Decreased levels of metalloproteinase-9 and angiogenic factors in skin lesions of patients with psoriatic arthritis after therapy with anti-TNF-alpha.

Clinical Pathology and Microbiology Laboratory, San Gallicano Dermatology Institute, 00144 Rome, Italy.
Journal of Autoimmune Diseases 02/2006; 3:5. DOI: 10.1186/1740-2557-3-5
Source: PubMed

ABSTRACT Inflammation represents an early and key event in the development of both the cutaneous psoriasis and psoriatic arthritis. Compelling evidences indicate that the production of TNF-alpha plays a central role in psoriasis by sustaining the inflammatory process in the skin as well as in the joints. Among the multiple effects produced by TNF-alpha on keratinocytes, the induction of matrix metalloproteinase-9 (MMP-9), a collagenase implicated in joint inflammatory arthritis which acts as an angiogenesis promoting factor, might represent a key mechanism in the pathogenesis of the disease. Aims of the present study were to investigate a) the role of MMP-9 in the development of psoriasis by assessing the presence of MMP-9 in lesional skin and in sera of psoriatic patients; b) the association of MMP-9 with the activity of the disease; c) the relationship between MMP-9 and TNF-alpha production.
Eleven psoriatic patients, clinically presenting joint symptoms associated to the cutaneous disease, were included in a therapeutic protocol based on the administration of anti-TNF-alpha monoclonal antibody (Infliximab). Sera and skin biopsies were collected before treatment and after 6 weeks of therapy. Tissues were kept in short term cultures and production soluble mediators such as TNF-alpha, MMP-9, MMP-2, VEGF and E-Selectin, which include angiogenic molecules associated to the development of plaque psoriasis, were measured in the culture supernatants by immunoenzymatic assays (ng/ml or pg/ml per mg of tissue). MMP-9 concentrations were also measured in the sera. The cutaneous activity of disease was evaluated by the Psoriasis Area and Severity Index (PASI).
Clinical and laboratory assessment indicated that all but one patients had a significant improvement of the PASI score after three months of therapy. The clinical amelioration was associated to a significant decrease of MMP-9 (P = 0.017), TNF-alpha (P = 0.005) and E-selectin (P = 0.018) levels, spontaneously released by lesional biopsies before and after therapy. In addition, significant correlations were found between the PASI measurements and TNF-alpha (r2 = 0.33, P = 0.005), MMP-9 (r2 = 0.25, P = 0.017), E-selectin (r2 = 0.24, P = 0.018) production. MMP-9 levels were significantly correlated with those of TNF-alpha (r2 = 0.30, P = 0.008). A significant decrease of MMP-9 in the sera, associated to the clinical improvement was also found.
Our findings show the existence of a direct relationship between MMP-9 and TNF-alpha production strongly suggesting that MMP-9 may play a key role in the skin inflammatory process in psoriasis.

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    ABSTRACT: Psoriasis is a chronic skin inflammatory disease in which a pleiotropic cytokine, tumor necrosis factor alpha (TNF-α), plays a central role, as demonstrated by the clinical success of anti-TNF-α therapy. Among the multiple effects of TNF-α on keratinocytes, the induction of matrix metalloproteinase-9 (MMP-9), a collagenase implicated in joint inflammation, might be one of the key mechanisms in psoriasis pathogenesis. Interestingly, MMP-9 expression can be enhanced also by osteopontin (OPN), a glycosylated protein whose levels are increased in skin and peripheral blood mononuclear cells (PBMC) of psoriasis patients. The aim of the current study is to investigate the relationship between OPN, MMP-9 and TNF-α in psoriasis. Our survey identified high levels of both OPN and MMP-9 in PBMC as well as skin of psoriatic patients with respect to healthy controls. Significant reduction of OPN and MMP-9 levels in PBMC, plasma and lesional skin of psoriasis patients was observed after 24 weeks of anti-TNF-α therapy. Moreover, OPN and MMP-9 were enhanced by TNF-α and down-regulated by anti-TNF-α treatment in healthy PBMC. These findings may suggest that OPN and MMP-9 may be regulated by TNF-α, indicating a possible role in the pathogenesis of psoriasis.
    Archives for Dermatological Research 06/2012; 304(6):481-5. · 2.71 Impact Factor
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    ABSTRACT: OBJECTIVE: Notch signalling pathways are critical for angiogenesis and endothelial cell (EC) fate; however the mechanisms regulating these processes in the inflamed joint remain to be elucidated. Here, we examine whether Notch signalling mediates vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2)-induced vascular function. METHODS: Notch-1 intracellular domain (Notch-1 IC), Notch-4 IC, Delta-like-ligand 4, Hes-related transcriptional repressors-1 and 2 (Hrt-1, Hrt-2) mRNA and/or protein expression was measured by Real-time PCR and/or western blot. VEGF/Ang2 induced EC function was assessed using transwell invasion chambers, matrigel tube formation assays and wound repair scratch assays ± Notch-1 siRNA or an γ-secretase inhibitor N-(N-(3,5-Difluorophenacetyl-L-alanly))-S-phenylglycine-t-Butyl Ester (DAPT) in RA synovial explants or human microvascular EC. Interleukin (IL)-6 and IL-8 were measured by ELISA and MMP2 and 9 by gelatine zymography. RESULTS: Notch-1 IC and Notch-4 IC protein expressions were demonstrated in RA and psoriatic arthritis synovial biopsies, with minimal expression observed in Osteoarthritis (OA). VEGF and Ang2 induced Notch-1 IC/ Notch-4 IC protein expression in synovial explant cultures and human microvascular EC levels were further potentiated by VEGF/Ang2 stimulation in combination. Notch-1, Delta-like-ligand 4, and Hrt-2 mRNA expression were significantly induced by VEGF and Ang2 alone and in combination. Furthermore VEGF/Ang2-induced EC invasion, angiogenesis and migration were inhibited by Notch-1 siRNA or DAPT. Conditioned media from VEGF/Ang2 stimulated RA synovial explants induced EC tube formation, an effect that was inhibited by DAPT. Finally, DAPT significantly decreased VEGF/Ang2 induced IL-6, IL-8, MMP2 and 9 expressions in RA synovial explants. CONCLUSIONS: Notch-1 mediates VEGF/Ang2-induced angiogenesis and EC invasion in inflammatory arthritis.
    Annals of the rheumatic diseases 11/2012; · 8.11 Impact Factor
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    ABSTRACT: Infliximab and adalimumab effectiveness might be related with changes in angiogenic factors. The aim of the study was to compare the concentrations of angiogenic proteins in patients with inflammatory bowel disease (IBD) and healthy controls and to analyze changes in the levels during infliximab and adalimumab treatment. A prospective case-control study was conducted in 37 patients with IBD starting treatment with infliximab (16 with Crohn's disease and 6 with ulcerative colitis) or adalimumab (15 with Crohn's disease) and 40 control subjects. Four samples were taken from IBD patients, one before each of the first 3 doses of infliximab/adalimumab and one at week 14. Serum levels of vascular endothelial growth factor (VEGF), placental growth factor, angiopoietin 1 (Ang1), angiopoietin 2, and Tie2 were measured using enzyme-linked immunosorbent assay. Patients with IBD had higher VEGF levels than control subjects (511.5 ± 255.6 versus 395.5 ± 256.4; P = 0.05). Patients who achieved remission at the third dose of anti-TNF-alpha had lower VEGF levels at baseline (453.5 ± 250.7 versus 667.5 ± 153.9 pg/mL) and before the second (409.7 ± 217 versus 681.3 ± 350.6 pg/mL) and third (400.5 ± 222.8 versus 630.4 ± 243.1 pg/mL) doses compared with those with no remission (P < 0.05). Ang1 levels decreased before each treatment dose in patients who achieved remission (P < 0.05). High baseline VEGF levels predicted for a poor response to anti-TNF-alpha therapy (area under the receiver operating characteristics curve = 0.8), whereas high Ang1 levels were associated with disease remission (area under the receiver operating characteristics curve = 0.7). Concentrations of angiogenic proteins did not correlate with clinical activity scores. Circulating VEGF and Ang1 levels decrease after anti-TNF-alpha therapy and may predict response to treatment. Whether these changes are a direct effect of anti-TNF-alpha therapy or a sign of disease improvement remains to be elucidated.
    Inflammatory Bowel Diseases 02/2014; · 5.12 Impact Factor

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