The extracellular matrix (ECM) is a complex combination of proteins and polysaccharides that is secreted and assembled by cells into a network in which the components bind to one another. The ECM is often involved in holding cells and tissues together. The composition, physical properties, and functions of the ECM are carefully controlled and can vary depending on the tissue type, its location, its physiological state, and chemical modifications of its components. These modifications include enzymatic phosphorylation, sulfation and desulfation, cross-linking, cleavage by proteases and glycosidases, and oxidation, as well as nonenzymatic addition of glucose (glycation).

The ECM is usually sensed by cells as a consequence of binding to adhesion receptors on their plasma membranes, which then instruct the cells to behave appropriately in response to their environments or modulate the structure and function of the ECM based on the state of the cells. Different cells can bind to the same patch of ECM via their adhesion receptors and thus be indirectly bound together. ECM components include proteoglycans, a unique type of glycoprotein (a protein with covalently attached sugars); collagens and other proteins that often form fibers; soluble multi-adhesive matrix proteins; and others (Table 20-1). Multi-adhesive matrix proteins, such as fibronectin and laminin, are long, flexible molecules that contain multiple domains. They are responsible for binding various types of collagen, other matrix proteins, polysaccharides, and extracellular signaling molecules as well as adhesion receptors. These proteins are important organizers of the extracellular matrix. Through their interactions with adhesion receptors, they also regulate cell-matrix adhesion—and thus cell shape and behavior.

Cells contribute to the assembly of the ECM not only by secreting its components, but also by participating directly in the assembly of those components into complex structures containing large fibrils and amorphous macromolecules. Once assembled, the ECM often is not static, but rather highly dynamic in that its chemical, physical, and biological properties can be altered quantitatively or qualitatively as a consequence of cells secreting enzymes, such as proteases, and other molecules into the extracellular space. These alterations in the ECM, which are usually referred to as “remodeling,” can involve covalent chemical modifications (including chemical cross-linking of ECM molecules), partial or essentially complete proteolytic cleavage of ECM components, and addition of newly synthesized ECM molecules.

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The relative volumes occupied by cells and their surrounding matrix vary greatly among different animal tissues. Some connective tissue, for instance, is mostly matrix with relatively few cells, whereas many other tissues, such as epithelia, are composed of very densely packed cells with relatively little matrix (Figure 20-4). The density of packing of the molecules within the ECM itself can also vary greatly.

H. V. Wilson’s classic studies of adhesion in marine sponge cells showed conclusively that one primary function of the ECM is to literally hold tissue together. Figures 20-5a and 20-5b, which re-create Wilson’s classic work, show that when sponges are mechanically dissociated and individual cells from two sponge species are mixed, the cells of one species will adhere to one another, but not to cells from the other species. This specificity is due in part to species-specific adhesive proteins in the ECM that bind to the cells via adhesion receptors. These adhesive proteins can be purified and used to coat colored beads, which, when mixed, aggregate with one another with a specificity similar to that of intact sponge cells (Figure 20-5c, d).

The ECM plays a multitude of other roles in addition to facilitating cell adhesion (Table 20-2). Different combinations of components tailor the ECM for specific purposes at different anatomic sites: strength in a tendon, strength and rigidity in teeth and bones, cushioning in cartilage, and transparency in the vitreous humor in the eyeball. The composition of the ECM also provides positional and signaling information for cells, letting a cell know where it is and what it should do. ECM remodeling can modulate the interactions of a cell with its environment. Furthermore, the ECM serves as a reservoir for many extracellular signaling molecules that control cell growth and differentiation. In addition, it provides a lattice through or on which cells either can move or are prevented from moving, particularly in the early stages of tissue assembly. Morphogenesis—the stage of embryonic development in which tissues, organs, and body parts are formed by cell movements and rearrangements—is critically dependent on cell-matrix adhesion as well as cell-cell adhesion. For example, cell-matrix interactions are required for branching morphogenesis (formation of branching structures) to form blood vessels, the air sacs in the lung, mammary and salivary glands, and other structures (Figure 20-6).

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Disruptions in cell-matrix and cell-cell interactions can have devastating consequences for the development of tissues. Figure 20-7 shows the dramatic changes in the skeletal system of embryonic mice when the genes for either of two key ECM molecules, collagen II and perlecan, are inactivated. Disruptions in adhesion and ECM functions are also characteristic of various pathologies, including cardiovascular, musculoskeletal, kidney, skin, eye, and bone diseases as well as metastatic cancer, in which cancer cells leave their normal locations and spread throughout the body.

Although many CAMs and adhesion receptors were initially identified and characterized because of their adhesive properties, they also play major roles in signaling, using many of the pathways discussed in Chapters 15 and 16. Figure 20-8 illustrates how one adhesion receptor, integrin, physically and functionally interacts, via adapters and signaling molecules, with a broad array of intracellular signaling pathways to influence cell survival, gene transcription, cytoskeletal organization, cell motility, and cell proliferation. Conversely, changes in the activities of signaling pathways inside cells can influence the structures of CAMs and adhesion receptors—for example, by altering adapter binding to the cytosolic portions of the CAMs—and so modulate their ability to interact with other cells and with the ECM. Thus outside-in and inside-out signaling involve numerous interconnected pathways.