Osteogenesis Imperfecta

Osteogenesis imperfecta is a condition inherited in mendelian fashion that illustrates many principles of human genetics. It is a heterogeneous and pleiotropic group of disorders characterized by a tendency toward fragility of bone. Advances in the last two decades demonstrate that nearly every case is caused by a mutation of the COL1A1 or

COL1A2 genes, which encode the subunits of type I collagen, pro1(I) and pro 2(I),
respectively. More than 100 different mutant alleles have been described for osteogenesis imperfecta; the relationships between different DNA sequence alterations and the type of disease (genotype-phenotype correlations) illustrate several pathophysiologic principles in human genetics.

Clinical Manifestations The clinical and genetic characteristics of osteogenesis imperfecta are summarized in Table 2–3, in which the timing and severity of fractures, radiologic findings, presence of additional clinical features, and family history are used to discriminate among four different subtypes. All forms of osteogenesis imperfecta are characterized by increased susceptibility to fractures ("brittle bones"), but there is considerable phenotypic heterogeneity, even within individual subtypes. Individuals with type I or type IV osteogenesis imperfecta present in early childhood with one or a few fractures of long bones in response to minimal or no trauma; x-ray films reveal mild osteopenia, little or no bony deformity, and often evidence of earlier subclinical fractures. However, most individuals with type I or type IV osteogenesis imperfecta do not have fractures in utero. Type I and type IV osteogenesis imperfecta are distinguished by the severity (less in type I than in type IV) and by scleral hue, which indicates the thickness of this tissue and the deposition of type I collagen. Individuals with type I osteogenesis imperfecta have blue scleras, whereas the scleras of those with type IV are normal or slightly gray. In type I, the typical number of fractures during childhood is 10 –20; fracture incidence decreases after puberty, and the main features in adult life are mild short stature, a

tendency toward conductive hearing loss, and occasionally dentinogenesis imperfecta. Individuals with type IV osteogenesis imperfecta generally experience more fractures than those with type I and have significant short stature caused by a combination of long bone and spinal deformities, but they often are able to walk independently. Approximately one fourth of the cases of type I or type IV osteogenesis imperfecta represent new mutations; in the remainder, the history and examination of other family members reveal findings consistent with autosomal dominant inheritance.

Table 2–3 Clinical and Molecular Subtypes of Osteogenesis Imperfecta.

Type Phenotype

Genetics

Molecular Pathophysiology Loss-of-function mutation in pro 1(I) chain resulting in decreased amount of mRNA; quality of collagen is normal; quantity is reduced twofold

Type Mild: Short stature, postnatal Autosomal I fractures, little or no deformity, blue scleras, premature hearing loss dominant

Type Perinatal lethal: Severe II bone formation, severe deformities, blue scleras, connective tissue fragility

Sporadic dominant)

Structural mutation in pro 1(I) or pro 2(I) chain that has mild effect on heterotrimer assembly; quality of collagen is severely abnormal; quantity often reduced also

prenatal fractures, abnormal (autosomal

Type Progressive deforming: III Prenatal fractures, deformities usually present at birth, very short stature,

Autosomal dominant1

Structural mutation in pro 1(I) or pro 2(I) chain that has mild effect on heterotrimer assembly; quality of collagen is severely

hearing loss Type Deforming with normal IV scleras: Postnatal fractures. multiple fractures. Unlike other forms of osteogenesis imperfecta. type III can be inherited in either a dominant or (rarely) recessive fashion. mild to moderate deformities. Nearly all cases of type II osteogenesis imperfecta represent a new dominant mutation. and blue scleras. pro 1(I) chain that has little or no effect on heterotrimer assembly. bony deformities. type III osteogenesis imperfecta is the least well understood form. From a biochemical and molecular perspective. Death usually results from respiratory difficulties. less frequently. It is intermediate in severity between types II and IV. Type II osteogenesis imperfecta presents at or before birth (diagnosed by prenatal ultrasonography) with multiple fractures. most affected individuals will require multiple corrective surgeries and lose the ability to ambulate by early adulthood. increased fragility of nonbony connective tissue. blue scleras. quality of collagen is usually abnormal. normal or gray scleras. Two typical radiologic findings are the presence of isolated "islands" of mineralization in the skull (wormian bones) and a beaded appearance to the ribs. quantity can be normal 1Autosomal recessive in rare cases. quantity can be normal Structural mutation in the pro 2(I). which are nearly always due to mutations that act dominantly. or. Type III osteogenesis imperfecta presents at birth or in infancy with progressive bony deformities.usually nonambulatory. premature hearing loss. and blue scleras and usually results in death in infancy. and there is no family history. dental abnormalities Autosomal dominant abnormal. .

which constitutes the major extracellular protein in the body. In some cases. It is the major collagen in the dermis. and the disease phenotypes for each subtype show a spectrum of severities that overlap one another. and there are additional disorders associated with congenital fractures that are usually not considered to be "classic" osteogenesis imperfecta. the connective tissue capsules of most organs. Distinguishing this presentation from type III osteogenesis imperfecta may be possible only if other affected family members exhibit a milder course. However. the approach to clinical classification depicted in Table 2–3 is helpful for most affected individuals in predicting the course and inheritance pattern of the illness. The classification also serves as an important framework within which to correlate molecular abnormalities with disease phenotypes. Similarly. respectively (Figure 2–2). Pathophysiology Osteogenesis imperfecta is a disease of type I collagen. mutations of type I collagen genes have been excluded as potential causes of these additional disorders. the classification presented in Table 2–3 is clinical rather than molecular. For example. and the vascular and GI adventitia and is the only collagen in bone.Although different subtypes of osteogenesis imperfecta can often be distinguished biochemically. Additional subtypes of osteogenesis imperfecta have been suggested for individuals that do not match types I–IV. some individuals with type IV osteogenesis imperfecta have fractures in utero and develop deformities that lead to loss of ambulation. A mature type I collagen fibril is a rigid structure that contains multiple type I collagen molecules packed in a staggered array and stabilized by intermolecular covalent cross-links. Each mature type I collagen molecule contains two 1 chains and one 2 chain. encoded by the COL1A1 and COL1A2 genes. a few individuals diagnosed with type II osteogenesis imperfecta based on the presence of severe bony deformities in utero will survive for many years and thus overlap the type III subtype. .

assemble with each other inside the cell. Increased levels of hydroxylation result in a more stable helix. Because the nonmutant .The COL1A1 and COL1A2 genes have 51 and 52 exons. During intracellular assembly. The 1 and 2 chains are synthesized as larger precursors with amino and carboxyl terminal "propeptide" extensions. and steric constraints allow only a proton in this position. the mutant COL1A1 allele gives rise to greatly reduced (partial loss-of-function) or no (complete loss-of-function) mRNA. where Y is proline about one third of the time. the three chains wind around each other in a triple helix that is stabilized by interchain interactions between hydroxy proline and adjacent carbonyl residues. In most cases. which begins at the carboxyl terminal end of the molecule. the amino acid sequence of virtually all collagen chains in the triple-helical portion is (Gly-X-Y)n. The nature of the triple helix causes the side chain of every third amino acid to point inward. There is a dynamic relationship between the posttranslational action of prolyl hydroxylase and assembly of the triple helix. The fundamental defect in most individuals with type I osteogenesis imperfecta is reduced synthesis of type I collagen resulting from loss-of-function mutations in COL1A1. but helix formation prevents further prolyl hydroxylation. Thus. and are ultimately secreted as a heterotrimeric type I procollagen molecule. of which exons 6–49 encode the entire triple-helical domain. respectively.

production of a truncated protein (as might be predicted from a nonsense mutation) would be more damaging to the cell than production of no protein at all. There are several potential molecular defects responsible for COL1A1 mutations in type I osteogenesis imperfecta. in many cases. the underlying defect is a single base pair change that creates a premature stop codon (also known as a "nonsense mutation") in exons 6–49. heterozygosity for a complete loss-of-function mutation results in a 50% reduction in the total rate of pro 1(I) mRNA synthesis. including alterations in a regulatory region leading to reduced transcription." partially synthesized mRNA precursors that carry the nonsense codon are recognized and degraded by the cell. splicing abnormalities leading to reduced steady state levels of RNA. whereas heterozygosity for a partial loss-of-function mutation results in a less severe reduction. Thus. nonsense-mediated decay. there is no dosage compensation). leading to (1) a reduced amount of structurally normal type I collagen and (2) an excess of unassembled pro 2(I) chains. With collagen and many other genes.COL1A1 allele continues to produce mRNA at a normal rate (ie. However. A reduced concentration of pro 1(I) chains limits the production of type I procollagen. and deletion of the entire COL1A1 gene. which has been observed to occur for mutations in many different multiexon . which are degraded inside the cell (Figure 2 –3). In a process referred to as "nonsense-mediated decay.

These appear to be critical events in the cellular pathogenesis of type II osteogenesis imperfecta. because each molecule in a fibril interacts with several others. only 25% of type I procollagen molecules will contain two normal pro 1(I) chains even though only one of the two COL1A1 alleles is mutated. Ineffective triple-helix formation leads to increased posttranslational modification by prolyl hydroxylase and a reduced rate of secretion. triple-helix formation is ineffective. These considerations help to explain why type II osteogenesis imperfecta is more severe than type I and exemplify the principle of dominant negative gene action. Because every type I procollagen molecule has two pro 1(I) chains. Collagen mutations that cause type III and type IV osteogenesis imperfecta are diverse and include glycine substitutions in the amino terminal portion of the collagen triple helix. .genes. incorporation of an abnormal molecule can have disproportionately large effects on fibril structure and integrity. However. because glycine substitutions toward the carboxyl terminal end of the molecule are generally more severe than those at the amino terminal end. which is caused by structurally abnormal forms of type I collagen and is more severe than type I osteogenesis imperfecta. An example of these principles is apparent from considering type II osteogenesis imperfecta. and some unusual alterations in the non–triple-helical extensions at the amino and carboxyl terminals of pro chains. Mutations in type II osteogenesis imperfecta can be caused by defects in either COL1A1 or COL1A2 and usually are missense alterations of a glycine residue that allow the mutant peptide chain to bind to normal chains in the initial steps of trimer assembly (Figure 2–3). serves as a protective phenomenon and is an important component of genetic pathophysiology. a few internal deletions of COL1A1 and COL1A2 that do not significantly disturb triple helix formation. often because amino acids with large side chains are substituted for glycine. The effects of an amino acid substitution in a pro 1(I) peptide chain are amplified at the levels of both triple-helix assembly and fibril formation. Furthermore.

For both type I and type IV osteogenesis imperfecta. in approximately one third of affected individuals. inheritance of the mutant allele can be predicted in future pregnancies. locus heterogeneity). even though the causative molecular defect is not known. which represents a challenge for the development of molecular diagnostic tests. as in type I osteogenesis . When allelic rather than locus heterogeneity is operative. In a family in which type I osteogenesis imperfecta is known to occur clinically and a proband seeks a diagnostic test for the purposes of reproductive planning. reproductive decision making in families at risk for osteogenesis imperfecta is influenced greatly by the relative likelihood of producing a child who will never walk and will require multiple orthopedic operations versus a child whose major problems will be a few long bone fractures and an increased risk of mixed sensorineural and conductive hearing loss in childhood and adulthood. Once this information is established for a particular family. the most important question in the clinical setting often relates to the natural history of the illness. can contribute to this phenotypic heterogeneity.Genetic Principles As already described. one distinguishes between chromosomes that carry the mutant and nonmutant COL1A1 alleles using closely linked DNA-based polymorphisms. and in this situation linkage analysis is more difficult because one cannot be sure which locus is abnormal. most cases of type I osteogenesis imperfecta are caused by partial or complete loss-of-function mutations in COL1A1. In this approach. For example. the disease is caused by a new mutation. there is a wide range of mutant alleles (ie. Consequently. as well as other genes that modify the osteogenesis imperfecta phenotype. For types III and IV osteogenesis imperfecta. As evident from the prior discussion. in addition. there are many ways in which DNA sequence alterations can reduce gene expression. However. both different mutant genes and different mutant alleles. it is possible in most cases to use linkage analysis at the COL1A1 locus. mutations can occur in COL1A1 or COL1A2 (ie. allelic heterogeneity).

Their clinical manifestations are highly variable.imperfecta. including type I osteogenesis imperfecta. which is X linked. It is the most common inherited disorder of connective tissue. Although the type II phenotype itself is never inherited. For most genetic diseases. ranging from lethal disease to premature osteoarthritis. It principally affects bone. eyes. 2. many other mutations. and teeth). In type II osteogenesis imperfecta. In fact. therefore. including Duchenne's muscular dystrophy. Osteogenesis imperfecta usually results from . 9. which is autosomal dominant. is a phenotypically diverse disorder caused by deficiencies in the synthesis of type 1 collagen. intrafamilial variability is less than interfamilial variability. has a dominant mechanism of action. there are rare situations in which a phenotypically normal individual harbors a COL1A1 mutant allele among his or her germ cells. ears. These individuals with so-called gonadal mosaicism can produce multiple offspring with type II osteogenesis imperfecta (Figure 2–4). and type 1 neurofibromatosis. a single copy of the mutant allele causes the abnormal phenotype and. and 11). but also impacts other tissues rich in type 1 collagen (joints. a pattern of segregation that can be confused with recessive inheritance. comparison of interfamilial with intrafamilial variability allows one to assess the relative contribution of different mutant alleles to phenotypic heterogeneity. 10. The importance of the structural bone proteins is exemplified by the diseases associated with deranged metabolism of the collagens important in bone and cartilage formation (types 1. or brittle bone disease. skin. Type 1 Collagen Diseases (Osteogenesis Imperfecta) Osteogenesis imperfecta. also occasionally show unusual inheritance patterns explained by gonadal mosaicism. DISEASES ASSOCIATED WITH DEFECTS IN EXTRACELLULAR STRUCTURAL PROTEINS The interaction of the organic components of bone matrix is complex and a focus of intense scientific investigation.

More severe or lethal phenotypes have abnormal polypeptide chains that cannot be arranged in the triple helix. and dental imperfections (small. Other findings include blue sclerae caused by decreased collagen content. and blue-yellow teeth) secondary to a deficiency in dentin.autosomal dominant mutations (over 800 have been identified) in the genes that enco de theα1 and α2 chains of collagen. osteogenesis imperfecta is separated into four major subtypes that vary widely in severity ( Table 26-3 ). The type II variant is at one end of the spectrum and is uniformly fatal in utero or during the perinatal period. It is characterized by extraordinary bone fragility with multiple intrauterine fractures ( Fig. Recently. making the sclera translucent and allowing partial visualization of the underlying choroid.[19] Many of these mutations involve the substitution of glycine residues in the triple-helical domain. thus constituting a type of osteoporosis with marked cortical thinning and attenuation of trabeculae. hearing loss related to both a sensorineural deficit and impeded conduction due to abnormalities in the bones of the middle and inner ear. misshapen. individuals with the type I form have a normal life span but experience childhood fractures that decrease in frequency following puberty.Subtypes of Osteogenesis Imperfecta Subtype Inheritance Collagen Defect OI type I Compatible with survival Autosomal dominant Decreased synthesis of pro-α1(1) chain Major Clinical Features Postnatal fractures. In contrast. blue sclera Abnormal pro-α1(1) Normal stature or pro-α2(1) chains Skeletal fragility Dentinogenesis imperfecta Hearing impairment Joint laxity Blue sclerae OI type II Perinatal lethal Most autosomal Abnormally short recessive pro-α1(1) chain Some autosomal dominant Death in utero or within days of birth Unstable triple helix Skeletal deformity with excessive fragility and multiple fractures Blue sclera ?New mutations Abnormal or insufficient pro- . 26-6 ). TABLE 26-3 -.[20] Clinically. mutations in the genes for cartilage-associated protein (CRTAP) and leucine proline-enriched proteoglycan 1 (LEPRE1) have been shown to be responsible for three rare variants of the disease. Mutations resulting in decreased synthesis of qualitatively normal collagen are associated with mild skeletal abnormalities. The basic abnormality in all forms of osteogenesis imperfecta is too little bone. The genotypephenotype relationship underlying osteogenesis imperfecta is based on the location of the mutation within the protein.

and its synthesis and degradation accompanies morphogenesis. Its various functions include: • • • • Mechanical support for cell anchorage and cell migration. tumor invasion. The type of ECM proteins can affect the degree of differentiation of the cells in the tissue. but also on interactions between cells and the components of the extracellular matrix (ECM). The maintenance of normal tissue structure requires a basement membrane or stromal scaffold. providing turgor to soft tissues. Maintenance of cell differentiation. ECM components can regulate cell proliferation by signaling through cellular receptors of the integrin family. The ECM sequesters water. proliferation. normal sclerae Short stature Sometimes dentinogenesis imperfecta Unstable triple helix Moderate skeletal fragility Extracellular Matrix and Cell-Matrix Interactions Tissue repair and regeneration depend not only on the activity of soluble factors. movement. Scaffolding for tissue renewal.Subtype OI type III Progressive. It is constantly remodeling. but it does much more than just fill the spaces around cells to maintain tissue structure. and metastasis. and minerals that give rigidity to bone. and maintenance of cell polarity Control of cell growth. also acting largely via cell surface integrins. The ECM regulates the growth. wound healing. The integrity of the basement membrane or the stroma of the parenchymal cells is critical for the organized regeneration of tissues. and differentiation of the cells living within it. It is . regeneration. deforming Inheritance Collagen Defect α2(1) Major Clinical Features Compatible with survival Autosomal Altered structure of dominant (75%) pro-peptides of proα2(1) Autosomal Impaired formation recessive (25%) of triple helix Growth retardation Multiple fractures Progressive kyphoscoliosis Blue sclera at birth that become white Hearing impairment Dentinogenesis imperfecta OI type IV Compatible with survival Autosomal dominant Short pro-α2(1) chain Postnatal fractures. chronic fibrotic processes.

fibronectin. Basement membrane acts as a boundary between epithelium and underlying connective tissue and also forms part of the filtration apparatus in the kidney. and smooth muscle cells. interconnected by a few neurons. such as collagens and elastins that provide tensile strength and recoil. The polypeptide is characterized by a repeating sequence in which glycine is in every third position (Gly-X-Y. as well as in connective tissue. Basement membranes are closely associated with cell surfaces. 3-2 ). and it contains . For example.particularly noteworthy that although labile and stable cells are capable of regeneration. The interstitial matrix is found in spaces between epithelial. and consist of nonfibrillar collagen (mostly type IV). providing the extracellular framework for all multicellular organisms. heparin sulfate. • Establishment of tissue microenvironments. proteoglycans. growth factors like FGF and HGF are secreted and stored in the ECM in some tissues. COLLAGEN Collagen is the most common protein in the animal world. endothelial. adhesive glycoproteins that connect the matrix elements to one another and to cells. and proteoglycans. like the “Blob” (the “gelatinous horror from outer space” of 1950s movie fame). laminin. These molecules assemble to form two basic forms of ECM: interstitial matrix and basement membranes. injury to these tissues results in restitution of the normal structure only if the ECM is not damaged. It consists mostly of fibrillar and nonfibrillar collagen. • The ECM is composed of three groups of macromolecules: fibrous structural proteins. and hyaluronan. Without collagen. a human being would be reduced to a clump of cells. elastin.[71] We will now consider the main components of the ECM. Each collagen is composed of three chains that form a trimer in the shape of a triple helix. in which X and Y can be any amino acid other than cysteine or tryptophan). This allows the rapid deployment of growth factors after local injury. Currently. or during regeneration. and proteoglycans and hyaluronan that provide resilience and lubrication. Storage and presentation of regulatory molecules. Disruption of these structures leads to collagen deposition and scar formation (see Fig. 27 different types of collagens encoded by 41 genes dispersed on at least 14 chromosomes are known[72] ( Table 3-2 ).

Types I. and XI are the fibrillar collagens. the specialized amino acids 4-hydroxyproline and hydroxylysine. in which the triplehelical domain is uninterrupted for more than 1000 residues. fibrillin. blood vessels Osteogenesis imperfecta. soft tissues Soft tissues. spondyloepiphysea dysplasia syndrome Vascular Ehlers-Danlos syndrome Classical Ehlers-Danlos syndrome . III and V. intervertebral disk. II. such as epidermis and dermis. proteoglycans.g. vitreous Hollow organs. many ECM components (e. Still other collagens are transmembrane and may also help to anchor epidermal and dermal structures. they are the main components of the basement membrane.Main Types of Collagens. Both epithelial and mesenchymal cells (e. and syndecan) are not included. Type IV collagens have long but interrupted triple-helical domains and form sheets instead of fibrils. hyaluronan.. fibroblasts) interact with ECM via integrins. these proteins are found in extracellular fibrillar structures. and adhesive glycoproteins. although there is some overlap in their constituents. and Genetic Disorders Collagen Type Tissue Distribution Genetic Disorders FIBRILLAR COLLAGENS I II III V Ubiquitous in hard and soft tissues Cartilage.g. Basement membranes and interstitial ECM have different architecture and general composition. Tissue Distribution. For the sake of simplification. together with laminin. Another collagen with a long interrupted triple-helical domain (type VII) forms the anchoring fibrils between some epithelial and mesenchymal structures. Ehlers-Danlos syndrome—arthrochalasias type I Achondrogenesis type II.FIGURE 3-12 Main components of the extracellular matrix (ECM).. including collagens. TABLE 3-2 -. Prolyl residues in the Yposition are characteristically hydroxylated to produce hydroxyproline. which serves to stabilize the triple helix. elastin.

including various forms of the Ehlers-Danlos syndrome and osteogenesis imperfecta[73] ( Chapters 5 and 26 . Genetic defects in collagen production (see Table 3-2 ) cause many inherited syndromes. a requirement that explains the inadequate wound healing in scurvy ( Chapter 9 ). Department of Pathology. intervertebral disks Transmembrane collagen in epidermal cells Genetic Disorders Stickler syndrome Alport syndrome Bethlem myopathy Dystrophic epidermolysis bullosa Multiple epiphyseal dysplasias Benign atrophic generalized epidermolysis bullosa BASEMENT MEMBRANE COLLAGENS OTHER COLLAGENS XV and Endostatin-forming collagens. Hydroxylation of proline and lysine residues and lysine glycosylation occur during translation. Vitamin C is required for the hydroxylation of procollagen. Collagen fibril formation is associated with the oxidation of lysine and hydroxylysine residues by the extracellular enzyme lysyl oxidase. University of Washington. Three chains of a particular collagen type assemble to form the triple helix ( Fig. This results in cross-linking between the chains of adjacent molecules. which stabilizes the array. Byers. and is a major contributor to the tensile strength of collagen. vitreous Basement membranes Ubiquitous in microfibrils Anchoring fibrils at dermalepidermal junctions Cartilage.Collagen Type IX IV VI VII IX XVII Tissue Distribution Cartilage. Seattle. Peter H. Knobloch syndrome (type XVIII collagen) XVIII endothelial cells Courtesy of Dr. 3-15 ). The messenger RNAs transcribed from fibrillar collagen genes are translated into pre-pro-α chains that assemble in a type-specific manner into trimers. . Procollagen is secreted from the cell and cleaved by proteases to form the basic unit of the fibrils. WA.

Regardless of the initiating mechanism. These fibers can stretch and then return to their original size after release of the tension. uterus. such as the aorta. and ligaments. and in the uterus. inherited defects in fibrillin result in formation of abnormal elastic fibers in Marfan syndrome. They also influence the availability of active TGFβ in the ECM. vessel maturation (stabilization) involves the recruitment of pericytes and smooth muscle cells to form the periendothelial layer. Proteins of the collagen family provide tensile strength. and lung require elasticity for their function. A. 2001. Substantial amounts of elastin are found in the walls of large blood vessels.FIGURE 3-15 Angiogenesis by mobilization of endothelial precursor cells (EPCs) from the bone marrow and from preexisting vessels (capillary growth). which associates either with itself or with other components of the ECM. elastic fibers consist of a central core made of elastin. As already mentioned. skin. as scaffolding for deposition of elastin and the assembly of elastic fibers.) ELASTIN. EPCs differentiate and form a mature network by linking to existing vessels. B. At these sites. AND ELASTIC FIBERS Tissues such as blood vessels. Cardiovasc Res 49:507. endothelial cells from these vessels become motile and proliferate to form capillary sprouts. manifested by changes in the cardiovascular system (aortic dissection) and the skeleton[74] ( Chapter 5 ). In angiogenesis from preexisting vessels. in part. a 350-kD secreted glycoprotein. (Modified from Conway EM et al: Molecular mechanisms of blood vessel growth. but the ability of these tissues to expand and recoil (compliance) depends on the elastic fibers. EPCs are mobilized from the bone marrow and may migrate to a site of injury or tumor growth. The peripheral microfibrillar network that surrounds the core consists largely of fibrillin. FIBRILLIN. surrounded by a peripheral network of microfibrils. skin. CELL ADHESION PROTEINS . Morphologically. The microfibrils serve.

PKC. 3-13 ). providing for interaction between the same cells (homotypic interaction) or different cell types (heterotypic interaction). can be classified into four main families: immunoglobulin family CAMs. The plasma form binds to fibrin. held together by disulfide bonds. polymers of laminin and collagen type IV form tightly bound networks. Fibronectin messenger RNA has two splice forms. establishing cell-to-cell contact. The integrin-cytoskeleton complexes function as activated receptors and trigger a number of signal transduction pathways. These proteins function as transmembrane receptors but are sometimes stored in the cytoplasm. It consists of two glycoprotein chains. fibrin.Most adhesion proteins. . and cell surface receptors. provide a mechanism for the transmission of mechanical force and the activation of intracellular signal transduction pathways that respond to these forces. Not only is there a functional overlap between integrin and growth factor receptors. and also to adhesive proteins in other cells. helping to stabilize the blood clot that fills the gaps created by wounds. and osteopontin providing a connection between cells and ECM. particularly for the integrins. Laminin is the most abundant glycoprotein in the basement membrane and has binding domains for both ECM and cell surface receptors. Fibronectin is a large protein that binds to many molecules. such as collagen.[75] As receptors. and PI3K pathways. proteoglycans. Selected aspects of other cell adhesion proteins are described here. apoptosis. vinculin. and selectins. These linkages. Selectins have been discussed in Chapter 2 in the context of leukocyte/endothelial interactions. and differentiation ( Fig. which are also activated by growth factors. CAMs can bind to similar or different molecules in other cells. and paxillin. Laminin can also mediate the attachment of cells to connective tissue substrates. integrins. cadherins. also called CAMs (cell adhesion molecules). Cadherins and integrins link the cell surface with the cytoskeleton through binding to actin and intermediate filaments. and serves as a substratum for ECM deposition and formation of the provisional matrix during wound healing (discussed later). Ligand binding to integrins causes clustering of the receptors in the cell membrane and formation of focal adhesion complexes. but integrins and growth factor receptors interact (“crosstalk”) to transmit environmental signals to the cell that regulate proliferation. including the MAP kinase. The cytoskeletal proteins that co-localize with integrins at the cell focal adhesion complex include talin. giving rise to tissue fibronectin and plasma fibronectin. laminin. Integrins bind to ECM proteins such as fibronectin. In the basement membrane.

present in epithelial and muscle cells. Signaling from ECM components and growth factors is integrated by the cell to produce various responses. . which. Migration of keratinocytes in the re-epithelialization of skin wounds is dependent on the formation of dermosomal junctions. and talin). thus completing the connection with the cytoskeleton. forming two types of cell junctions called (1) zonula adherens. locomotion. connects to actin. Linkage of cadherins with the cytoskeleton occurs through two classes of catenins. Integrins bind ECM components and interact with the cytoskeleton at focal adhesion complexes (protein aggregates that include vinculin. stronger and more extensive junctions. The name cadherin is derived from the term “calcium-dependent adherence protein. This can initiate the production of intracellular messengers or can directly mediate nuclear signals. small. which participate in interactions between cells of the same type. β-catenin links cadherins with α-catenin. α -actin. including changes in cell proliferation. in turn.” This family contains almost 90 members.FIGURE 3-13 Mechanisms by which ECM components and growth factors interact and activate signaling pathways. Cell-to-cell interactions mediated by cadherins and catenins play a major role in regulating cell motility. proliferation. These interactions connect the plasma membrane of adjacent cells. Cell surface receptors for growth factors may activate signal transduction pathways that overlap with those activated by integrins. spotlike junctions located near the apical surface of epithelial cells. and (2) desmosomes. and differentiation.

some other secreted adhesion molecules are mentioned because of their potential role in disease processes: (1) SPARC (secreted protein acidic and rich in cysteine). act as modulators of inflammation. a family of large multifunctional proteins. Mutation and altered expression of the Wnt/β-catenin pathway is implicated in cancer development. particularly in gastrointestinal and liver cancers ( Chapter 7 ). contributes to tissue remodeling in response to injury and functions as an angiogenesis inhibitor. vascular remodeling.and differentiation and account for the inhibition of cell proliferation that occurs when cultured normal cells contact each other (“contact inhibition”). GAGs consist of long repeating polymers of specific disaccharides. which consist of large multimeric proteins involved in morphogenesis and cell adhesion. (2) the thrombospondins. also inhibit angiogenesis. immune responses. GAGs are linked to a core protein. GLYCOSAMINOGLYCANS (GAGS) AND PROTEOGLYCANS GAGs make up the third type of component in the ECM.[78] Proteoglycans are remarkable in their diversity. With the exception of hyaluronan (discussed later). and cell growth and differentiation. but it is now recognized that these molecules have diverse roles in regulating connective tissue structure and permeability ( Fig. Proteoglycans can be integral membrane proteins and. At most sites. also known as osteonectin. and fibrosis in various organs[76. (3) osteopontin (OPN) is a glycoprotein that regulates calcification. through their binding to other proteins and the activation of growth factors and chemokines. ECM may contain several different core proteins. free β-catenin acts independently of cadherins in the Wnt signaling pathway. whose main function was to organize the ECM. Diminished function of E-cadherin contributes to certain forms of breast and gastric cancer. is a mediator of leukocyte migration involved in inflammation. 3-14 ).][77] (discussed later in this chapter). forming molecules called proteoglycans. . some of which. each containing different GAGs. which participates in stem cell homeostasis and regeneration. Proteoglycans were originally described as ground substances or mucopolysaccharides. similar to SPARC. and (4) the tenascin family. In addition to the main families of adhesive proteins described earlier. besides the fibrous structural proteins and cell adhesion proteins. As already mentioned.

It binds a large amount of water (about 1000-fold its own weight). Heparan sulfate binds FGF-2 (basic FGF) secreted into the ECM. and hyaluronan. By contrast. and the umbilical cord. and hyaluronan (HA). skin and skeletal tissues. extracellular GAG side chains that can bind FGF-2. and osteoarthritis. 2004. Multiple proteoglycans may attach to hyaluronan chains in the ECM. while still attached to hyaluronan synthase. The first three of these families are synthesized and assembled in the Golgi apparatus and rough endoplasmic reticulum as proteoglycans.[79] It is a huge molecule that consists of many repeats of a simple disaccharide stretched end-to-end. Regulation of FGF-2 activity by ECM and cellular proteoglycans. scleroderma. notably for the cartilage in joints. synovial fluid.FIGURE 3-14 Proteoglycans. Its concentration increases in inflammatory diseases such as rheumatoid arthritis. HA is produced at the plasma membrane by enzymes called hyaluronan synthases and is not linked to a protein backbone. chondroitin/dermatan sulfate. and a cytoplasmic tail that binds to the actin cytoskeleton. (B and C. psoriasis. the vitreous of the eye. HA is a polysaccharide of the GAG family found in the ECM of many tissues and is abundant in heart valves. B.) There are four structurally distinct families of GAGs: heparan sulfate. forming a viscous hydrated gel that gives connective tissue the ability to resist compression forces. Nat Rev Cancer 4:528. Hyaluronan chains in the extracellular space are bound to the plasma membrane through the CD44 receptor. Synthesis of hyaluronan at the inner surface of the plasma membrane. Enzymes called hyaluronidases fragment HA into lower molecular weight molecules (LMW HA) that have different functions than the parent . The molecule extends to the extracellular space. HA helps provide resilience and lubrication to many types of connective tissue. A. modified from Toole KR: Hyaluronan: from extracellular glue to pericellular cue. C. Syndecan is a cell surface proteoglycan with a transmembrane core protein. Syndecan side chains bind FGF-2 released by damage to the ECM and facilitate the interaction with cell surface receptors. keratan sulfate. glycosaminoglycans (GAGs).

. LMW HA produced by endothelial cells binds to the CD44 receptor on leukocytes. but their persistence may lead to prolonged inflammation. The leukocyte recruitment process and the production of proinflammatory molecules by LMW HA are strictly regulated processes. these activities are beneficial if short-lived. In addition. LMW HA molecules stimulate the production of inflammatory cytokines and chemokines by white cells recruited to the sites of injury. promoting the recruitment of leukocytes to the sites of inflammation.molecule.

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