Normal Biology of Stromal/Epithelial Cell Interactions in the Gut

proteases whose primary function is in extracellular matrix (ECM) degradation and remodelling (9, 42, 43). MMPs are mostly secreted as latent, inactive zymogens by various stromal and epithelial cell types, including mesenchymal cells, T cells, monocytes, macrophages, neutrophils, keratinocytes, and tumor cells. Activation into active enzyme usually occurs in the pericellular or extracellular space. MMP proteolysis of the extracellular matrix creates space into which cells can migrate, produces specific fragments of extracellular matrix proteins with independent biological activity, regulates tissue architecture, and activates, deactivates, and modifies the activity of signalling molecules (58). MMPs are structurally related but can be subdivided according to their primary substrate specificities: collagenases (MMP-1, -8, -13, -18), gelatinases (MMP2, -9), stromelysins (MMP-3, -7, -10, -11), elastase (MMP-12), membrane types (MMP-14, -15, -16, -17, 24, -25), and others (MMP-19, -20, -23, -26, -27, -28) (Table 1). MMPs work together to create a cascade of activation, whereby, once one MMP is activated, it catalyses the conversion of other MMP zymogens to their active forms so that many MMPs are “switched on” with the potential to degrade all classes of the extracellular matrix. Endogenous MMP inhibitors are the tissue inhibitors of metalloproteinases (TIMPs), produced by the same cells that produce MMPs and that act by forming 1:1 complexes with MMPs. Under normal conditions, MMPs are present in tissues at low levels usually in the latent form and are responsible for normal physiological tissue turnover. They are regulated in four ways: at the level of transcription, at the point of activation from the precursor zymogens, by interaction with specific ECM components, and by TIMP inhibition (10; 19). TIMPs control the local activities of MMPs in tissues. However, if the production of MMPs is excessive, TIMP inhibition can be inadequate to control the flood of MMPs, leading to an imbalance in the ECM breakdown and repair system. For example, if ECM degradation is excessive and the healing response cannot maintain integrity, tissue will be digested away with structural loss, as in the fistulous tracts often seen in Crohn’s disease (27).