Expression and role of matrix metalloproteinases and the laminin-5 y2-chain in wound healing and cell migration
Year: 2003
Type: dissertation
Abstract: Inflammation is the host response to resolve any intrusion or attack to the organism.The host response involves removal of the foreign particles or regeneration of open surfaces, extracellular matrix (ECM) remodelling and cell migration.At the tissue level, inflammation occurs through the co-ordinated action of multiple molecular pathways.The matrix metalloproteinases (MMPs) are endopeptidases which cleave most ECM and basement membrane proteins.MMPs mediate important functions during normal physiological remodelling and development, however, MMP activity is known to be aberrantly upregulated during pathological conditions, including chronic inflammatory diseases and tumor cell invasion.Thus, many attempts have been made to develop synthethic inhibitors against MMP activity.Laminin-5 (Ln-5) is a heterotrimeric glycoprotein part of the hemidesomosomal complex which anchors surface epithelia to the underlying stroma.The Ln-5 γ2-chain can be cleaved by MMP-2 and -14, which induces cell migration.In this study, the role and expression of MMPs were studied in chronic inflammatory periodontal disease tissue representing a typical disease state, where the hosts ability to resolve the primary inflammation is impaired.In conjunction with this, the effect of inflammatory-related cytokines was studied in cultured human oral mucosal keratinocytes and different MMP inhibitors (MMPIs) were tested.Wound healing is known to be delayed due to estrogen-deprivation, which is a typical state affecting women past menopause.In this study, MMP expression and activity as well as the Ln-5 γ2-chain processing were studied in cutaneous wound healing of estrogen-deficient rats, and the effect of estrogen or MMPI treatment was additionally assessed.Finally, the direct ability of different MMPs to process the Ln-5 γ2-chain and subsequently induce carcinoma cell migration was studied in vitro.The results demonstrate a role for cytokine regulation of MMP-2 and -9 in human oral mucosal keratinocytes.MMP-2 and -9 activities could be downregulated in vitro by chemically modified tetracyclines as well as in situ by an MMP-2 and -9 specific inhibitor, the CTTHWGFTLC-peptide.Cutaneous wound healing in estrogen-deprived rats was impaired due to significantly reduced collagen deposition and content, instability of the re-epithelialized wound surface, changes in MMP activity and expression as well as aberrant Ln-5 γ2-chain processing.These changes could be reversed by treating the animals with estrogen or a chemically modified tetracycline.Several MMPs in addition to the previously characterized MMP-2 and -14 were found to process the Ln-5 γ2-chain and induce carcinoma cell migration.In summary, the results demonstrate a role for MMPs and the Ln-5 γ2-chain in tissue degradation and remodelling associated with inflammatory processes and in regulating cell migration.The use of MMPIs could be useful in the treatment of both cancer and chronic inflammatory diseases.
Source: Työväentutkimus Vuosikirja
Author: Emma Pirilä
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
Funder: Helsingin Yliopisto
OpenAlex ID: W2147300462