Fig. 1.15 ). Proteoglycans form highly hydrated gels that confer resistance to compressive forces; in joint cartilage, proteoglycans also provide a layer of lubrication between adjacent bony surfaces. 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 hyaluronan in a manner reminiscent of the bristles on a test-tube brush. The highly negatively charged, densely packed sulfated sugars attract cations (mostly sodium) and abundant water molecules, producing a viscous, gelatin-like matrix. Besides providing compressibility to tissues, proteoglycans 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 concentrating growth factors and chemokines (
Fig. 1.15
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
Fig. 1.16 CellandECMinteractions:adhesiveglycoproteinsandintegrinsignaling.(A)Fibronectin consistsofadisulfide-linkeddimer,withseveraldistinctdomainsthatallowbindingtoECMandintegrins,thelatterthrougharginine-glycine-asparticacid(RGD)motifs.(B)Thecross-shapedlaminin moleculeisoneofthemajorcomponentsofbasementmembranes;itsmultidomainstructureallowsinteractionsbetweentypeIVcollagen,otherECMcomponents,andcell-surfacereceptors.(C)Integrinsandintegrin-mediatedsignalingeventsatfocaladhesioncomplexes.Eachα–β heterodimericintegrinreceptorisatrans-membranedimerthatlinksECMandtheintracellularcytoskeleton.Itisalsoassociatedwithacomplexoflinkingmolecules(e.g.,vinculinandtalin)thatcanrecruitandactivatekinasesthatultimatelytriggerdownstreamsignalingcascades.
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 immunoglobulins family members, cadherins, and selectins.
Fibronectin is a large (450 kD) disulfide-linked heterodimer that exists in tissue and plasma forms; it is synthesized by a variety of cells, including fibroblasts, monocytes, and endothelium. Fibronectin has specific domains that bind to distinct ECM components (e.g., collagen, fibrin, heparin, and proteoglycans), as well as integrins (
Fig. 1.16 ). In healing wounds, tissue and plasma fibronectin provide a scaffold for subsequent ECM deposition, angiogenesis, and reepithelialization.
Laminin is the most abundant glycoprotein in the basement membrane. It is an 820-kD cross-shaped heterotrimer 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.