.…”