Extracellular Matrix

Extracellular matrix (ECM) is a general term for extracellular networks of fibrous glycoproteins, proteoglycans, and carbohydrates that are secreted by cells. There are a wide variety of matrix types that fulfill many important functions in developing and mature animals and plants. ECM can be categorized as strong connective tissue ECM or loose connective tissue ECM. In strong connective tissue, such as bones, teeth, antlers and horns, a meshwork of fibrous protein is strengthened by deposition of calcium phosphate. Loose connective tissue includes specialized structures such as tendons, ligaments, fascia, cartilage, cell walls, and cuticles. Also in this category are the basal laminae (or basement membranes) that underlie epithelial cell layers and surround muscle cells, fat cells, and Schwann cells, and the collagenous interstitial matrix that is secreted by fibroblasts and lies beneath the basal laminae.

ECM contributes to the structure of organisms, acting as a scaffold for building strong connective tissue, and organizing cells into specific patterns in loose connective tissue. Tendons and ligaments contain molecules that give them their unique structural features in connecting bone and muscle. ECM in the joints provides cushioning, and elastic layers around blood vessels allow control of blood flow. The basal lamina in the kidney glomerulus acts as a molecular filter, allowing smaller molecules to pass from the blood to the urine. ECM can form important barriers in tissues to coordinate cellular movements and organization of cellular layers. For example, the basal lamina underlying endothelial cells in blood vessels prevents cells from leaving the circulation, except for certain cells that have the ability to pass through. This barrier is especially important during inflammation and metastasis.

 While the important structural roles played by ECM have been recognized for a long time, recent research has uncovered crucial instructive activities that direct cellular movement and regulate cellular differentiation and gene expression. Individual molecules have now been purified, and their activities have been characterized. Many ECM molecules have been shown to support adhesion of cells, and some (such as tenascin) display anti-adhesive activities that may be important in establishing tissue boundaries or pathways of migration. Early in development, neuroblasts and myoblasts contact ECM as they migrate to their final destinations. ECM is also important in axon pathfinding and synapse formation. The basal lamina surrounding muscle cells has specialized regions in the synaptic cleft at the neuromuscular junction that contains molecules important for synapse function, such as acetylcholinesterase. In addition, synaptic basal lamina contains molecules that help guide synapse formation and regeneration, such as laminins containing the b-2 subunit and agrin. beta-2 laminins are also important in photoreceptor development and synapse formation. ECM also acts as a reservoir of positively charged growth factors, many of which bind to negative charges in ECM molecules. Growth factors and ECM molecules act in concert to direct a wide variety of cellular traffic during tissue morphogenesis. For example, fibroblast growth factor must bind to heparan sulfate chains from proteoglycans to be stable and active. In addition, the activity of some growth factors is enhanced when cells are bound to ECM, due to a synergy of their respective intracellular signaling pathways. Finally, some ECM molecules are proteolyzed to generate smaller soluble factors. Collagen XVIII is cleaved to generate endostatin, an antiangiogenic motility factor that can prevent tumor progression in mice. It has become clear that the ECM is in part the mortar that holds cells together in tissues, but it also acts as the brick mason, guiding the development and deposition of cells within the organism.

 Cells interact with and respond to specific matrix molecules via cell surface receptors such as the Integrins, which bind matrix on the outside of the cell, and send signals across the plasma membrane to regulate intracellular events. Some cells make identifiable, stable junctions with ECM via integrins. These include focal adhesions which link to the actin cytoskeleton and hemidesmosomes, which connect to intermediate filaments. Other cell interactions with ECM are more transient. Contact with the matrix can alter the polymerization dynamics of the cytoskeleton to bring about changes in cell shape important in cell adhesion, migration and polarity. Adhesion to ECM is important in cellular responses to physical/mechanical forces, such as shear stress caused by blood flow over endothelial cells. ECM can activate signaling cascades involving tyrosine kinases which control cell growth, differentiation and apoptosis. Other receptors may also play roles in interacting with the ECM, including proteoglycans and galactosyl transferases.

 The molecular complexity of the ECM is formidable, and many components are polymerized and then interwoven by covalent and noncovalent cross-links. The specific molecular attributes of ECM components give rise to their specific functional roles. For example, collagen I, the most abundant protein in animals, forms covalently cross linked fibrils with the tensile strength of steel that are found in skin, tendon, ligament, and bone. In contrast, Collagen IV forms sheets that polymerize with heparin sulfate proteoglycans and laminin-1 to give rise to the basal lamina. The presence of negatively charged, unbranched carbohydrate polymers called glycosaminoglycans (GAGs), both as free molecules and attached to protein backbones in proteoglycans, form a cushion-like hydrated gel important in the function of joints. For example, hyaluronan, a free GAG molecule that can be as long as 20 mm if stretched from end to end, forms a viscous random coil that provides turgor pressure in spaces between cells. Aggrecan, a proteoglycan, is a key cushioning element in cartilage. The elastic properties of cross-linked elastin arrays allow lung bronchial sacs to expand and arteries to change their diameter. Many ECM proteins are composed of repeated motifs that arise from individual exons, suggesting that new proteins evolved by shuffling various exons. Electron micrographs of purified ECM molecules have revealed striking geometries, from cross-shaped structures like laminin-1, to centipede like arrays of proteoglycans in an aggrecan aggregate, to pentameric and hexameric asterisks like thrombospondin-4 and tenascin, respectively. Some ECM proteins have many different isoforms arising from both alternative splicing and multiple genes that encode homologous families of subunits. For example, there are over 20 varieties of collagens made from 38 distinct polypeptides. At least 15 types of laminin have been identified. Other ECM components such as vitronectin and fibronectin are made in one form and deposited in matrices, and a second form is an abundant component of blood plasma.

The macromolecules that make up the ECM are synthesized by cells that reside within the matrix. This includes fibroblasts in the interstitial matrix, chondroblasts in cartilage, and osteoblasts in bone. Some fibril forming ECM proteins such as collagen are made initially with N- and C-terminal extensions called propeptides that prevent polymerization until the propeptides are cleaved outside the cell. Collagen also contains posttranslationally modified hydroxyproline and hydroxy lysine, which are important for hydrogen bonds that stabilize fibrils. The enzymatic addition of the hydroxyl groups requires ascorbic acid (vitamin C), and deficiencies lead to weakened blood vessels and loose teeth characteristic of the disease Scurvy. Outside the cell, triple helical collagen monomers are cross-linked via covalent bonds to form 50 nm extracellular fibrils. Cells can assemble complex ECM arrays on their surface via the activity of integrin and dystroglycan receptors.

 Once assembled, ECM is insoluble and fairly stable. For example, a collagen I molecule in bone might last 10 years before it is replaced. However, in some cases the degradation and turnover of matrix does occur, and it is carefully regulated. White blood cells must degrade the vascular basal lamina to leave blood vessels and enter inflamed tissue, and metastatic cancer cells can migrate to distant sites by violating ECM boundaries. Matrix is also degraded at certain times during development and wound healing, such as in the sprouting of new blood vessels (angiogenesis). In these cases most matrix is degraded by a family of over 20 secreted proteases called Matrix Metalloproteinases (MMPs), which require bound Zn²⁺ or Ca²⁺ for activity. MMPs are secreted as inactive precursors which are activated by proteolytic cleavage. Activity is also regulated by a family of secreted protease inhibitors called tissue inhibitors of metalloproteinases (TIMPS). The process of matrix degradation is of great importance to medical researchers interested in controlling inflammation, tumorgenesis, and metastasis.

 The importance of ECM is underscored by the consequences of mutations that ablate or alter matrix components. For example, human mutations in collagen I can result in osteogenesis imperfecta) weak bones) or Ehlers-Danlos Syndrome (defective joints), or even death. Over 1,000 mutations have been identified in 22 different collagen genes, and these lead to a variety of diseases characterized by defective connective tissue. Mutations in fibrillin results in Marfan's syndrome, a disease characterized by defects in elastic tissue such as the aorta, which is subject to aneurysms.

Mutations in laminin genes can lead to congenital muscular dystrophy and junctional epidermolysis bullosa, a skin blistering disease. More recently, genetic studies in model animal systems have also demonstrated the importance of ECM. For example, loss of laminin in the worm Caenorhabditis elegans results in defective mesodermal cell migration and axonal pathfinding under the epidermis. Mice with null (knockout) mutations in the fibronectin gene fail to develop notochord, somites, neural tube, and heart and die by embryonic day 10.

 There is still a great deal to learn about the ECM. New molecular components continue to be discovered, and their functions are not yet known. Furthermore, alternatively spliced variants of known molecules, and isoforms derived from separate genes have been discovered which differ in structure and function. Proteolytic fragments of ECM molecules, such as endostatin, angiostatin, and tumstatin, are being investigated as possible anticancer treatments. The exact molecular structure of complex ECMs such as the basal lamina are not yet clear, and how cells adhere to, migrate on, and move across matrices is still not completely understood. As more genomes are sequenced, we should get a better idea of ECM complexity and evolution. Developing better treatments for important human diseases such as arthritis, cancer, and macular degeneration may be made possible by a better understanding of the ECM.

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