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Vitreous Biochemistry and Pharmacologic Vitreolysis J CHAPTER 4 Vitreous Biochemistry and Pharmacologic Vitreolysis J. Sebag and Kevin R. Tozer Throughout history, medical therapeutics have advanced condition (2). Thus, in vitreous as elsewhere, great care as a result of increased understanding of disease patho- must be taken when extrapolating from the adult to the genesis. With limited knowledge, little could be done. As diseased child. knowledge increased, surgical procedures were histori- This chapter reviews the biochemical composi- cally early therapeutic approaches. Further increases in tion and organization of the human vitreous (4–6) and, knowledge saw surgical treatments replaced by medical where information is available, describes differences (usually pharmacologic) therapies. Advanced under- between adults and in youth. A review of the various standing of disease pathogenesis leads to prevention, agents being developed for pharmacologic vitreolysis the ultimate goal of medicine. Vitreoretinal surgery is a will also be presented. paradigm of this evolution. The end of the last millen- nium witnessed the development of revolutionary sur- gical approaches to treat vitreoretinal diseases—scleral VITREOUS BIOCHEMISTRY buckle and vitrectomy. At present, expanding knowledge of the biochemistry, structure, and pathophysiology of Vitreous is an extended extracellular matrix composed vitreous and the vitreoretinal interface is enabling drug of 98% water and 2% structural components, primarily therapies such as pharmacologic vitreolysis (1,2). Ini- collagens and glycosaminoglycans (GAGs). tially, this approach will be used as an adjunct to facili- tate and enhance surgery. The next implementation Collagens phase, which has already begun (3), will replace surgery Collagen content is highest where the vitreous is a gel to treat vitreomacular diseases. Ultimately, pharmaco- (7). As shown in Figure 4.1, individual vitreous colla- logic vitreolysis will be used to prevent disease in high- gen fibrils are organized as a triple helix of three alpha risk individuals. chains. The major collagen fibrils are heterotypic, con- Vitreoretinal surgery in pediatric patients is among sisting of more than one collagen type. Recent studies the most challenging and difficult of all eye surgery. This of pepsinized forms of collagen confirm that vitreous is largely due to the solid gel vitreous structure in youth contains collagen type II, a hybrid of types V/XI, and and firm vitreoretinal adhesion. It is thus no surprise type IX (4,6). that the first attempts to develop pharmacologic vitre- olysis were in a pediatric setting where the intent was Type II Collagen to facilitate vitreous separation from the retina during Type II collagen, a homotrimer composed of three iden- surgery. It is important, however, to consider that the tical alpha chains designated as [α1 (II)]3, comprises biochemistry, molecular organization, and structure of 75% of the total collagen content in vitreous. When vitreous and the vitreoretinal interface in youth are not first synthesized as a procollagen and secreted into the the same as in adults and the elderly. Thus, the experi- extracellular space, type II collagen is highly soluble. ence and agents employed in adult pharmacologic vit- The activity of N-proteinase and C-proteinase enzymes reolysis may not directly translate to pediatric patients. reduces the solubility and enables type II collagen mol- Furthermore, the specific abnormalities in pediatric ecules to cross-link covalently in a quarter-staggered vitreoretinal diseases may require tailoring of phar- array. Within this array are likely to be N-propeptides, macologic approaches to the idiosyncrasies of each which probably extend outward from the surface of the 30 Hartnett9781451151404-ch04.indd 30 4/30/2013 2:29:29 PM CHAPTER 4 VItreOUs BIOcheMIstrY aND PharMacOLOGIc VItreOLYsIs 31 Chondroitin sulfate FIGURE 4.1 Schematic diagram of colla- glycosaminoglycan chain gen fibril structure in the human vitreous. of type IX collagen (From Bishop PN. Structural macromol- ecules and supramolecular organisation N - propeptide of of the vitreous gel. Prog Retin Eye Res type V/ XI collagen 2000;19:323–344, with permission.) Type V/ XI collagen Type IX collagen N - propeptide of type II collagen Type II collagen forming fibril (5). This may influence the interaction of the molecule to assume a proteoglycan form. Electron the collagen fibril with other components of the extra- microscopy of vitreous stained with cationic dyes visu- cellular matrix. Recent studies (8) combined immunolo- alizes the chondroitin sulfate chains of type IX collagen, calization with Western blot analysis of macromolecules occasionally found distributed along the surface of vit- extracted from bovine vitreous collagen fibrils and reous collagen fibrils (13) and often bridged between found that the pN-type IIA procollagen is located on the neighboring collagen fibrils. Duplexing of GAG chains surface of the vitreous collagen fibril. The findings (9) from adjacent collagen fibrils may result in a “ladder- that type IIA procollagen propeptides bind growth fac- like” configuration (14). tors such as transforming growth factor-β1 and bone morphogenic protein-2 support the concept that growth Type V/XI Collagen factors interact with vitreous fibrils to at times promote Ten percent of vitreous collagen is a hybrid V/XI col- enough cell migration and proliferation to result in pro- lagen that is believed to comprise the central core of liferative vitreoretinal disorders, such as proliferative the major collagen fibrils of vitreous (15). Type V/XI vitreoretinopathy in adults and retinopathy of prematu- is a heterotrimer that contains α1 (XI) and α2 (V) in rity in infants. two chains, while the nature of the third chain is pres- ently not known (16). Along with type II collagen, type Type IX Collagen V/XI is a fibril-forming collagen. While the interaction Type IX collagen is a heterotrimer that is disulfide of the fibril with other extracellular matrix components bonded with an [α1 (IX) α2 (IX) α3 (IX)] configuration. is probably influenced by a retainedN -propeptide that It is oriented regularly along the surfaces of the major protrudes from the surface of the fibril in cartilage (15), collagen fibrils in a “D periodic” distribution, where it is not known whether this is the case in vitreous (6). it is cross-linked onto the fibril surface. Type IX is a member of the fibrillar-associated collagens with inter- Type VI Collagen rupted triple helixes group of collagens. It contains col- Although there are only small amounts of type VI colla- lagenous regions described as COL1, COL2, and COL3 gen in vitreous, the ability of this molecule to bind both interspersed between noncollagenous regions called type II collagen and hyaluronan (HA) suggests that it NC1, NC2, NC3, and NC4 (10,11). In vitreous, as opposed could be important in organizing and maintaining the to cartilage, the NC4 domain is small and not highly supramolecular structure of vitreous gel. charged, thus not likely to exhibit extensive interac- tion with other extracellular matrix components (12). Glycosaminoglycans In vitreous, type IX collagen always contains a chon- GAGs do not normally occur as free polymers in vivo droitin sulfate GAG chain (10,11), which is linked cova- but are covalently linked to a protein core, the ensemble lently to the α2 (IX) chain at the NC3 domain, enabling called a proteoglycan. A sulfated group is attached to Hartnett9781451151404-ch04.indd 31 4/30/2013 2:29:34 PM 32 SECTION I DEVELOPMENT OF THE EYE AND RETINA oxygen or nitrogen in all GAGs except HA. Studies in the In human (but not bovine) vitreous versican is believed rabbit (17) found a total vitreous GAG content of 58 ng to form complexes with HA as well as microfibrillar pro- with 13% chondroitin sulfate and 0.5% heparan sulfate. teins, such as fibulin-1 and fibulin-2 (6). Hyaluronan Heparan Sulfate Although HA is present throughout the body, it was first This sulfated proteoglycan is normally found in base- isolated from bovine vitreous. HA appears in human ment membranes and on cell surfaces throughout the vitreous after birth possibly synthesized by hyalocytes body. It was first detected in bovine vitreous in 1977 (27) (18), although other plausible candidates are the cili- and in chick vitreous (as “agrin”) in 1995 (28). However, ary body and retinal Müller cells. HA is synthesized at it is not clear whether heparan sulfate is a true compo- a constant rate in the adult. Although there is no extra- nent of vitreous or a “contaminant” from adjacent base- cellular degradation, HA levels are in a steady state ment membranes, such as the internal limiting lamina of because the molecule escapes via the anterior segment the retina (29). As pointed out by Bishop (6), this may of the eye (19). also be the case for nodogen-1, the aforementioned fibu- HA is a long, unbranched polymer of repeating gluc- lins, and fibronectin. uronic acid β-1,3-N,N-acetylglucosamine disaccharide moieties linked by β 1–4 bonds (20), with a molecular Noncollagenous Structural Proteins weight of 3–4.5 × 106 in adult human vitreous (19). HA Fibrillins is a linear, left-handed, threefold helix with a rise per Fibrillin-containing microfibrils are more abundant in disaccharide on the helix axis of 0.98 nm (21). This vitreous than type VI collagen microfibrils. They are periodicity, however, can vary depending on whether found in vitreous gel as well as in the zonules of the lens, the helix is in a “compressed” or “extended” configu- explaining why in Marfan syndrome defects in the gene ration (22). Changes in the degree of “extension” of encoding fibrillin-1 (FBN1 on chromosome 15q21) result HA could be important in retinal disease, since the in both ectopia lentis and vitreous liquefaction (6). The volume of the unhydrated HA molecule is about 0.66 latter probably plays a role in the high incidence of cm3/g, whereas the hydrated specific volume is 2,000 rhegmatogenous retinal detachment in these patients.
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