Current Pharmaceutical Design - Volume 15, Issue 12, 2009

The connective tissue is exceptional in terms of its huge versatility and variability. An important characteristic of the connective tissue is the intercellular space. The mesenchymal cells of the connective tissue are spaced widely apart and form a huge extracellular space between them. This space is filled with a dense meshwork of mainly fibrillar extracellular matrix (ECM) molecules, which together with elastic fibers bestow on the connective tissue the ability to withstand tensile forces plastically and elastically. The fibrillar meshwork is embedded in an electron microscopically amorphous substance, a negatively charged ground substance which because of its swelling capacity is responsible for the tissue pressure. Proteoglycans, the major constitutents of this ground substance, are abundant in cartilage, whereas incompressible biominerals make up most of ground substance in bone, thus enabling them to serve as the nondeformable skeletal framework of our body. Yet, the recent decades have revealed that the tissue which because of its mechanical ability to shape the body, organs and tissues has been called the stromal compartment in contrast to the organ-specific parenchyme, can do much more than to function as mere ‘stuffing material’. One characteristic of ECM proteins is their ability to aggregate into supramolecular structures, such as fibers and twodimensional networks, in a highly ordered manner. In most cases, this formation of ECM aggregates is a self-organizing process, which additionally can be initiated and influenced by cells. In the first review, P. Yurchenco and B. Patton [1] describe the latest findings and models concerning the (self-) assembly of the basement membrane (BM), a two-dimensional sheet-like ECM structure, which is the borderline of the connective tissue to other tissues, such as epithelium, endothelium, muscle and neuronal tissue, as well as fat cells. Several deficiencies of the BM cause severe human diseases, partially due to misorganized BM formation. In addition to explaining the molecular mechanisms, P. Yurchenco and B. Patton describe therapeutic approaches and strategies to treat some of these diseases. A special emphasis is put on defects of muscle tissue and the nervous system. Although the connective tissue/stromal compartment of these tissues are generally regarded as less important for the physiological roles of these organs, the described disease examples show, that the stromal ECM and BM are indispensably required for their full functionality.

Basement membranes are sheet-like cell-adherent extracellular matrices that serve as cell substrata and solidphase agonists, contributing to tissue organization, stability and differentiation. These matrices are assembled as polymers of laminins and type IV collagens that are tethered to nidogens and proteoglycans. They bind to cell surface molecules that include signal-transducing receptors such as the integrins and dystroglycan and form attachments to adjacent connective tissues. The cell receptors, in turn, provide links between the matrix and underlying cytoskeleton. Genetic diseases of basement membrane and associated components, collectively the basement membrane zone, disrupt the extracellular matrix and/or its linkages to affect nerve, muscle, skin, kidney and other tissues. These diseases can arise due to a loss of matrix integrity, adhesion strength and/or receptor-mediated signaling. An understanding of the mechanisms of basement membrane zone assembly and resulting structure can provide insights into the development of normal tissues and the pathogenic mechanisms that underlie diverse disorders.

Extracellular matrix (ECM) and ECM-hydrolytic enzymes play critical roles in reproduction, development, morphogenesis, wound healing, tissue repair, regeneration, and remodeling. They are also involved in pathological processes such as inflammation, arthritis, cardiovascular diseases, stroke, neurodegeneration, metabolic syndrome, and cancer invasion and metastasis. Other reviews summarized the structure and function of ECM-degrading enzymes in cancer and other diseases. This review will focus on current insights of major protease families and other digestive enzymes that play significant roles in ECM remodeling and ECM-related pathologies. For example, the functions of matrix metalloproteinases in modulating adipogenesis, and their subsequent implications in obese patients, are discussed. Recent discovery and characterization of nineteen members of the human disintegrin-metalloproteinase with thrombospondin motif family have revealed new opportunities of investigating these enzymes in human pathologies, especially in the pathogenesis of osteoarthritis. Although kallikrein-3 was discovered many years ago as prostate specific antigen, the biomarker for detecting human prostate cancer and monitoring its recurrence in patients after surgery, fifteen members of the kallikrein family were reported to participate in physiological and pathological processes. Furthermore, exciting research has been carried out on other important ECM-digestive enzymes, including heparanase, cathepsins, hyaluronidases, and matriptases. Research data have suggested that these enzymes are potential therapeutic targets and biomarkers for cancer, arthritis, obesity, diabetic complications, multiple sclerosis, cardiovascular diseases, cerebral vascular diseases, and many other pathological conditions.

Extracellular matrix (ECM) is composed of large collagen fibrils. Glycoproteins, such as fibronectin, can bind to collagen or form their own networks. Collagen fibrils are also decorated by proteoglycans, proteins that have large glycosaminoglycan sidechains. In addition, extracellular space often contains hyaluronan, a large glycosaminoglycan molecule that has no core protein. Basement membranes represent a specialized form of extracellular matrix. Basement membranes are built by laminin and type IV collagen networks. In multicellular animals cells are anchored to ECM and basement membranes. Cell locomotion during development and after tissue injury is also based on cellular interactions with different matrix molecules. Specific cell surface receptors mediate these interactions. The largest family of receptors, which mediates cell adhesion to fibronectin, laminins and collagens is called the integrins. Several other cellular receptors have also evolved to bind to various matrix components. Here, we review the basic facts about these receptors and shortly describe their role in human diseases, including cancer and inflammation.

After injury the body normally undergoes a repair process, however when this event becomes deregulated the pathological condition of fibrosis occurs. There are many similarities with respect to the fundamental mechanisms that regulate sclerosis in different organ systems. In this review we utilize the pathological entity of glomerulosclerosis in the kidney to highlight some of the general paradigms whereby extracellular matrix (ECM) is deposited in greater quantities than it is degraded. Our review discusses how genetic and structural abnormalities of specific ECM components can result in fibrosis. In addition, we outline how some key growth factors, integrins and oxidative stress play a role in the development of glomerulosclerosis.

The extracellular matrix (ECM) is a complex of self assembled macromolecules. It is composed predominantly of collagens, non-collagenous glycoproteins, hyaluronan and proteoglycans. ECM is not only a scaffold for the cells; it serves also as a reservoir for growth factors and cytokines and modulates the cell activation status and turnover. ECM should be considered a dynamic network of molecules secreted by cells that in turn regulate cell behavior by modulating their proliferation and differentiation. The ECM provides structural strength to tissues, maintaining a complex architecture around the cells and the shape of organs. Various cell types secrete different matrix molecules and the nature and the amount of these molecules change during developmental age. Cartilage ECM is composed mainly of two components defining its mechano-physical properties: the collagenous network, responsible for the tensile strength of the cartilage matrix, and the proteoglycans (mainly aggrecan), responsible for the osmotic swelling and the elastic properties of the cartilage tissue. The conversion of cartilage into bone requires several processes that directly involve the different ECM components. Homeostasis of cartilage and bone is maintained by complex mechanisms controlling turnover and remodeling of ECM. In bone, as well as in cartilage, the ECM resident cells produce local factors, inflammatory mediators, and matrix-degrading enzymes. Turnover and degradation of normal and pathological matrices are dependent on the responses of the local cell to auto and paracrine anabolic and catabolic pathway.

Extracellular matrix (ECM) provides a physical scaffold for cells but also provides specific molecular and spatial information that influences cell proliferation, differentiation and apoptosis. This review addresses the multiple roles of ECM in inflammatory responses, in particular in leukocyte extravasation at sites of inflammation, and the potential of exploiting such cell-ECM interactions to interfere with defined steps in the inflammatory process. In the course of an inflammation leukocytes not only have to penetrate the vascular endothelial cell monolayer, but also the underlying endothelial cell basement membrane and invade the interstitial matrix of the stroma to reach the site of inflammation. The endothelial cell basement membrane may directly influence leukocyte recruitment to the inflammed tissue by providing differential signals resulting from its spatial and molecular composition, or indirectly by its potential to bind and present cytokines or chemotactic factors. Proteases (in particular matrix metalloproteinases (MMP)) released at sites of inflammation selectively process ECM and cell surface molecules, which may result in the release of bioactive fragments that may function as chemoattractants for different leukocytes subsets or modulate the activity/ function of resident mesenchymal and immune cells. In addition, MMPs have been shown to process chemokines modulating their chemoattractant properties. To be able to mimic or inhibit some of the ECM functions or proteolytic events that occur during inflammation, through the use of specific protein fragments, would provide a means by which the inflammatory process could be manipulated, an area however that remains largely unexplored.

The prevention of excessive blood loss to avoid fatal haemorrhage is a pivotal process for all organisms possessing a circulatory system. Increased circulating blood volume and pressure, as required in larger animals, make this process all the more important and challenging. It is essential to have a powerful and rapid system to detect damage and generate an effective seal, and which is also exquisitely regulated to prevent unwanted, excessive or systemic activation so as to avoid blockage of vessels. Thus, a highly specialised and efficient haemostatic system has evolved that consists of cellular (platelets) and protein (coagulation factors) components. Importantly, this is able to support haemostasis in both the low shear environment of the venous system and the high shear environment of the arterial system. Endothelial cells, lining the entire circulation system, play a crucial role in the delicate balance between activation and inhibition of the haemostatic system. An intact and healthy endothelium supports blood flow by preventing attachment of cells and proteins which is required for initiation of coagulation and platelet activation. Endothelial cells produce and release the two powerful soluble inhibitors of platelet activation, nitric oxide and prostacyclin, and express high levels of CD39 which rapidly metabolises the major platelet feedback agonist, ADP. This antithrombotic environment however can rapidly change following activation or removal of endothelial cells through injury or rupture of atherosclerotic plaques. Loss of endothelial cells exposes the subendothelial extracellular matrix which creates strong signals for activation of the haemostatic system including powerful platelet adhesion and activation. Quantitative and qualitative changes in the composition of the subendothelial extracellular matrix influence these prothrombotic characteristics with life threatening thrombotic and bleeding complications, as illustrated by formation of atherosclerotic plaques or the disorder Ehler-Danlos syndrome, which is caused by a defect in collagen synthesis and is associated with fragile blood vessels. This review will focus on the role of the subendothelial matrix in haemostasis and thrombosis, highlighting its potential as a target for novel antithrombotics.

Emerging evidence points towards a key role of the extracellular matrix (ECM) during tumor progression and therapy resistance. Paradoxically, in today's routine of cancer management the ECM is not taken into account. It is the aim of the present review to broaden our understanding of the mechanisms of therapy resistance, taking the ECM as a presumptive central regulator. The stromal ecosystem drives the accumulation of ECM at the invasion front. Therefore, we address the question whether the detection of ECM signatures in histopathology and biofluids may help predicting therapy resistance and determining the prognosis of cancer. Since the ECM is an attractive target for tumor therapy, current therapeutic strategies in preclinical or clinical development will be discussed.

Blood vessels are highly organized and complex structure, which are far more than simple tubes conducting the blood to almost any tissue of the body. They are able to autonomously regulate the blood flow, thus providing the tissues an optimal support of oxygen and nutrients and an efficient removal of waste products. In higher organisms, the blood vessel forms a closed circuit system, which additionally has the ability to seal itself in case of leakage as a result of injury. The blood vessel system does not only transport soluble substances, but also serves as “highway” system for leukocytes to patrol the body during the immunological surveillance and to reach the inflammation site quickly. In a complex interplay with the vascular wall, leukocytes are able to penetrate the blood vessel without any obvious leakage. Pathologically, tumor cells subvert the blood vessel system to disseminate from the primary tumor and colonize distant organs during metastasis. The extracellular matrix (ECM) of a blood vessel contributes substantially to the diverse functions of the blood vessel. First, the ECM constitutes the scaffold which keeps the histological structure of the vessel wall in shape but also bears the enormous and permanent mechanical forces levied on the vessel by the pulsatile blood flow in the arteries and by vasoconstriction, which regulates blood flow and pressure. The complex network of elastic fibers and tensile forces-bearing networks are well adapted to accomplish these mechanical tasks. Second, the ECM provides informational cues to the vascular cells, thus regulating their proliferation and differentiation. Third, ECM molecules can store, mask, present or sequester growth factors, thereby modulating their effects remarkably. Furthermore, several ECM molecules serve additional functions within the blood vessel. Their expression is altered in a spatial and temporal pattern during blood vessel formation and remodeling. In contrast to vasculogenesis during embryonic development, blood vessel shows a remarkably and life-long plasticity, which allows the formation and regeneration of new blood vessel even in adulthood. Both physiologically during wound healing and pathologically during tumor growth, the sprouting of new blood vessels during angiogenesis is an important process, in which the ECM takes a key role.