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elastin . cross-linking glycation . Ainadori

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. lysyl Maillard

IT HAS BEEN RECOGNIZED for more than 40 years that collagen fibrils and elastin are stabilized by covalent cross-links (1-8), information regarding specific locations and chemical structures has evolved only recently Our goal is to extend and complement previous reviews that have emphasized structural, analytical, and pathophysiological aspects of collagen and elastin cross-linking. Both enzymatic (1-4) and nonenzymatic (5) processes that contribute to collagen and elastin cross-linking are addressed. An understanding of collagen and elastin cross-linking is important in many disciplines, as a stabilized extracellular matrix is essential for all animal forms higher than protozoans. Indeed, development beyond gastrulation appears to require the deposition of cross-linked collagen (6). Given this key role, it is not surprising that abnormalities of collagen and elastin cross-linking may affect virtually every tissue and organ in the body. Reported abnormalities range from hypertrophic scar formation and fibrosis to heritable diseases, such as Menke’s disease, cutis laxis, or forms of EhlersDanlos syndrome (7). Endocrine, pharmacological, and nutritional factors also influence extracellular matrix cross-

ALTHOUGH

AND ROBERT

...

..

.

.,

R RUCKERt,’

ent of Nutrition, Univemty of California, Davis, of Wyoming, Lararnie, Wyoming 82070, USA

Science,

ABSTRACT Knowledge regarding the steps and mechanisms related to the intraand interchain crosslinking of collagen and elastin has evolved steadily during the past 30 years. Recently, effort has been directed at identifying the location and types of cross-links that are found in collagen and elastin. There are two major groups of cross-links: those initiated by the enzyme lysyl oxidase and those derived from nonenzymatically glycated lysine and hydroxylysine residues. The formation of enzymatic cross-links depends on specific enzymes, amino acid sequences, and quaternary structural arrangements. The cross-links that are derived nonenzymatically occur more adventitiously and are important to pathobiological processes. Considerable progress has been made in elucidating the pathways of synthesis for several of the enzymatically mediated cross-links, as well as possible mechanisms regulating the specificity of cross-linking. Although less is known about the chemistry of cross-links arising from nonenzymatically glycated residues, recent progress has also been made in understanding possible biosynthetic pathways and control mechanisms. This review focuses on such progress and hopes to underscore the biological importance of collagen and elastin crosslinking.Reiser, K.; McCormick, R. J.; Rucker, R. B. Enzymatic and nonenzymatic cross-linking of collagen and elastin. FASEBJ. 6: 2439-2449; 1992. Key Words: collagen oxidase ‘ glycosylation products

-..

California,

USA;

linking and maturation (8). The controlling steps, however, remain intriguing as well as elusive. We have divided this review into six sections: the crosslinking of fibrillar collagens (types I-Ill), the cross-linking of basement membrane and the so-called minor collagens (types IV-XIV), the tissue distribution of collagen crosslinks, elastin cross-linking, lysyl oxidase, and nonenzymatic cross-linking via glycated products. Although we have chosen to emphasize the biochemical features of collagen and elastin cross-linking, an additional aim is to underscore the relevance of collagen and elastin cross-linking to normal development and pathobiological relationships.

ENZYMATICALLY TYPES I, II, AND

MEDIATED CROSS-LINKS III COLLAGENS

IN

Type I, II, and III collagens, the fibrillar collagens, are characterized by an uninterrupted helical region with alternating polar and nonpolar domains. This arrangement allows head-to-tail, lateral alignment of molecules in a quarter staggered array, an absolute requirement for lysine-derived cross-linking in the fibrillar collagens. Once the fibrils are aligned, lysine- or hydroxylysine-derived aldehyde functions (allysine or hydroxyallysine) then react with corresponding aldehydes on adjacent polypeptide chains to form aldol condensation products (ACP),2 or with unmodified lysine and hydroxylysine residues to form difunctional cross-links such as dehydrolysinonorleucine (-LNL), dehydrohydroxylysinonorleucine (-HLNL), or dehydrodihydroxylysinonorleucine (-DHLNL) (Fig. 1 and Fig. 2). Further, ACP can react with histidine to form aldol histidine, which in turn may react with another lysyl residue to form the tetrafunctional cross-link histidinohydroxymerodesmosine (HHMD). These cross-links are often referred to as reducible cross-links, as they contain Schiff base double bonds that may be reductively labeled with agents such as sodium borotritiide. The reducible cross-links vary in their stability; for example, &DHLNL may undergo an Amadori rearrangement to form a more stable ketoamine derivative (4). -HLNL and -DHLNL also undergo further reactions to

form

nonreducible

trifunctional

compounds.

Mechanic

‘To whom correspondence of Nutrition,

should be addressed, at: Department of California, Davis, California 95616, USA. ACP, aldol condensation products; -LNL, de-HLNL, dehydrohydroxylysinonorleucine;

University

2Abbreviations: hydrolysinonorleucine;

-DHLNL, dehydrodihydroxylysinonorleucine; HHMD, histidinohydroxymerodesmosine; OHP, hydroxypyridinium; LP, lysylpyridinium; BAPN, j3-aminopropionitrile; TOPA, trihydroxy(oxo)phenylalanine; CB, cyanogen bromide peptide.

na-.c.snJo,Irr,ssain1 en E Library (163.15.154.53) on August 13, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber() 2439 m www.fasebj.org by Kaohsiung Medical University

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and colleagues have shown that i-HLNL may histidine to form the nonreducible trifunctional

of selected

lysine-derived

react with cross-link, His-HLNL or HHLNL (9-12). -DHLNL may react with hydroxylysine to form hydroxypyridinium (OHP). Two minor analogs of OHP (referred to as pyridinoline by some investigators) have also been reported, lysylpyridinium (LP), a fluorescent cross-link derived from two residues of hydroxylysine and one residue of lysine (13), and a so-called pyridinium analog found in skin (14). Details of the chemical structures and reaction pathways of these cross-links have been described by Yamauchi and Mechanic (12). Many of these cross-links are also glycosylated.3 The glycosyl moieties, most often glucosyl or glucosylgalactosyl residues, are 0-linked enzymatically to hydroxylysyl functions. Such 0linked glycosylation reactions are distinct from nonen?44fl

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and

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zymatic glycation in which sugars usually condense with the c-amino group of either lysine or hydroxylysine (5). The location of the residues involved in cross-linking has been the subject of intensive investigations. There is now a consensus concerning several of the sites for difunctional cross-links in type I collagen (Fig. 3). One site involves a

3There is not yet a consensus concerning terminology describing the addition of sugars to proteins. For example, the nonenzymatic addition of sugars to protein amino groups has been referred to as nonenzymatic “glycosylation,” “glucosylation,” and “glycation.” In this review, the term “glycation” will be used for nonenzymatic processes and “glycosylation” for the enzymatic addition of sugars (90).

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REISER FT AL

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With

respect

to the trifunctional

cross-links,

Yamauchi

et

al.(11)found that the locus of His-HLNL was ai(I)16C X ai(I)-Hyl-87X a2-His-92. Two sites have been described for hydroxypyridinium. One is at ai(I)16C X ai(I)-16C X a1(I)-87 (or a2-87). The other location, occurring less frequently, has been identified as a,(I)9N X a19N X a1(I)-930 (12, 16).

ENZYMATICALLY TYPES IV-XIV

Figure 2. Reactions of peptidyl lysine and hydroxylysine in the biosynthesis of cross-links in collagen and elastin. After oxidative deamination to form reactive aldehydes (Fig. 1), subsequent condensation reactions result in various di-, tn-, and tetrafunctional cross-links. The numbers of residues involved in each cross-link are indiated by arrows at the top of the box. Cross-links common to both collagen and elastin are shown in black boxes; cross-links specific to elastin are indicated by the stippled boxes; cross-links specific to collagen are indicated by the open boxes. As the reactive aldehydes are assayed after chemical reduction, they are designated in the figure as either HNL (hydroxylysine) or DHNL (dihydroxynorleucine). The other abbreviations and designations are: ACP, aldol condensation products; LNL, lysinonorleucine or dehydrolysinonorleucine; DHLNL, dihydroxylysinononleucine or dihydroxydehydrolysinonorleucine; h-ACP, histidine-aldol condensation product; h-HMD, histidinohydroxymerodesmosine; h-HLNL, histidinohydroxylysinonorleucine; OHP, hydroxypyridinium; LP, lysylpyridinium; and PA, pyridinium analog.

cross-link between the hydroxylysine at position 930 (in the CNBr peptide CB6) and lysine (or hydroxylysine) aldehyde present in the short, nonhelical region of the collagen molecule at the NH2 terminus. Conventionally, residues in either the COOH-terminal or NH2-terminal extension region are numbered independently of residues in the helical region, and are identified by the superscript N or C. Thus, the lysine aldehyde in the NH2-terminal extension is referred to as Lys 9N, or more completely as ai(I)_Lysk9N. A cross-link involving this NH2-terminal aldehyde and Lys 930 links two a1(I) chains, and might be described as having the locus aj9N X a,-930. An analogous cross-link site linking a2 chains has also been described (15) in which a29N is cross-linked at locus a2-930. Further, a cross-link site between a2N5 and a2927 has been described (10, 15). Other sites consist of the COOH-terminal nonhelical lysine (or hydroxylysine) aldehyde l7 (or l6, depending on the collagen source) and the lysine (or hydroxylysine) at position 86 (or 87) in the CNBr peptide a1(I) CB5 (10-12). Cross-linking at any of these sites presupposes a 4D stagger configuration (16). Similar cross-linking sites have been described in type III collagen from fetal calf skin: Hyl-930 X Lys8N and Hyl-75 X Lys20C (17, 18). A cross-linking site between two helical regions has also been identified that dictates a 3D stagger between molecules, i.e., Hyl-219 on a2CB4 is crosslinked to either Hyl-915 or Hyl-927 on a,CB6 (12).

MEDIATED COLLAGENS

CROSS-LINKS

IN

Collagen types IV through type XIV, frequently designated minor collagens, occur in tissues in relatively small quantities. Classification schemes for collagen types IV-XIV are based on their degree of structural similarity to types I-Ill. Types V and XI have been grouped with the fiber-forming collagens because they possess an uninterrupted helical domain of about 300 nm and can form fibrillar structures. The other collagens form a second group, as a primary structure that permits lateral association, and as a consequence subsequent 4D-staggered fibril conformation, is apparently absent (19). These collagens possess helical domains interrupted by nonhelical regions. Regions of molecular overlap and stabilization by a covalent cross-linking process have been demonstrated or can be predicted in each collagen type. Type

IV collagen

Type

IV

collagen,

basement

membrane

collagen,

forms

a

collagenous scaffold that together with associated glycoproteins and proteoglycans comprises the basement membrane of vertebrates and most invertebrates (20-23). Type IV collagen occurs uniquely in basement membranes

where it forms an open lattice, nonfibrous structure (Fig. 4). Type IV molecules are trimers (400 nm long) composed of two different polypeptides ai(IV) and a2(IV). Formation of an open network rather than a fibrous structure is dictated by the association of the COOH-terminal domain of two molecules (6 a chains) producing a globular hexameric structure and the parallel and antiparallel lateral alignment of four molecules (12 a chains) in the NH2-terminal region (7S domain) (21). Extensive disulfide and lysine-derived cross-linking in the 7S domain has been demonstrated, which can result in an elevated melting temperature and marked resistance to proteolysis relative to fibrillar collagens. Many lysine residues in type IV are hydroxylated and glycosylated (22, 23). The predominant reducible cross-link is -DHLNL (24-2 7). Both ai(IV) and a2(IV) have similar functional regions within the 7S cross-linking domain, including triple helical and nontriple helical segments at the NH2-terminus containing lysine residues, glycosylated hydroxylysine residues, and abundant cysteine residues, all with the potential to form intermolecular covalent crosslinks. For example, a putative lysine-derived cross-link between lysine (position 14) in nonhelical segments and hydroxylysine (position 105) in helical segments has been described, which would allow a 110 residue overlap in the 7S domain for two ai(IV) molecules in antiparallel alignment (24-27). Cysteine residues at positions 17 and 101 in the nontriple helical and helical segments, respectively, also allow disulfide bridge formation (25). The covalent association of COOH-terminus regions of two type IV molecules is by disulfide bond formation (24-27). The COOH-terminal domain also contains a nonreducible, covalent cross-link; however, its structure is unknown (28). Cross-linking in type IV collagen differs from that in the fibrillar collagens in several respects. For example, the highly

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or 927

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Figure 3. Cross-linking loci in type I collagen. Two major cross-link sites are known to link fibnils that are overlapped in a 4D stagger configuration. These sites involve a cross-link between residues on either the nonhelical COOH-terminal or NH2-terminal extension and residues in the helical region of either al(I) or a2 chains. A third cross-link site has been identified in which fibnils overlap in a 3D stagger configuration. Cross-links are indicated by dotted tines and the number of the residue participating in the cross-link is shown above or below the cross-linked chain. Structural features of the type I tropocollagen molecule are shown schematically. The cs2 chains are indicated by a heavy black line; location of methionine residues is indicated by short vertical lines; and the numbers above both the cr(I) and cs2 chains at the bottom of the figure indicate the CNBr peptide number. The nonhelical COOH-terminal and NH2-terminal extensions are indicated by jagged lines. References for each of the loci indicated are given in the text.

conserved sequence Gly-X-Hyl-Gly-His-Arg, which contains the triple helical region cross-linking loci for all the fibrilforming collagens, is absent from type IV collagen (23). The putative cross-linking site in the triple helical region of the 7S domain occurs in the sequence Gly-Cys-Arg-Gly-Thr-HylGly-Glu-Arg. This sequence also contains a potential disulfide cross-linking site. In a2(IV) chains the hydroxylysine residue at position 105 is replaced by glutamic acid, which precludes intermolecular cross-linking at this site (27). However, the exact nature of the mature cross-links derived from -DHLNL and -HLNL in the 7S domain remains to be elucidated (1, 2, 24). Neither OHP nor His-HLNL, the maturation products of -DHLNL and -HLNL, respectively, have been described in basement membrane collagen. Types

V and

XI collagens

In contrast to type IV collagen, both type V collagen and type XI collagen, which are found in cartilage, have a fibrillar structure (29-34). Moreover, the cross-links arising from hydroxylysine aldehydes, &DHLNL and OHP, have been demonstrated in types V and XI collagen. The highly conserved triple helical cross-link sites present at positions 87 and 930 in tri(I), a,(II) and a,(III) are located at position 87 in a,(V) (29) and at position 930 in a2(V) (30). The location of other sites remains obscure.

collagenous regions of a,(VI) and a2(VI) chains contain highly hydroxylated and glycosylated lysine residues and abundant cysteine residues, but lack the conserved Gly-XHyl-Gly-His-Arg cross-linking sequence of fibrillar collagens (34-37). Thermal stability and resistance to proteolysis of type VI oligomeric structures are conferred by disulfide bonds.

Type

VI collagen

Type VI collagen is unique among the matrix-associated collagens in that it apparently possesses no lysine aldehydederived cross-linking residues (35-37). Amino acid and DNA-derived amino acid sequence data indicate that the

2442

Vol. 6

Anril

1992

collagen

The presence of lysine aldehyde-derived cross-links in type VII collagen also has not been demonstrated by direct analysis. Type VII collagen is the major component of anchoring fibrils associated with the basal lamina and exists as antiparallel dimers. A 60 nm triple helical overlap region at the NH2-terminus is linked to a large COOH-terminal globular domain. The dimers aggregate laterally to form fibrils (Fig. 4). Although cross-links are present, it appears that type VII collagen is not extensively cross-linked by nonreducible, covalent bonds. Type VII collagen has been sequenced at the gene level (38). Like many of the other minor collagens, the lack of chemical data at the protein level is due in part to codistribution of these collagens in relatively small quantities with more abundant fibril-forming collagens and difficulties involved in quantitative extraction. Type

Type

VII

VIII

collagen

A major component of Descement’s membrane is type VIII collagen, which consists of a short, 454-residue collagenous triple helical region flanked by noncollagenous domains at the NH2-terminus and COOH-terminus (39-41). Type VIII collagen is structurally similar to type X collagen with

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link to type II collagen molecules via reducible and nonreducible lysine aldehyde-derived cross-links. The cross-linking sites for a1(IX) and a2(IX) chains have been identified as hydroxylysines (at positions 15 and 3, respectively) at the amino termini of the COL 2 domain near the NC3 domain. The exact position of the cross-link formed at these sites, identified as either -DHLNL or OHP on the a3(IX) chain in the COL 2 domain, however, has not been identified.

8

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Figure 4. Diagrams depicting the association of collagen chains for types IV, VII, VIII, IX, and XII collagen. For type IV collagen the lattice structure is formed by the antiparallel association of the NH2-terminal of two pairs of type IV collagen molecules in the socalled 7S domain and the end-to-end interaction of two COOHterminal non-collagen-like domains (NC). Cross-linking sites occur within the 7S domain of type IV collagen between the antiparallel al(IV) chains. It should be appreciated, however, that the schematic for type IV collagen is overly simplified and does not reflect the 20 or more interruptions of the ci, -helix. For type VII collagen, the aggregation is antiparallel to form fibrils from the overlap of molecules at the NH2-terminal regions of respective chains. Covalent crosslinking sites arise in the triple helical regions (redrawn from ref 51). For type VIII collagen, less is known about the organization of aggregates. However, it is known that the molecule is flanked by non-collagenous domains (NC) at the NH2and COOH-terminal domains of the molecule. Arrows () represent interruptions in Gly-X-Y-repeats; putative covalent crosslinking sites are located in the region designated COL 1. The type IX collagen molecule also contains three triple helical regions interrupted by non-collagen-like domains. In type IX collagen, lysinederived cross-links form adjacent to NC in the COL 2 domain. Finally, a type XII molecule is depicted, based on nucleotide sequence and rotary shadowing image (56). Triple helical domains are interrupted by non-collagen-like domains. homologous genes encoding the a1 polypeptide chains for both collagens (39-41). They are often designated the shortchain collagen family (Fig. 4). Recently an a2(VIII) collagen has been characterized (39), which like a1(VIII) and X collagens, has a triple helical domain. In type VIII and IX collagens, the a-chains of the triple helical region are stabilized by strong noncovalent interactions and acid-stable covalent cross-links that are 13-aminopropionitrile (BAPN) insensitive (41). BAPN is a well-characterized inhibitor of enzymatically catalyzed lysine-derived cross-link formation (1, 8), and because disulfide bonds are not present the deposition of large (>50%) amounts of acid-insoluble type VIII collagen in the presence of BAPN suggests the possibility of novel crosslinks. Type

IX collagen

Type IX collagen occurs in cartilage in association with type II and type XI collagen (42, 43). Type IX collagen consists of three collagenous domains separated by noncollagenous regions and with noncollagenous domains at the NH2 and COOH terminals (Fig. 4). In cartilage fibrils, all three a chains in the COL 2 domain of type IX collagen can cross-

X-XIV

collagen

Likewise, little is known about the location of cross-links in types X, XII, XIII, or XIV collagen. Type X collagen occurs in hypertrophic cartilage. It has been demonstrated recently that extractability of type X collagen from chick embryo cartilage is increased after treatment with BAPN (44), suggesting the presence of lysyl oxidase-mediated cross-linking. Although no direct evidence of cross-linkages in types XII, XIII, or XIV collagen is available (45-48), it is noteworthy that the COL 1 domain of type XII collagen is similar to COL 1 domain of type IX collagen (46) (Fig. 4). For example, type XII collagen could interact with the surface of type I collagen fibrils via its collagenous triple helical domain in a manner similar to type IX and type II collagen interactions.

THE DISTRIBUTION SELECTED TISSUES

OF

CROSS-LINKS

IN

The prevalence and distribution of specific lysine aldehydederived cross-links appear to be dependent primarily on tissue source and its physiological function rather than on the genetic type of collagen. Cartilage (predominantly type II collagen), bone (mostly type I collagen), and skeletal muscle and myocardium collagen (primarily mixtures of types I and III collagen) have common reducible (-HLNL, .-DHLNL) and nonreducible (OHP) cross-links that share the same molecular loci. Mineralized connective tissues such as bone also contain the OHP analog LP in small amounts (3). Skin collagen, composed of predominantly types I and III collagen, possesses an additional reducible cross-link, the tetrafunctional cross-link HHMD, as well as the nonreducible cross-link His-HLNL, but OHP is not detectable in normal skin (12). Although cross-link location appears to be remarkably constant among different tissue sources and even different species, considerable variability has been observed in other aspects. Further, the mechanisms regulating characteristics such as the total numbers of cross-links, predominant crosslinks, and relative proportions of di-, tn-, and tetrafunctional cross-links are poorly understood. Lysyl oxidase may play a role in regulating the total number of cross-links. However, it seems unlikely that this enzyme modulates the tissue and species specificity of cross-linking by itself. It is as likely that factors such as the steric relationship between molecules, fibrillar heterotype, and other posttranslational modifications such as glycation and hydroxylation play important roles. For example, Yamauchi et al. (12) have shown that enzymatic glycation of the hydroxyl moiety of a key hydroxylysine residue in bone collagen determines the nature of the cross-link at that locus. Nonenzymatic glycation may also affect lysyl oxidase-mediated cross-linking (5). Possible mechanisms include the known effects of nonenzymatic glycation on ligand binding and collagen conformation (5, 49-52).

There is considerable evidence that levels of lysine ylation may affect patterns of collagen cross-linking.

hydroxFor ex-

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to OHP in type IX collagen that is dependent on whether ample, Henkel et al. (16) have provided evidence that the exthe C or N telepeptide site of type II collagen participates in tent of hydroxylation of the telopeptide lysine residues may cross-link formation (42, 43). regulate the relative proportion of the tnifunctional cross-link In a somewhat analogous fashion, bone contains a mixOHP to its difunctional precursor -DHLNL. Recent data ture of types I and V collagen with similar concentrations concerning cross-linking changes in experimental pulmoand ratios of reducible (-HLNL, -DHLNL) and nonredunary fibrosis (53) also suggest that the relative amounts oftcible cross-links present in both collagen types. Cross-linking DHLNL to -HLNL might be regulated in part by changes also occurs between types I and V collagen in bone (29). in lysyl hydroxylation via lysyl hydroxylase. In conditions Skin, lung, and intramuscular connective tissues from skelewhere under-hydroxylation of lysine occurs, such as in tal and cardiac muscle are composed primarily of types I and Ehlers-Danlos syndrome type VI, decreased OHP and inIII collagen. Immunofluorescence studies suggest that type I creased LP levels occur (2). and type III collagens coexist in the same fibril (59-61). EviControl of lysine hydroxylation clearly is complex, and dence for covalent cross-linking between types I and III there is far more variability in levels of lysine hydroxylation molecules from human leiomyoma and calf aorta has also among the various collagen types and among different tisbeen reported (18). sues than there is in levels of proline hydroxylation. Although it has been suggested that there are collagen typeIn most species, collagen cross-linking patterns within a given tissue may also change over time. During normal agspecific lysyl hydroxylases, the data of Puistola (54) provide evidence that such isoenzymes do not exist. A more likely exing, the initial divalent, reducible cross-links -DHLNL and planation for hydroxylysine variability may be differences in -HLNL may be partially replaced in many tissues in a precursor-product manner with the nonreducible cross-links the levels of lysyl hydroxylase activity in different cells (55). Other factors that may influence hydroxylation of lysine inOHP, LP, and His-HLNL (61). For example, in human bone clude variability in concentrations of substrate and cofactors samples, Eyre et al. (62) have reported that concentrations in different cells and variability in the time that the substrate of -DHLNL and -HLNL decreased about fivefold between 1 month and 80 years of age whereas OHP and LP increased is exposed to active enzymes during processing. Further from birth until 25 years of age, and thereafter remained hydroxylation of collagen chains and isolated peptides can be nearly constant throughout the remainder of adult life. The increased by incubation with purified lysyl hydroxylase in ratio of-DHLNL:&HLNL also decreases with age. In carvitro. However, further hydroxylation of prolyl and lysyl residues is retarded as newly synthesized chains assume a tilage, -DHLNL was replaced completely with OHP by helical conformation within the cell (55, 56). Thus, differ10-15 years of age whereas some reducible cross-links were present in bone throughout adult life (62). In the rodent ences among tissues in several aspects of processing may well affect hydroxylysine content. Of particular interest in terms lung, OHP concentration increased about sixfold between 6 and 22 wk of age and -DHLNL decreased proportionately as of potential effects on cross-linking are studies by Royce and Barnes (57) suggesting that hydroxylation of the telopeptide the reducible cross-link matured to the nonreducible form regions of collagen may be subject to independent biological (63). A similar increase with chronological age in OHP concontrol, as the degree of hydroxylation at this site appears to tent was described in collagen extracted from skeletal musbe unrelated to the overall state of lysine hydroxylation of the cles of goats and cattle (64). In bovine and human skin collagen the nonreducible cross-link His-HLNL increased with collagen chain. age throughout life (12). In vitro incubation studies with boThe steric relationship between collagen molecules may vine skin collagen demonstrated a 1:1 stoichiometric relaalso affect cross-linking patterns. For example, the collagen molecules of skin are tilted 16#{176} from the longitudinal axis of tionship between the disappearance of-HLNL and the formation of His-HLNL over a 24-wk period (11). In contrast, the fibnil whereas skeletal collagen molecules have only a 7#{176} rat and mouse skin contains no detectable His-HLNL and tilt relative to the fibril axis (9). This results in the characteristic 65 nm periodicity for skin collagen fibnils rather than the HLNL content does not appear to change in the skin of 67 nm for the skeletal collagens (12). It also places the histithe mouse throughout its life span (63). dine at position 92 in the at(I) chain such that potential reactions with Hyl (position 87) and Lys (position l6C) residues ELASTIN CROSS-LINKING in the a1(I) chain can occur. As noted previously, this results in the formation of the trifunctional cross-link His-HLNL, Elastin is a rubber-like protein that is highly cross-linked and in which two residues from helical regions are cross-linked to ischaracterized by a high content of hydrophobic amino acid a residue from a nonhelical region (9). In contrast, the sequences. The deposition of elastin is regulated to coincide trifunctional OHP of skeletal tissue collagens links two with specific periods important to the development of tissues telopeptide sites (Lys16C or Hyl-16’) on two molecules to a wherein compliance is essential. Once elastic fibers are fully helical site (Hyl-87) on a third molecule (9, 12). mature, they function for exceedingly long periods (8). Because most tissues contain more than one collagen type, With respect to cross-linking, alternative splicing of the amounts of heterotypic fibnils may also influence patterns elastin-specific mRNA exons represents an interesting of cross-linking. As noted previously, the covalent interacstrategy for modification of both distribution and amounts of tions between collagens composed of heterotypic fibrils is a cross-linking amino acids in elastin (65). It has been obfeature of cartilage collagens; collagen types II, IX, and XI served that in elastin all exons are multiples of three nucleoin cartilage appear stabilized by lysine aldehyde-derived tides and that the exon-intron borders appear to be consiscross-links. Within a given cartilage sample, however, the tently split in the same way. Cassette-like alternative splicing proportions of reducible and nonreducible cross-links vary can occur, which often involves exons that encode the crosswith collagen-type and cross-link location within an a-chain. linking segments in elastin. These polypeptide segments For example, type XI cartilage collagen contains mostly iarising from such exons are rich in alanyl and lysyl residues DHLNL, suggesting that maturation of the reducible crossand are interspersed among hydrophobic segments. Analolink to OHP is impeded by fibnil formation (58). There is gous to collagen, all of the other known cross-linking amino also a differential response to reducible cross-link maturation acids are derived from lysine except for indirect evidence

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that the elastic precursor, tropoelastin, is first anchored to microfibrillar components by cysteine-denived cross-links. The degree of cross-linking, however, is much more extensive than that found in most collagens (1). Nevertheless, there remain many perplexing problems related to changes in the distribution and apparent regulation of elastin cross-link formation as well as the mechanism for oxidation and reduction steps involved in cross-link formation. First, the elastic fiber, unlike fibrous collagen, consists of two distinctly different components (66). The major component is elastin and the second component, the elastic fiber microfibril, appears to be composed of a number of proteins, e.g., fibrillin (67) and so-called microfibrillarassociated proteins (66). The microfibrils are readily observed in new fibers and are thought to determine the eventual form taken by the elastic fiber. Of recent interest, defects in fibrillin appear to be associated with the expression of Marfan’s snydrome (67). At least one protein has also been identified that is involved in delivery of elastin to the microfibrils for elastic fiber assembly (68). It is not clear, however, exactly how the microfibrillar components interact and are involved in cross-link formation. Moreover, features of the process are elusive because of the difficulty of assessing how cross-linking is influenced by the alternative splicing of elastin mRNA. Deletion of given exons should result in altered alignment of elastin chains, perhaps a novel strategy for creating randomly cross-linked hydrophobic chains in keeping with an entropic rubber. Alternative splicing may also provide a way of changing the orientation of tropoelastin polypeptide chains to effect new branch points. The pathways for cross-link formation in elastin are also elusive. As in collagens, two molecules of allysine can form ACP; one molecule of allysine can form an imine by condensation with lysine, e.g., -LNL. Successive addition to merodesmosine and cyclization to dihydrodesmosine represents one possible pathway for eventual desmosine formation (Fig. 1 and Fig. 2). Alternatively, direct condensation of a dehydrated ACP with dehydrolysinonorleucine could result in desmosine. Moreover, whether the final product is desmosine or isodesmosine depends on the orientation of the lysine that contributes to the pyridinium nitrogen. An aromatic amino acid next to lysine appears to prevent the oxidation of lysine to allysine and may direct this orientation (1). The mechanism of specific internal oxidation and reduction steps have also been of concern. Raju and Anwar (69) have observed that LNL is often found directly adjacent to (iso)desmosine residues. They suggest that the formation of ..“

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LNL from -LNL may be the driving force for dehydrodesmosine oxidation to desmosine (Fig. 5). Indeed, an incredible amount of structural information appears to be built into elastin to facilitate desmosine formation or the formation of related cross-links such as pentosine, an unusual pentafunctional cross-link (70). There is also limited information on the distribution of cross-linking amino acids in elastin. Changes in desmosine during the rapid synthesis and degradation of elastin in the uterus have been reported by Gunja-Smith et al. (71). Desmosine in the rat uterus varies from 1.4 mol per mole of elastin (at day 12-15) to 0.9 mol per mole of elastin at term. Uterine elastin desmosine synthesis does not keep pace with net elastin deposition. Changes in the ratio of isodesmosine to desmosine during neonatal lung development have also been reported (72). The extent to which alternative splicing contributes to this phenomenon is not clear.

LYSYL OXIDASE AND SELECTED OF LYSYL OXIDASE INHIBITION

CONSEQUENCES

Lysyl oxidase (E.D. 1.4.3.13) has now been isolated from human, pig, avian, rodent, and bovine sources (73-76). Lysyl oxidase functions extracellularly and may be an example of a copper-containing quinoprotein with peptidyl tnhydroxy(oxo)phenylalanine (TOPA), i.e., 6-hydroxydopa, at its active site (77). The oxidative deamination of primary amine substrates by lysyl oxidase occurs by a-proton abstraction and carbanion formation. The enzyme apparently follows a ping pong biter kinetic course; a histidine at the active site is most probably involved in the initial proton abstraction and copper at the active site may facilitate the transfer of electrons to oxygen (76). The enzyme is often isolated as isoforms with molecular weights near 32,000 (76). Trackman et al. (75) have recently characterized a lysyl oxidase eDNA from a X gtll eDNA library prepared from embryonic rat aorta. The lysyl oxidase eDNA recognizes a 4.5 and 5.8 kbase mRNA, which encodes initially a 46- to 48-kDa product. This putative proform of the enzyme appears to be processed further to a short-lived 40-kDa species that is processed ultimately to the 32-kDa form of lysyl oxidase (74). With respect to regulation, the functional activity of lysyl oxidase is influenced by hormones, factors that influence substrate conformation, and by environmental and nutritional factors (8, 76). The enzyme has the highest affinity for collagens precipitated in the form of native fibrils or coacer-

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I ACkI AkIn El Medical ACTIkI ,-or\cc I IkivE IA A E m www.fasebj.org by Kaohsiung University Library (163.15.154.53) on August 13, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber()

vated elastin. However, simple alkyl amines or lysine-rich proteins or peptides, e.g., histone and lysine vasopressin, may serve as substrates in vitro. Environmental factors and agents that elicit fibrotic responses, e.g., ozone or cadmium, are associated with increased lysyl oxidase activity. Moreover, functional activity can vary as much as 10-fold in response to varying dietary copper (8). Lysyl oxidase is inhibited by vicinal diamines, hepanin, short-chained aminonitrites and semicarbazides, hydrazines, and some alkylating agents, presumably by interacting with the quinone at the catalytic active center of lysyl oxidase (76, 77). The most characteristic of these compounds are /3-aminopropionitrile, semicarbazide, and isoniazid (8, 76). There is still much to learn, however, concerning the relationship between lysyl oxidase expression and regulation of cross-link formation. For example, Romero et al. (74) have recently shown that lysyl oxidase is normally not the ratelimiting step for cross-link formation in some tissues, e.g., skin. The argument is based on estimates that lysyl oxidase carries out 400 catalytic cycles per mole of enzyme before it is inactivated, and that mammalian skin and arteries contain 3-6 nmol of functional lysyl oxidase per gram of tissue. It is possible to conclude that in skin and aorta there are relatively high concentrations of enzyme with the ability to generate at any given time 1.2-2.4 mol of peptidyl allysine in collagen or elastin per gram of tissue. This amount is more than sufficient for the daily deposition of new elastin and collagen.Also, the enzyme may become immobilized as it becomes a part of the matrix (76). Such phenomena would also complicate the interpretation of changes in enzyme based solely on values from functional assays. Nevertheless, a marked inhibition of lysyl oxidase at critical stages in the developmental expression of connective tissue proteins can have dynamic and important effects. The resistance of both collagen and elastin to nonspecific proteolysis is highly dependent on normal cross-linking. When lysyl oxidase is inhibited at critical stages in development, the effects are often long-lasting. An excellent example is the permanent dilation of terminal airways that occurs when a lysyl oxidase inhibitor is administered during the alveolarization phase of lung development (78). Under certain conditions inhibition of lysyl oxidase might prove beneficial, e.g., the possible modulation of excessive collagen deposition by lysyl oxidase inhibitors in response to fibrotic agents. NONENZYMATIC

CROSS-LINKS

lions in mechanical strength, solubility, ligand binding, and conformation. Such changes are believed to be responsible for the observed association between the accumulation of browning products and the development of diabetic complications (5). Clearly, a better understanding of the specific reactions involved in glycation of collagen is critical to developing more effective strategies for modulating such reactions. Glycation reactions may be divided into three groups (5), shown schematically in Fig. 6. The first group, the “early Maillard reactions,” include the formation of a Schiff base (between the c-amino function of lysine or hydroxylysine and a reducing sugar) and its rearrangement into more stable Amadori products. The “intermediate reactions” include the degradation and dehydration of Amadori products to form reactive compounds that may serve as the propagators of other nonenzymatic glycation reactions.The advanced reactions involve the reaction of the intermediate products with amino groups to form fluorescent, pigmented cross-links. Advanced Maillard products may also undergo extensive polymerization reactions in vitro, yielding deeply colored compounds referred to as melanoidins. These reactions, however, are unlikely to occur in vivo (79). The firststep in the Maillard reaction in collagen involves condensation of a sugar aldehyde or ketone with the c-amino function of eitherlysineor hydroxylysine. Evidence indicates that other sugars in addition to glucose may participatein nonenzymatic glycation in vivo. Both fructose and pentose react far more rapidly with collagen in vitro to form Maillard products than does glucose. There is also evidence that fructation of collagen occurs in vivo (5). Sell and Monnier (80) recently elucidated the structure of a Maillard product derived from pentose, which they named pentosidine (not to be confused with pentosine discussed under elastin).They suggest that the most likelyprecursor in this reaction is ribose or one of its metabolites,such as might arisefrom ADPnibosylationreactions.For most proteins,including collagen, there appears to be a glycation limitof 2 mol of glucose per mole of protein even when the proteins are incubated with sugar in vitro for extended periods of time. Within this glycation limit,the extent of glycation may vary considerably among differentcollagen types and among different tissues.

EARLY MAILLARD PRODUCTS

Sugar Aldehydesand Ketones Ascorbic Acid

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Although the biosynthesis of sugar-derived cross-links is less well understood than that of the lysyl oxidase-initiated crosslinks (5, 6), recent data have emphasized the importance of such cross-links in connective tissue pathophysiology in both aging and diabetes. Nonenzymatic glycation of fibrillar collagens as well as of basement membrane collagens is increased in diabetes (5). Advanced Maillard products, which are derived from glycated lysine and hydroxylysine residues, are known to be increased in diabetic subjects relative to agematched controls. During normal aging, browning products have also been observed to increase in collagen in virtually all tissues studied. There is considerable evidence that these changes in nonenzymatic glycation of collagen in both aging and diabetes are directly associated with alterations in the physicochemical properties of collagen (5). For example, changes in early glycation products (glycated lysine and hydroxylysine residues) may affect conformation, ligand binding, enzymatic cross-linking, and interactions between collagen and other macromolecules, whereas the accumulation of browning products in collagen is associated with altera7.o.4c

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Variables known to affect glycation include pH, temperature, protein and glucose concentrations, and duration of exposure to glucose (5, 81). Because pH and temperature are closely regulated in vivo, it has been suggested that degree and duration of hyperglycemia are the most important variables governing glycation levels. However, other factors may also play a role in regulating the addition of sugars to the collagen chain. Recently, Wolff and co-workers (82, 83) have suggested that glucose oxidation may modulate nonenzymatic glycation. They provided evidence that, through sequential reduction of a transition metal and molecular oxygen, glucose auto-oxidizes to a highly reactive dicarbonyl compound that can bind to proteins. Their data suggest that there are two pathways by which proteins bind to glucose: the metal-catalyzed pathways that involve generation of ketoaldehydes through auto-oxidation, and the metalindependent pathway that involves the formation of Schiff base adducts followed by enolization to Amadori products. Their data also suggest that browning products may form from the ketoimine generated from the metal-catalyzed pathway. Whether such reaction pathways are similar to those followed by the Amadoni products remains to be elucidated. In addition to its contribution to formation of glucoseprotein adducts, glucose auto-oxidation also generates peroxides and free radicals that may in themselves alter protein conformation, thus contributing to the change in properties associated with nonenzymatic glycation (83). It has also been suggested that rates of glycation of proteins may be influenced by the location of glycation sites (5). Although specificity of glycation sites has been documented in several proteins such as albumin, hemoglobulin, low density lipoprotein, fibrin, and RNAse (6), collagen glycation sites have not been studied in detail. We have recently reported evidence for preferential glycation sites on a cyanogen bromide peptide (CB3) from type I collagen, both in vivo and in vitro (49, 84). Our studies suggest that suprastructural effects may influence site specificity, perhaps by affecting availability of certain residues. Baynes et al. (85) have recently reviewed possible mechanisms responsible for site specificity of glycation. In general, lysine reactivity with glucose is increased when pK values for the c-amino group of the lysine side chain are relatively decreased. Proximity to carboxylic acid residues or certain binding sites (such as for phosphate ion or organic phosphates) may also favor glycation (5). After the sugar molecule has reacted with the amino group to form a Schiff base, it may undergo an Amadori rearrangement to form a more stable product. This reaction may be catalyzed by neighboring carboxylic acid residues and histidine or arginine residues (85). Although the kinetics of the equilibrium between aldimines (Schiff base) and ketoimines (Amadori rearrangement product) have been studied extensively in hemoglobin (86), such kinetic data are not available for nonenzymatically glycated collagen. Several potential regulatory mechanisms that control concentration of Amadori products, however, have been described. One such mechanism may involve a degradation pathway that converts Amadori products to inert colorless compounds, sometimes referred to as nonbrowning products (Fig. 6). Ahmed et al. (87) reported the presence, in vivo, of a degradation pathway in which oxidative cleavage of the carbohydrate chain of the Amadoni product results in formation of carboxymethyllysine (CML) and erythronic acid. The reaction is pHdependent and sensitive to phosphate, chelators, and radical scavengers. Carboxymethyllysine has been detected in vivo in lens protein, tendon collagen, and urine. Ahmed et al. (88) have also identified a second set of oxidative cleavage

products, 3-(N-lysine)-lactic acid and D-glyceric acid. These compounds have been detected in urine and human lens protein. The authors suggest that oxidative cleavage of Amadori adducts may limit potential damage resulting from accumulation of advanced Maillard products, as the oxidation products are chemically inert and do not contribute to further cross-linking. The sequence of reactions that Amadoni products undergo to form Maillard products is complex and poorly understood in vivo, especially as it pertains to collagen. Recent data suggest that the initial Amadoni products are degraded into one of the several a-dicarbonyl groups that are more reactive than their precursors and thus serve as propagators of the Maillard reaction. One such group, the deoxyglucosones, has been extensively studied in vitro (5). These compounds may react with free amino groups to form pyrrole-based pigmented and fluorescent adducts and cross-links. Although advanced Maillard reactions have been extensively studied in model reaction systems in vitro, elucidation of biosynthesis pathways and characterization of specific cross-linking compounds present in vivo have been remarkably difficult due to low yields, difficulties in purifying desired compounds, and generation of fluorescent artifacts during hydrolysis. Pentosidine, a trifunctional cross-link composed of arginine, lysine, and pentose, is the only fully characterized Maillard product known to be present on collagen (80); however, its biosynthetic pathway in vivo has not been elucidated. Although a pyrrole compound (pyrraline) derived from 3-deoxyglucosone has been identified in human albumin using an immunoassay, this compound has not yet been identified in collagen, although indirect evidence suggests that either pyrraline or a related compound may be present in collagen. Scott et al. (89) have shown that an Ehrlich’s chromogen, which they infer to be a pyrrolic compound, is present in a three-chain cross-linked peptide derived from type III and type IV collagen. The chromogen is also present in preparations of bone, tendon, skin, cartilage, and penosteum. There is evidence that control mechanisms may exist in vivo to regulate tissue content of advanced Maillard products. Recent studies by Vlassara et al. (81) have reported the characterization of a high-affinity macrophage receptor that mediates the uptake and degradation of glycated proteins. There is evidence that the macrophage system may be involved in remodeling of aging tissue, as two monokines, tumor necrosis factor and interleukin-1, are released by macrophages when they bind proteins containing Maillard-type adducts.

CONCLUDING

COMMENTS

Considerable advances have been made concerning how and why cross-links are formed at specific loci in collagen and elastin. However, a number of challenges remain. The extent to which mechanical and physical forces influence the distribution of type, location, and number of cross-links is poorly understood. The regulation of extracellular matrix processing enzymes, such as lysyl oxidase, remains challenging, as the connection between their intracellular synthesis and secretion and extracellular function is not clear. Further, nonenzymatic modifications, when they can be linked to altered extracellular matrix turnover and function, excite interest because of the possible relationship to disease. Fortunately, improved methods coupled with existing knowledge should provide an excellent foundation for future studies in each of these areas.

2447 (01 byLAC.EN ANDMedical ELASTIN CROSS-LINKS m www.fasebj.org Kaohsiung University Library (163.15.154.53) on August 13, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumber()

The following sources of support have contributed to this review: National Institutes of Health (NIH) grants HL-15965, DK-35747, and HD-26777 and a grant from the California Tobacco Related Disease Program to R.B.R.; NIH grants AG-05324 and AG-077l1 to KR.; NIH grant HL 34286 and a grant from the American Heart Association to R.J. McC. REFERENCES

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