effect of pioglitazone on matrix metalloproteinase-9, matrix metalloproteinase-2, tumor necrosis factor-a, vascular endothelial growth factor and E-selectin in skin lesions in psoriatic patients with and without psoriatic arthritis

ABSTRACT

Psoriasis is a common inflammatory skin disease characterized by infiltration of inflammatory cells into the epidermis and altered keratinocyte differentiation. The aim of the present study was to investigate 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 with and without psoriatic arthritis, the association of MMP-9 with the activity of the disease, the relationship between MMP-9 and TNF-alpha production as well as to evaluate the effect of pioglitazone [one of the agents thiazolidinediones] on TNF- alpha, MMP-9, MMP-2, VEGF and E-selectin production and in treatment of psoriasis. Thirty-five psoriatic patients [28 males, 7 females] were included in this study. They were divided into 2 groups. Group I [PsA] included 15 psoriatic patients, clinically presenting joint symptoms associated to the cutaneous disease [PsA]. Group II [Ps] included 20 psoriatic patients, clinically presenting cutaneous disease without psoriatic arthritis [PsA]. Each psoriatic patient received pioglitazone 30 mg/day orally for 10 weeks. Lesional tissue specimens were taken, in the same skin area before and after 10 weeks pioglitazone treatment. 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 ELISA. MMP-9 concentrations were also measured in the sera. The cutaneous activity of disease was evaluated by the Psoriasis Area and Severity Index [PAST]. Clinical and laboratory assessment indicated that all patients had a significant improvement of the PAS1 score after 10 weeks of pioglitazone therapy. The clinical improvement was associated to a significant decrease of TNF- alpha, MMP-9, MMP-2, VEGFand E-selectin levels [P < 0.05], spontaneously released by lesional biopsies before and after therapy. A significant decrease of MMP-9 [P < 0.01] in the sera, associated to the clinical improvement was also found. In addition, significant positive correlations [P < 0.01] were found between the TNF- alpha and PASI score, MMP-9, MMP-2, VEGFand E-selectin [r = 0.85, 0.84, 0.58, 0.63, 0.67 respectively], as well as between the MMP-9 and PASI, MMP-2, VEGFand E-selectin [r = 0.82, 0.39, 0.69, 0.41 respectively] of patients with PsA after pioglitazone treatment. In psoriatic patients without psoriatic arthritis after pioglitazone treatment there were also significant positive correlations between the TNF- alpha and PASI score, MMP-9, MMP-2, VEGF and E-selectin [r =.0.87, 0.68, 0.53, 0.61, 0.51 respectively], as well as between MMP-9 and PASI, MMP-2, VEGF and E-selectin [r = 0.95, 0.51, 0.58, 0.45 respectively]. The current study shows 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. Our findings also demonstrated that pioglitazone could be considered as an efficacious and safe agent for the treatment of psoriasis. The optimum dose and duration of pioglitazone therapy remain to be determined