MMPs/TIMPs imbalances in the peripheral blood and cerebrospinal fluid are associated with the pathogenesis of HIV-1-associated neurocognitive disorders.

HIV-1-associated neurocognitive disorders (HAND) continue to be a major concern in the infected population, despite the widespread use of combined antiretroviral therapy (cART). Growing evidence suggests that an imbalance between matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs) contributes to the pathogenesis of HAND. In our present study, we examined protein levels and enzymatic activities of MMPs and TIMPs in both plasma and cerebrospinal fluid (CSF) samples from HIV-1 patients with or without HAND and HIV-1-negative controls. Imbalances between MMPs and TIMPs with distinct patterns were revealed in both the peripheral blood and CSF of HIV-1 patients, especially those with HAND. In the peripheral blood, the protein levels of MMP-2, MMP-9, TIMP-1, TIMP-2, and the enzymatic activities of MMP-2 and MMP-9 were increased in HIV-1 patients with or without HAND when compared with HIV-1-negative controls. The enzymatic activity of MMP-2, but not MMP-9, was further increased in plasma samples of HAND patients than that of HIV-1 patients without HAND. Notably, the ratio of MMP-2/TIMP-2 in plasma was significantly increased in HAND patients, not in patients without HAND. In the CSF, MMP-2 activity was increased, but the ratio of MMP-2/TIMP-2 was not altered. De novo induction and activation of MMP-9 in the CSF of HAND patients was particularly prominent. The imbalances between MMPs and TIMPs in the blood and CSF were related to the altered profiles of inflammatory cytokines/chemokines and monocyte activation in these individuals. In addition, plasma from HIV-1 patients directly induced integrity disruption of an in vitro blood-brain barrier (BBB) model, leading to increased BBB permeability and robust transmigration of monocytes/macrophages. These results indicate that imbalances between MMPs and TIMPs are involved in BBB disruption and are implicated in the pathogenesis of neurological disorders such as HAND in HIV-1 patients.

Differential expression of matrix metalloproteinases in brain- and bone-seeking clones of metastatic MDA-MB-231 breast cancer cells.

Matrix Metalloproteinases (MMPs) play a crucial role in breast cancer metastasis. We examined the mRNA and protein expression of several MMPs in brain- and bone-seeking clones of MDA-MB-231 breast cancer cells, their transcriptional regulation and their functional role in the metastatic process. MMP mRNA expression was examined using real-time reverse transcription polymerase chain reaction. Protein expression was examined using enzyme linked immunosorbent essay (ELISA). The inducibility of mRNA and protein expression was tested with TPA (phorbol 12-myristate 13-acetate; 50 microM); epidermal growth factor and transforming growth factor beta (20 ng/ml both). Migration and invasion assays were performed with the QCM 96-Well Migration/Invasion Assay (8 microm; Chemicon) over 24 h with or without specific MMPs inhibitors (MMP Inhibitor I Mix (5 microM); MMP-2/MMP-9 Inhibitor III (50 microM); EMD Biosciences). We found significantly higher mRNA expression of MMP-1 and -9 in brain-seeking 231-clones in comparison to -bone and -parental cells. In contrast, the mRNA expression of MMP-3 and -14 was comparable in all cells lines examined and MMP-13 expression was lower in both selective metastatic lines. MMP-2 and -8 were not expressed. ELISA revealed a higher amount of total as well as active MMP-1 and -9 in brain-seeking cells. TPA stimulation showed that MMP-1 and -9 transcription was inducible on the mRNA and protein level in 231-parental but not in 231-brain or -bone. 231-brain showed the highest migration and invasive capacity which could be decreased by the application of MMP-1 and/or MMP-9 inhibitor. Our results indicate functional importance of MMP-1 and -9 overexpression in brain metastasis in an in vitro model.

Lipoprotein docosapentaenoic acid is associated with serum matrix metalloproteinase-9 concentration.

BACKGROUND: Polyunsaturated fatty acids (PUFA) are thought to play important roles in inflammation. The n-3 series is considered as anti-inflammatory, and some studies have reported increased plasma n-3 polyunsaturated fatty acid pattern in chronic inflammatory conditions. In this study we sought to clarify relationships of the levels of arachidonic acid and the polyunsaturated n-3 fatty acid compositions of isolated LDL, HDL2 and HDL3 particles with matrix metalloproteinase-9 (MMP-9), a marker of inflammation. RESULTS: The subjects were divided into two groups: those with lower and those with higher than the median serum MMP-9 concentration. In all lipoprotein fractions, the mean percentage of docosapentaenoic acid (C22:5n-3) was higher in the group of subjects with higher MMP-9 level than in those with lower serum MMP-9 concentration (P < 0.01 for all). Likewise, the ratio of docosapentaenoic acid to arachidonic acid (C20:4n-6) was higher in the subjects with higher MMP-9 compared with the lower MMP-9 group (P < 0.001 for all). CONCLUSION: So far, the evidence for an anti-inflammatory role of the n-3 PUFA has come from dietary interventions. Our results were obtained from a free-living population and indicate that there is a positive correlation between n-3 docosapentaenoic acid and MMP-9. What had triggered the rise in MMP-9 is not known, since serum level of MMP-9 is raised in many inflammatory conditions. These findings may indicate an increased biosynthesis of n-3 polyunsaturated fatty acids in subclinical inflammation.