Transforming Growth Factor-β Induces Collagenase-3 Expression by Human Gingival Fibroblasts via p38 Mitogen-activated Protein Kinase

Human collagenase-3 (matrix metalloproteinase 13 (MMP-13)) is characterized by exceptionally wide substrate specificity and restricted tissue specific expression. Human skin fibroblasts in culture express MMP-13 only when they are in three-dimensional collagen (Ravanti, L., Heino, J., Lopez-Otin, C., and Kahari. V.-M. (1999) J. Biol. Chem. 274, 2446-2455). Here we show that MMP-13 is expressed by fibroblasts during normal human gingival wound repair. Expression of MMP-13 by human gingival fibroblasts cultured in monolayer or in collagen gel was induced by transforming growth factor-beta1 (TGF-beta1). Treatment of gingival fibroblasts with TGF-beta1 activated two distinct mitogen-activated protein kinases (MAPKs): extracellular signal-regulated kinase 1/2 (ERK1/2) in 15 min and p38 MAPK in 1 and 2 h. Induction of MMP-13 expression by TGF-beta1 was blocked by SB203580, a specific inhibitor of p38 MAPK, but not by PD98059, a selective inhibitor of ERK1/2 activation. Adenovirus-mediated expression of dominant negative p38alpha and c-Jun potently inhibited induction of MMP-13 expression in gingival fibroblasts by TGF-beta1. Infection of gingival fibroblasts with adenovirus for constitutively active MEK1 resulted in activation of ERK1/2 and JNK1 and up-regulation of collagenase-1 (MMP-1) and stromelysin-1 (MMP-3) production but did not induce MMP-13 expression. In addition, activation of p38 MAPK by constitutively active MKK6b or MKK3b was not sufficient to induce MMP-13 expression. These results show that TGF-beta-elicited induction of MMP-13 expression by gingival fibroblasts is dependent on the activity of p38 MAPK and the presence of functional AP-1 dimers. These observations demonstrate a fundamental difference in the regulation of collagenolytic capacity between gingival and dermal fibroblasts and suggest a role for MMP-13 in rapid turnover of collagenous matrix during repair of gingival wounds, which heal with minimal scarring

CCHCR1 Is Up-Regulated in Skin Cancer and Associated with EGFR Expression

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Matrix metalloproteinases in the restorative proctocolectomy pouch of pediatric ulcerative colitis

WOS:000307986700015Peer reviewe

Polymorphisms of the ITGAM Gene Confer Higher Risk of Discoid Cutaneous than of Systemic Lupus Erythematosus

Background Lupus erythematosus (LE) is a heterogeneous disease ranging from mainly skin-restricted manifestations (discoid LE [DLE] and subacute cutaneous LE) to a progressive multisystem disease (systemic LE [SLE]). Genetic association studies have recently identified several strong susceptibility genes for SLE, including integrin alpha M (ITGAM), also known as CD11b, whereas the genetic background of DLE is less clear. Principal findings To specifically investigate whether ITGAM is a susceptibility gene not only for SLE, but also for cutaneous DLE, we genotyped 177 patients with DLE, 85 patients with sporadic SLE, 190 index cases from SLE families and 395 population control individuals from Finland for nine genetic markers at the ITGAM locus. SLE patients were further subdivided by the presence or absence of discoid rash and renal involvement. In addition, 235 Finnish and Swedish patients positive for Ro/SSA-autoantibodies were included in a subphenotype analysis. Analysis of the ITGAM coding variant rs1143679 showed highly significant association to DLE in patients without signs of systemic disease (P-value = 4.73x10-11, OR = 3.20, 95% CI = 2.23-4.57). Significant association was also detected to SLE patients (P-value = 8.29x10-6, OR = 2.14, 95% CI = 1.52-3.00), and even stronger association was found when stratifying SLE patients by presence of discoid rash (P-value = 3.59x10-8, OR = 3.76, 95% CI = 2.29-6.18). Significance We propose ITGAM as a novel susceptibility gene for cutaneous DLE. The risk effect is independent of systemic involvement and has an even stronger genetic influence on the risk of DLE than of SLE.Peer reviewe

Identification of MAMDC1 as a candidate susceptibility gene for systemic lupus erythematosus (SLE)

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Human corneal epithelial cells require MMP-1 for HGF-mediated migration on collagen I

PURPOSE. To investigate the potential regulation of matrix metalloproteinases (MMPs) by hepatocyte growth factor (HGF), and to identify individual MMPs essential for migration of human corneal epithelial cells.METHODS. Migration of human corneal epithelial cells (HCECs) was measured with a colony dispersion assay in response to concentrations of HGF (0-50 ng/mL). MMP activity in the conditioned media collected from the dispersion assay was assessed by zymography. The broad-spectrum MMP inhibitor ilomastat (1-100 muM) or an MMP-9-neutralizing antibody (1-10 mug/mL) were included in the dispersion assay to determine their effects on HCEC migration. Immunocytochemistry and in situ hybridization were used to localize MMP-1 in HCECs in the colony dispersion assay and in a human ex vivo corneal wound-healing model, respectively. ELISA for MMP-1 was performed on conditioned medium from migrating HCECs. Neutralizing antibodies to MMP-1 and -9 were added to an in vitro scratch-wound model to assess the effect on HCEC healing.RESULTS. HCEC migration (P < 0.05) and MMP-2 and -9 released into the medium increased in response to HGF in a dose-dependent manner up to 20 ng/mL. Broad-spectrum MMP inhibition significantly reduced HCEC migration (P < 0.05). In contrast, neutralization of MMP-9 increased migration (P < 0.05). MMP-1 was found in association with HCECs at the migratory leading edge in both the dispersion and the ex vivo wound-healing experiments, and was found to be stimulated above basal levels by HGF. Neutralization of MMP-1 significantly decreased (P < 0.05), whereas neutralization of MMP-9 significantly increased (P < 0.05), scratch-wound closure.CONCLUSIONS. This study provided novel data regarding HCEC migration in response to HGF and highlighted the importance of MMPs, particularly MMP-1 in migration and possibly reepithetialization in Vivo. MMP-9 and/or -2 may be released by HCECs to remodel matrix behind the leading migratory front. Studies such as this are essential to assist in the safe and efficacious design of MMP inhibitors for therapeutic use in the eye