Cytokine regulation of matrix metalloproteinase activity and its regulatory dysfunction in disease

Abstract

Matrix metalloproteinases (MMPs) represent a family of structurally and functionally related enzymes responsible for the proteolytic degradation of extracellular matrix (ECM) components such as basement membrane or interstitial stroma. MMPs are important participants of normal tissue remodeling. Due to their potential hazardous effects MMPs are highly regulated at different levels. At the transcriptional level, MMP expression is precisely controlled by various cytokines acting through positive or negative regulatory elements of its genes. Moreover, MMP activity is post-transcriptionally regulated by proteolytic activation of the latent proenzymes and by interaction with specific tissue inhibitors of metalloproteinases (TIMPs). Expression and secretion of both MMP activating enzymes and TIMPs are also influenced by cytokines. Dysregulation of MMP production and activation may cause altered extracellular proteolysis that is associated with a number of diseases such as rheumatoid arthritis and tumor metastasis. Thus, the molecular analysis of the regulatory mechanisms of gene expression and activity of MMPs and their inhibitors is essential for understanding the complex scenario of tissue remodeling and ECM degradation under both normal and pathological conditions.