CD40 engagement modulates the production of matrix metalloproteinases by gingival fibroblasts

Chronic periodontitis is a destructive inflammatory disease linked with unbalanced production between matrix metalloproteinases (MMPs), such as interstitial collagenase (MMP-1) and stromelysin-1 (MMP-3) and their endogenous tissue inhibitors of MMPs (TIMPs). In addition to aberrant MMP-1 and MMP-3 expression, periodontal lesions are characterized by dense infiltrations of activated T lymphocytes which may interact with CD40-expressing gingival fibroblasts in the connective tissue via the CD40L-CD40 pathway. In this study we investigated whether CD40 cross-linking influenced MMP production by gingival fibroblasts. Therefore, we analysed the CD40L-induced MMP production by these fibroblasts in the presence of cytokines that are increased in periodontal lesions, such as IL-1β, tumour necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ). We show that CD40 ligation on gingival fibroblasts resulted in a decrease of their MMP-1 and MMP-3 production, while MMP-2 and TIMP-1 production were unaffected as determined by Western blot. This down-regulatory effect of CD40 engagement on MMP-1 and MMP-3 production by gingival fibroblasts was also present when MMP production was up-regulated by IL-1β and TNF-α or down-regulated by IFN-γ. These results suggest that CD40 ligation on gingival fibroblasts leads to a restraining of MMP-1 and MMP-3 production by gingival fibroblasts and thereby may be an important mechanism in the retardation of further periodontal tissue damage

Gingival Crevicular Fluid Matrix Metalloproteinase (MMP)-7, Extracellular MMP Inducer, and Tissue Inhibitor of MMP-1 Levels in Periodontal Disease

WOS: 000243801300014PubMed ID: 17209789Background: During periodontal inflammation, matrix metalloproteinases (MMPs) are under the control of several regulatory mechanisms including the upregulation of expression by inducers and downregulation by inhibitors. Our study aimed to examine the levels and molecular forms of MMP-7, tissue inhibitor of MMP (TIMP) - 1, and extracellular matrix metalloproteinase inducer (EMMPRIN) in gingival crevicular fluid (GCF) from patients with different periodontal diseases. Methods: A total of 80 subjects (20 patients with generalized aggressive periodontitis [GAgP], 20 with chronic periodontitis [CP], 20 with gingivitis, and 20 periodontally healthy subjects) were included in this study. Periodontal status was evaluated by measuring probing depth, clinical attachment loss, presence of bleeding on probing, and plaque. GCF MMP-7, TIMP-1, and EMMPRIN levels and molecular forms were analyzed by enzyme-linked immunosorbent assay (ELISA) and Western immunoblot techniques using specific antibodies. Results: Total amounts of GCF MMP-7 were found to be similar between the study groups. GAgP, CP, and gingivitis groups had significantly higher total amounts of GCF EMMPRIN compared to healthy subjects (P < 0.008). Among the patient groups, the GAgP group had the highest total amount of GCF EMMPRIN relative to the gingivitis group (P= 0.0004). Soluble EMMPRIN existed in GCF in multiple molecular-weight species especially in periodontitis -affected GCF under non-reducing conditions, i.e., 30-, 55-, 100-, 180-, and 200-kDa species. All patient groups had significantly elevated total amounts of GCF TIMP-1 relative to the healthy group (P < 0.0001). GAgP and CP groups also had a higher total amount of GCF TIMP-I compared to the gingivitis group (P < 0.0001 and P < 0.0001, respectively). The GAgP group had higher GCF TIMP-1 and EMMPRIN levels compared to the CP group, but this elevation did not reach statistical significance. Conclusions: Our data indicate that MMP-7 is associated with the innate host defense in periodontal tissues. Increased EMMPRIN and TIMP-1 levels in GCF are associated with the enhanced severity of periodontal inflammation, indicating that these molecules can participate in the regulation of progression of periodontal diseases. To our knowledge, the present study demonstrated the presence of soluble forms of EMMPRIN in GCF of patients with different periodontal diseases for the first time