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Hepatocyte growth factor. Hepatocyte growth factor (HGF; also known as scatter factor) has mitogenic effects on hepatocytes and most epithelial cells. HGF acts as a morphogen during embryonic development (i.e., it influences the pattern of tissue differentiation), pro- motes cell migration (hence its designation as scatter factor), and enhances hepatocyte survival. HGF is pro- duced by fibroblasts and most mesenchymal cells, as well as endothelium and nonhepatocyte liver cells. It is synthesized as an inactive precursor (pro-HGF) that is proteolytically activated by serine proteases released at sites of injury. The receptor for HGF is MET, which has intrinsic tyrosine kinase activity. It is frequently overex- pressed or mutated in tumors, particularly renal and thyroid papillary carcinomas. Consequently, MET inhibitors are being evaluated as cancer therapies. #280 в контекст | | |
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Platelet-derived growth factor. PDGF is a family of several closely related proteins, each consisting of two chains (designated by pairs of letters). Three isoforms of PDGF (AA, AB, and BB) are constitutively active, while PDGF-CC and PDGF-DD must be activated by proteo- lytic cleavage. PDGF is stored in platelet granules and is released on platelet activation. Although originally isolated from platelets (hence the name), it also is pro- duced by many other cells, including activated macro- phages, endothelium, smooth muscle cells, and a variety of tumors. All PDGF isoforms exert their effects by binding to two cell surface receptors (PDGFR α and β), both having intrinsic tyrosine kinase activity. PDGF induces fibroblast, endothelial, and smooth muscle cell proliferation and matrix synthesis, and is chemotactic for these cells (and inflammatory cells), thus promoting
recruitment of the cells into areas of inflammation and tissue injury. #282 в контекст | | |
Vascular endothelial growth factor. Vascular endothelial growth factors (VEGFs)—VEGF-A, -B, -C, and -D, and PIGF (placental growth factor)—are a family of homodi- meric proteins. VEGF-A is generally referred to simply as VEGF; it is the major factor responsible for angiogen- esis, inducing blood vessel development, after injury and in tumors. In comparison, VEGF-B and PIGF are involved in embryonic vessel development, and VEGF-C and -D stimulate both angiogenesis and lymphatic development (lymphangiogenesis). VEGFs also are involved in the maintenance of endothelial cells lining mature vessels. Its expression is highest in epithelial cells adjacent to fenestrated endothelium (e.g., podo- cytes in the kidney, pigment epithelium in the retina, and choroid plexus in the brain). VEGF induces angio- genesis by promoting endothelial cell migration and proliferation (capillary sprouting), and the formation of the vascular lumina. VEGFs also induce vascular dila- tion and increase vascular permeability. As might be anticipated, hypoxia is the most important inducer of VEGF production through pathways that involve acti- vation of the transcription factor hypoxia-inducible factor (HIF-1). Other VEGF inducers—produced at sites of inflammation or wound healing—include PDGF and TGF-α. #283 в контекст | | |
VEGFs bind to a family of receptor tyrosine kinases (VEGFR-1, -2, and -3). VEGFR-2 is highly expressed in endothelium and is the most important for angiogene- sis. Antibodies against VEGF are approved for the treat- ment of several tumors such as renal and colon cancers because cancers require angiogenesis for their spread and growth. Anti-VEGF antibodies also are used in the treatment of a number of ophthalmic diseases, includ- ing: “wet” age-related macular degeneration (AMD a disorder of inappropriate angiogenesis and vascular permeability that causes adult-onset blindness); the reti- nopathy of prematurity; and the leaky vessels that lead to diabetic macular edema. Finally, increased levels of soluble versions of VEGFR-1 (s-FLT-1) in pregnant women may contribute to preeclampsia (hypertension and proteinuria) by “sopping up” the free VEGF required for maintaining normal endothelium. #284 в контекст | | |
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Fibroblast growth factor. Fibroblast growth factor (FGF) is a family of growth factors with more than 20 members. Acidic FGF (aFGF, or FGF-1) and basic FGF (bFGF, or FGF-2) are the best characterized; FGF-7 is also referred to as keratinocyte growth factor (KGF). Released FGFs associate with heparan sulfate in the ECM, which serves as a reservoir for inactive factors that can be subsequently released by proteolysis (e.g., at sites of wound healing). FGFs transduce signals through four tyrosine kinase receptors (FGFR 1–4). FGFs contribute to wound healing responses, hematopoiesis, and development; bFGF has all the activities necessary for angiogenesis as well. #287 в контекст | | |
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Transforming growth factor-β. TGF-β has three isoforms (TGF-β1, TGF-β2, and TGF-β3) that belong to a family with about 30 members, including bone morphogenetic proteins (BMPs), activins, inhibins, and Müllerian inhib- iting substance. TGF-β1 has the most widespread distri- bution, and it is more commonly referred to simply as TGF-β. It is a homodimeric protein produced by mul- tiple cell types, including platelets, endothelium, and mononuclear inflammatory cells. TGF-β is secreted as a precursor that requires proteolysis to yield the biologi- cally active protein. There are two TGF-β receptors, both with serine/threonine kinase activity that induces the phosphorylation of several downstream cytoplasmic transcription factors called Smads. Phosphorylated Smads form heterodimers with Smad4, allowing nuclear translocation and association with other DNA-binding proteins to activate or inhibit gene transcription. TGF-β produces multiple and often opposing effects depend- ing on the tissue type and concurrent signals. Agents with such multiplicity of effects are called pleiotropic, and TGF-β is “pleiotropic with a vengeance.” Primarily, TGF-β drives scar formation by stimulating matrix syn- thesis through decreased matrix metalloproteinase (MMP) activity and increased activity of tissue inhibi- tors of proteinases (TIMPs). TGF-β also applies brakes to the inflammation that accompanies wound healing
by inhibiting lymphocyte proliferation and the activity of other leukocytes. #289 в контекст | | |
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The ECM is a network of interstitial proteins that consti- tutes a significant proportion of any tissue. Cell interac- tions with ECM are critical for development and healing, as well as for maintaining normal tissue architecture (Fig. 1.13). Much more than a simple “space filler” around cells, ECM serves several key functions: #291 в контекст | | |
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Mechanical support for cell anchorage and cell migration, and maintenance of cell polarity. #293 в контекст | | |
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Control of cell proliferation, by binding and displaying growth factors and by signaling through cellular recep- tors of the integrin family. The ECM provides a depot for a variety of latent growth factors that can be acti- #295 в контекст | | |
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Scaffolding for tissue renewal. Because maintenance of normal tissue structure requires a basement membrane or stromal scaffold, the integrity of the basement mem- brane or the stroma of parenchymal cells is critical for the organized regeneration of tissues. Thus, ECM disruption results in defective tissue regeneration and repair, for example, cirrhosis of the liver resulting from the collapse of the hepatic stroma in various forms of hepatitis. #298 в контекст | | |
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Establishment of tissue microenvironments. The basement membrane acts as a boundary between the epithelium and underlying connective tissue; it does not just provide support to the epithelium but is also functional, for example, in the kidney, forming part of the filtration apparatus. #300 в контекст | | |
The ECM is constantly being remodeled; its synthesis and degradation accompany morphogenesis, tissue regen- eration and repair, chronic fibrosis, and tumor invasion and metastasis. ECM occurs in two basic forms: interstitial matrix and basement membrane (Fig. 1.14 #301 в контекст | | |
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Interstitial matrix is present in the spaces between cells in connective tissue, and between the parenchymal epi- thelium and the underlying supportive vascular and smooth muscle structures. The interstitial matrix is synthesized by mesenchymal cells (e.g., fibroblasts), forming an amorphous three-dimensional gel. Its major constituents are fibrillar and nonfibrillar collagens, as well as fibronectin, elastin, proteoglycans, hyaluronate, and other constituents (see later). #303 в контекст | | |
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Basement membrane. The seemingly random array of interstitial matrix in connective tissues becomes highly organized around epithelial cells, endothelial cells, and smooth muscle cells, forming the specialized basement membrane. This is synthesized conjointly by the overly- ing epithelium and the underlying mesenchymal cells, forming a flat lamellar “chicken wire” mesh (although labeled as a membrane, it is quite porous). The major constituents are amorphous nonfibrillar type IV colla- gen and laminin.) #305 в контекст | | |
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The components of the ECM fall into three groups of pro- teins (Fig. 1.15): #307 в контекст | | |
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Fibrous structural proteins such as collagens and elastins that confer tensile strength and recoil #309 в контекст | | |
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Water-hydrated gels such as proteoglycans and hyaluro- nan that permit compressive resistance and lubrication #311 в контекст | | |
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Adhesive glycoproteins that connect ECM elements to one another and to cells #313 в контекст | | |
Collagens. Collagens are composed of three separate polypeptide chains braided into a ropelike triple helix. About 30 collagen types have been identified, some of which are unique to specific cells and tissues. #314 в контекст | | |
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Some collagen types (e.g., types I, II, III, and V colla- gens) form linear fibrils stabilized by interchain hydro- gen bonding; such fibrillar collagens form a major proportion of the connective tissue in structures such as bone, tendon, cartilage, blood vessels, and skin, as well as in healing wounds and scars. The tensile strength of the fibrillar collagens derives from lateral crosslinking of the triple helices by covalent bonds, an unusual post-translational modification that requires hydroxyl- ation of lysine residues in collagen by the enzyme lysyl oxidase. Because lysyl oxidase is a vitamin C-dependent enzyme, children with ascorbate deficiency have skele- tal deformities, and people of any age with vitamin C deficiency heal poorly and bleed easily because of “weak” collagen. Genetic defects in collagens cause dis- eases such as osteogenesis imperfecta and certain forms of Ehlers-Danlos syndrome (Chapter 7). #316 в контекст | | |
Nonfibrillar collagens variously contribute to the struc- tures of planar basement membranes (type IV collagen); help regulate collagen fibril diameters or collagen- collagen interactions via so-called “fibril-associated col- lagen with interrupted triple helices” (FACITs, such as type IX collagen in cartilage); and provide anchoring fibrils within basement membrane beneath stratified squamous epithelium (type VII collagen). #317 в контекст | | |
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Elastin. The ability of tissues to recoil and recover their shape after physical deformation is conferred by elastin (Fig. 1.15). Elasticity is especially important in cardiac valves and large blood vessels, which must accommodate recurrent pulsatile flow, as well as in the uterus, skin, and ligaments. Morphologically, elastic fibers consist of a central core of elastin with an associated meshlike network composed of fibrillin. The latter relationship partially #319 в контекст | | |
explains why fibrillin defects lead to skeletal abnormalities and weakened aortic walls, as in individuals with Marfan syndrome. Fibrillin also controls the availability of TGF-β (Chapter 7). #320 в контекст | | |
Proteoglycans and hyaluronan (Fig. 1.15). Proteogly- cans form highly hydrated gels that confer resistance to compressive forces; in joint cartilage, proteoglycans also provide a layer of lubrication between adjacent bony sur- faces. Proteoglycans consist of long polysaccharides called glycosaminoglycans (examples are keratan sulfate and chondroitin sulfate) attached to a core protein; these are then linked to a long hyaluronic acid polymer called hyal- uronan in a manner reminiscent of the bristles on a test-tube brush. The highly negatively charged, densely packed sul- fated sugars attract cations (mostly sodium) and abundant water molecules, producing a viscous, gelatin-like matrix. Besides providing compressibility to tissues, proteogly- cans also serve as reservoirs for secreted growth factors (e.g., FGF and HGF). Some proteoglycans are integral cell membrane proteins that have roles in cell proliferation, migration, and adhesion, for example, by binding and con- centrating growth factors and chemokines (Fig. 1.15). #321 в контекст | | |
Adhesive glycoproteins and adhesion receptors. These are structurally diverse molecules variously involved in cell-cell, cell-ECM, and ECM-ECM interactions (Fig. 1.16). Prototypical adhesive glycoproteins include fibronectin (a major component of the interstitial ECM) and laminin (a major constituent of basement membrane). Integrins are representative of the adhesion receptors, also known as cell adhesion molecules (CAMs); the CAMs also include immu- noglobulins family members, cadherins, and selectins. #322 в контекст | | |
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Fibronectin is a large (450 kD) disulfide-linked heterodi- mer that exists in tissue and plasma forms; it is synthe- sized by a variety of cells, including fibroblasts, monocytes, and endothelium. Fibronectin has specific domains that bind to distinct ECM components (e.g., col- lagen, fibrin, heparin, and proteoglycans), as well as inte- grins (Fig. 1.16). In healing wounds, tissue and plasma fibronectin provide a scaffold for subsequent ECM depo- sition, angiogenesis, and reepithelialization. #324 в контекст | | |
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Laminin is the most abundant glycoprotein in the base- ment membrane. It is an 820-kD cross-shaped heterotri- mer that connects cells to underlying ECM components such as type IV collagen and heparan sulfate (Fig. 1.16). Besides mediating the attachment to the basement membrane, laminin can also modulate cell proliferation, differentiation, and motility. #326 в контекст | | |
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Integrins are a large family of transmembrane heterodi- meric glycoproteins composed of α- and β-subunits that allow cells to attach to ECM constituents such as laminin and fibronectin, thus functionally and structurally linking the intracellular cytoskeleton with the outside world. Integrins also mediate cell-cell adhesive interac- tions. For instance, integrins on the surface of leukocytes are essential in mediating firm adhesion to and transmi- gration across the endothelium at sites of inflammation (Chapter 3), and they play a critical role in platelet aggregation (Chapter 4). Integrins attach to ECM com- ponents via a tripeptide arginine-glycine-aspartic acid motif (abbreviated RGD). In addition to providing focal attachment to underlying substrates, binding through the integrin receptors can also trigger signaling cascades that influence cell locomotion, proliferation, shape, and differentiation (Fig. 1.16). #328 в контекст | | |
