inverse relationship between hyaluronan and collagens in development and angiogenesis

Differentiation (1993) 54: 1-9

Ontogeny, Neoplasis and Differentiation Therapy

0 Springer-Verlag t 993

Short review

Inverse relationship between hyaluronan and collagens in development and angiogenesis Paul Rooney ', Shant Kumar

Department of Pathological Sciences, University of Manchester, Manchester M13 9PT, UK Christie Hospital NHS Trust, Manchester, M20 9BX, UK

Accepted in revised form February 4, 1993

Abstract. The extracellular matrix plays a vital role in regulating normal tissue development and function ~

largely via the specific arrangement of macromolecules such as collagens, proteoglycans, glycosaminoglycans and glycoproteins. Previous reports have concentrated on associations between combinations of collagens/proteoglycans, collagens/glycoproteins and proteoglycans/ glycosaminoglycans whilst little information is available on associations between collagens and free glycosaminoglycans.

In this review, we discuss possible associations between collagens and the glycosaminoglycan hyaluronan ; macromolecules which are known to exhibit changes in amount and composition during development and under pathological conditions. We demonstrate two types of collagen/hyaluronan association in vivo : the first, during the formation of extracellular matrix structures where neither collagens nor hyaluronan are degraded, resulting in the regulation of collagen fibrillogenesis, and the second, involving an inverse correlation between collagen synthesis and hyaluronan degradation and vice versa. We suggest that associations between collagens and hyaluronan play an important role in the initiation and maintenance of angiogenesis and put forward a model of cartilage vascularisation which relies on these associations.

Introduction

Connective tissue is a term commonly used to describe an association of cells with an extracellular matrix (ECM) [2, 911. The ECM was once thought to be a relatively inert structural scaffolding but it is now real- ised that it plays a vital role in influencing cellular development, migration, proliferation and morphology. The role played by the ECM is largely due to the specific spatial arrangement of a number of macromolecules

Correspondence to: P. Rooney

such as Collagens, proteoglycans, glycosaminoglycans, glycoproteins and often elastin [23, 30, 70, 711. The main components of the ECM, by quantity and by function, are collagens and proteoglycans ; collagens provide ten- sile strength whilst proteoglycans form a hydrated gel which resists compressive forces and allows diffusion of nutrients and other soluble molecules [23, 701. The amount of ECM associated with tissues can vary greatly e.g. skin, bone or cartilage are almost entirely comprised of ECM whilst brain and spinal cord have very little.

Two distinct types of ECM have been described - one associated with interstitial connective tissues and one associated with basement membrane. The main dif- ferences between these two forms is that basement membrane ECM takes the shape of a condensed sheet-like structure (composed primarily of type IV collagen, the glycoprotein laminin and proteoglycans such as heparan sulphate) 1861, whilst the ECM of interstitial connective tissue is generally an expanded mass [composed of one or more of several types of collagen (excluding type IV), glycoproteins such as fibronectin, several types of proteoglycans and free glycosaminoglycans such as hyaluronan (HA)] [2, 311.

Many studies have been performed on the structure, biosynthesis and biological activities of the ECM components and several have looked at associations between combinations of collagen/proteoglycan, collagen/glycoprotein (particularly fibronectin) and proteoglycan/hyaluronan [l, 44, 58, 621. Surprisingly, very few studies have looked at the possibility of associations between collagen and free glycosaminoglycans, particularly HA [lo, 561. These macromolecules are known to exhibit changes in amount and composition both spatially and temporally during development and under pathological conditions, however, the possibility that they may work in conjunction has not been examined. Here we review occasions, both in vivo and in vitro where alterations in the amount and/or composition of collagens and HA occur simultaneously. We demonstrate that two types of distinct, but possibly related, associations are observed both during development and in post-natal pro-

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cesses such as tumour formation, wound healing and angiogenesis. The first association, in the formation of ECM structures, occurs when neither HA nor collagens are being degraded, and results in the regulation of collagen fibrillogenesis. The second type of association is observed in more dynamic situations and involves changes in the relative amounts and synthesis of existing ECM macromolecules, in particular, either the destruction of existing collagens with subsequent stimulation of HA synthesis or the degradation of existing HA and the up regulation of collagen synthesis.

Collagen

Collagens are the most abundant proteins in mammals and are defined as proteins within the ECM which play a role in matrix assembly or organisation and have as a central feature one or more triple-helical rod-like structures composed of three LY chains (either in a homotrimeric or a heterotrimeric form) (Fig. 1) [55, 671. Within the triple helix, every third amino acid is glycine but there is also high concentrations of hydroxyproline and hydroxylysine. The family of collagen proteins includes 14 numbered members with other possible members being investigated. Many collagen molecules have special- ised functions and are found in specific locations (Ta- ble 1). The collagen family can be sub-divided into five groups depending on whether the molecules form fibrils (collagens types I, 11, 111, V and XI) [6, 8, 39, 571; are associated with fibrils and have interrupted triple helices (collagens types IX, XI1 and XIV ~ FACIT collagens) [20, 21, 28, 681; form sheets (collagens types IV, VIII and possibly X) [86, 971 ; form beaded filaments (collagen type VI) [9, 411 or form anchoring fibrils (collagen type VII) [65]. The presence of the protein form of collagen type XI11 has not yet been discovered and this collagen is identified by cDNA and antibody studies [64].

Hyaluronan

HA is a non-sulphated glycosaminoglycan composed of a repeating disaccharide unit of D-glucuronic acid and N-acetyl-D-glucosamine (Fig. 2) [ 121. It is a major component of the ECM during morphogenesis and sur- rounds proliferating and migrating cells during regeneration, remodelling and healing of tissues [46, 87, 891. HA may exert a role on cells in two ways, either by its hydro- dynamic properties or by cell-surface interactions [88]. HA binds to fibronectin, chondroitin sulphate and the

...

... *- Triple helix .-+

Fig. 1. Schematic rcpresentation of the structure of the triple-helical portion of an interstitial, fibrillar collagen molecule

Table 1. Major sites of localisation of collagen types

Type Chemical formula Tissues

I I1 I11 IV V VI

VTI VIII c

IX X XI XI1 XI11 XIV

bone, tendon, skin cartilage, vitreous skin, blood vessels basement, membrane bone, skin, articular cartilage articular cartilage, skin,

blood vessels anchoring plaques endothelial cells,

cartilage, vitreous hypertrophic cartilage cartilage embryonic skin and tendon endothelial cells embryonic skin and tendon

Descemet's membrane

a This is the most common form of type IV collagen, however, other a chains have been identified - x3(IV), a4(IV), x5(IV) - the precise molecular form of these chains is unknown

This is the most common form of type V collagen, however, other x chains and other molecular forms have also been identified, e.g., [al(V)], from cell cultures; xl(V), a2(V), a3(V) from synovial membranes and placental tissue c The molecular form of type VIII collagen has not yet been fully determined, the most probable form being [EI(VIII)]~, x2(VIII)

The molecular form of type XI11 collagen has not been determined, al(X1II) has been discovered by cDNA cloning

chondroitin sulphate proteoglycans aggrecan and versi- can [93]. Binding proteins which attach preferentially to HA also bind with decreasing affinity to fibronectin, collagen, laminin, chondroitin sulphate and chondroitin sulphate proteoglycans [92]. One unusual property of HA is its ability to be present in the ECM in two states, either associated with an aggregating proteoglycan molecule, linked via link proteins (e.g. in cartilage) (Fig. 2), or on its own as a free glycosaminoglycan (although the hyaluronan may not be directly linked to proteoglycan in this state, it may be associated with other proteins [lo]).

In vivo studies

Role of hyaluronan in the,formation of ECM structures

Collagen fibrils (mainly type I collagen) are present in developing rat tail tendon in two distinct sizes, 10-1 5 nm and 25 nm in thickness. The smaller protofibrils are pro- minant in young tissues and with increasing age these coalesce into the larger subfibrils. HA (in combination with proteoglycan) is present at high concentration, is bound to the protofibrils, in young tissue, and its function is believed to be to keep the collagen protofibrils and subfibrils from coalescing [78]. A similar HA/collagen complex (type IX collagen) is seen in the development of the vitreous humour of the eye, where HA again prevents collagen fibril aggregation allowing the vitreous to remain clear. With increasing age and in some dis-

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Inverse correlation between collagen synthesis and hyaluronan degradation

I I

I I

I ,

Hyaluronan core

I I I I L

I I c=o I I CH3 2

D-Glucuronic acid N-Acetyl-D-Glucosamine

Fig. 2. Diagrammatic representation depicting the association between proteoglycans and the hyaluronan core in a proteoglycan aggregate. Hyaluronan is composed of a repeating disaccharide unit of glucuronic acid and N-acetylglucosamine which is con- nected to individual proteoglycan monomers via link protein. Each proteoglycan monomer consists of a core protein linked to glycosaminoglycan side chains

eases, this complex is broken down, the collagen fibrils aggregate, and macroscopic fibres can be observed [79, 801. As yet, no direct physical interaction between HA and collagen has been observed in the vitreous [66].

HA also regulates collagen fibrillogenesis and bundle formation in skin, e.g. the skin of the mouse steel mutant has normal levels of both collagens (mainly type I and type 111) and HA. The mutation alters the organisation of the collagen bundles and HA within the ECM resulting in easily extractible HA [59]. In contrast, low concentrations of HA are present in the skin of scoliotic chick- ens allowing easily extractible collagen [53]. Thus HA and collagens have to be present at not only the correct concentration but also in the correct conformation for normal bundle formation. In addition, recent studies have demonstrated a direct interaction between HA and type VI collagen in skin [42, 561.

Development and tumour formation. High molecular weight HA and collagens are involved in normal morphogenesis and differentiation. The normal sequence of events during morphogenesis often involves the synthesis of (high molecular weight) HA which promotes the migration of mesenchymal cells to appropriate sites. Dur- ing this migration, collagen synthesis is minimal, however, when the appropriate site is reached, HA synthesis is down regulated, the HA is degraded, collagen synthesis is up regulated and the cells begin to differentiate. This programme of events has been studied extensively in limb development (involving types I, I1 and I11 collagen) [46, 87, 891 but it is also a feature of neural crest cell migration in the gut (type I and type IV collagen) [27], myoblast formation (type I and I11 collagen) [47], somite chondrogenesis (type I1 collagen) [94], testes development (type I collagen) [26] and the migration of cells into the cardiac jelly of the developing heart (type I collagen) [ 51. Although the precise biological actions are not fully understood, it is believed that the hydrody- namic properties of HA allow the existing ECM spaces to open up further and, perhaps with the aid of fibronectin [27], cells are directed through the open spaces until the appropriate site is reached.

A similar process whereby the existing ECM is modified to allow cell migration prior to cell attachment, proliferation and differentiation can also be observed in tumour formation and spread. Several invasive tumours are enriched in HA which is synthesised by host fibro- blastic cells [45, 631, and evidence indicates that the site of tumour growth and invasion has enhanced levels of HA synthesis [7, 34, 461. Recently, tumour cells have also been found to synthesise a low molecular weight collagen stimulating factor which results in increased collagen synthesis by host fibroblasts [61]. Taken together, these observations imply that tumour cells ‘migrate’ (metastasise) by a mechanism recapitulating that observed during development; once at the appropriate site the tumour cells then induce HA breakdown and collagen synthesis allowing differentiation to proceed. An increase in serum levels of low molecular weight HA (i.e. degraded HA) have also been noted in human and ani- mal tumours. Sera from children with a rare type of renal tumour, which has a predilection for bone metasta- sis, have increased levels of HA oligosaccharides whilst sera from a non-bone metastasizing renal tumour pos- sessed no such low molecular mass HA [48].

Wound healing. The normal process of wound healing broadly involves three overlapping phases; inflamma- tion, granulation tissue production and ECM formation and remodelling [13]. The earliest events in wound healing involve the destruction/perturbation of the existing ECM (collagens, proteoglycans, glycoproteins etc.), and the production of a temporary ECM composed of fibronectin, HA and fibrin (HA is by far the most abundant glycosaminoglycan synthesised during the first four days). Macrophages, fibroblasts and angiogenic tissue

4

migrate into the wound site, high molecular weight HA and fibrin are degraded, the fibroblasts continue to synthesise fibronectin, synthesis of type I11 and then type I collagen is initiated and the macromolecules associate to form a loose ECM. Proteoglycans with associated sulphated glycosaminoglycans accumulate from the fifth day. With increasing time the fibroblasts accumulate ac- tin filaments within their cytoplasm, the cells align up along the collagen fibrils and begin to contract the wound. During repair of skin wounds, re-epithelialisa- tion is also dependant on the synthesis of type V collagen

The amount of collagens present and the amount of contraction determines the degree of scarring observed in a wound. In contrast, wounds to foetal skin demonstrate no scarring [14]. This has been linked to the scar- city of collagens and the abundance of HA in foetal skin [15, 541. The ability of HA to down regulate collagen synthesis during wound healing has been demonstrated experimentally by the addition of exogenous HA, both topically and by injection, to wounds [32, 82, 901. In addition to a decrease in collagen synthesis, the degree of subsequent scarring was also reduced. In other reports where the synthesis of HA has been experimentally stim- ulated, e.g. by the addition of interferon gamma, a concomitant decrease in collagen synthesis is observed and once again the degree of scarring is reduced [29]. Colla- gen synthesis and subsequent scarring are also greatly reduced when the action of transforming growth factor- 8, a known fibrotic agent, is eliminated by the addition of a neutralising antibody [81]. It is not yet known whether HA levels are enhanced in this system.

In each of the cases outlined above, development, tumour formation and wound healing, the migration of cells is triggered by the synthesis of high molecular weight HA, and this migration ceases as the HA is degraded and collagen synthesis is initiated. A different pattern of events is observed in angiogenesis.

~ 4 1 .

Angiogenesis. Changes in the relative levels and types of collagens and HA in angiogenesis are well known, but the roles played by these macromolecules are un-

Fig. 3. Electron micrograph of a portion of the chorioallantoic membrane of the chick embryo which has been treated with angiogenic oligosaccharides of hyaluronan. Large amounts of collagen fibrils are clearly evident. Bur, 0.1 pm

clear. Type I collagen synthesis is known to be initiated de novo when bovine aortic endothelial cells undergo capillary sprout formation [37], and metabolic reduction of collagen synthesis inhibits capillary formation on the chorioallantoic membrane (CAM) [33], suggesting that type I collagen may play a role as a substrate for endothelial cell migration during capillary sprout formation. Recently, type VIII collagen has also been proposed to play a role in angiogenesis [36, 721. Type VIII collagen is produced by vascular endothelial cells but, only if undergoing active cell proliferation [73, 741 and it has been immunolocalised to vascular tissues [38, 431. Type VIII collagen is thought to interact with extracellular matrix components such as HA or some other polyan- ionic glycosaminoglycan and it has been postulated that type VIII collagen may facilitate the assembly of endothelial cords and tubes during angiogenesis [35, 361.

Hyaluronun plays u dual role in angiogenesis. An ECM rich in high molecular weight HA inhibits blood vessel formation in chick embryo limb buds and within granulation tissue [4, 22, 241, whereas HA oligosaccharides (which should be considered as equivalent to degradation products of high molecular weight HA) stimulate angiogenesis on the CAM [96]. We have shown that this stimulation of angiogenesis on the CAM is associated with the appearance of a very marked increase in the number of collagen fibrils when viewed under the electron microscope (Fig. 3) [49]. The tips of the induced capillary sprouts contain HA but how the breakdown of HA regulates the initiation of angiogenesis is unknown [3]. It is likely that breakdown of HA stimulates angiogenesis associated with synthesis of existing and novel collagens.

The sequence of events observed in angiogenesis differs from those in development and wound healing in that the presence of high molecular weight HA inhibits endothelial cell migration. Rather, i t is the breakdown products of HA which stimulate migration. Once HA degradation is initiated, collagen synthesis is up regulated as described above. One possible explanation for this could be that endothelial cells require type I collagen

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as a substrate for cell migration and since they are en- cased within a basement membrane consisting of type IV collagen, one of the initial events must be the de novo synthesis of type I collagen, thus HA is broken down into oligosaccharides capable of stimulating collagen synthesis.

The angiogenic potential of HA oligosaccharides may play a role in the repair of internal tissue damage due to disease. Once again, in the repair phase of disease, there appears to be a direct relationship between collagens and HA. At early stages of alveolar lung disease, collagen is broken down and HA synthesis is enhanced prior to the migration of fibroblasts with subsequent new collagen synthesis [60]. As this collagen synthesis proceeds, HA synthesis decreases but the HA remaining is closely associated with the invading proliferating cells [60]. It is important to note that degradation of HA will result in the production of angiogenic oligosaccharides enabling ready access of nutrients to the repairing tissue.

Hyaluronan - collagen associations in vitro

Many of the observations noted above are emulated by cells in vitro, where most of the experimental data have been obtained from the study of the action of cells in collagen gels or sponges in the presence or absence of external factors such as HA. The general interpretations from these experiments are that in the absence of HA, various types of cells attach to collagen, align along the collagen fibres and do not migrate into the substrate. When HA is added, the collagen expands [93] and cells migrate into the centre of the gel where they begin to synthesise their own ECM [16, 18, 191. The size of the HA and the concentration added influences the cellular behaviour, e.g. low concentrations alter the structure of the collagen and make it more chemoattractant [ 171 whereas a concentration in excess of 5% prevents attachment of fibroblasts [83]. This may be in accordance with hyaluronan aiding cell migration, by not allowing strong cell-ECM attachments, in vivo [27]. Since HA and its oligosaccharides have a notable effect on endothelial cells during angiogenesis, we have studied the effect of HA on endothelial cells in vitro.

The addition of moderate amounts of high molecular weight HA to endothelial cells, grown on plastic, has little effect on the morphology and proliferation of the cells. However, if oligosaccharides of two-ten disaccharide units are added to the cells, they exhibit increased proliferation and migration in an apparent emulation of angiogenesis [95]. These cells have now been shown to greatly increase the synthesis of both type I and type VIII collagens (Table 2) [69]. These results imply that the production of large bundles of collagen fibres when HA oligosaccharides are added to the CAM (Fig. 3) [49] may be due to the production of type I collagen by endothelial cells in the newly forming capillary sprouts. The production of type VIII collagen has also been observed by other workers when endothelial cells are al- lowed to undergo spontaneous angiogenesis in vitro [36].

Table 2. Enhancement of collagen production by bovine aortic endothelial cells (BAEC) in vitro by hyaluronan

Type of collagen Relative proportions of collagens produced by BAEC

Control Hyaluronan treated

Type I 1 4.5 Type VIII 1 5.8

Relative proportions of collagens were evaluated from sodium do- decyl sulfate gels following pepsin treatment and laser densitomet- ric analysis

Since type VIII collagen is only produced by actively dividing endothelial cells and as it appears to be stimu- lated by angiogenic factors, or by spontaneous angiogenesis in vitro, it has been proposed to play an important role in angiogenesis [36]. It seems possible that, in vivo, breakdown of native, high molecular weight HA could result in the production of angiogenic oligosaccharides capable of inducing cell proliferation, collagen synthesis and initiating cell migration and differentiation. If type I collagen is the substrate used for the cells to migrate [33, 371 then type VIII collagen production may be the initial trigger for the proliferation or migration observed [36, 691.

Hyaluronan - collagen associations in vascularisation of cartilage

The observations that the addition of HA oligosaccharides to the CAM and to endothelial cells in vitro both result in alterations in collagen synthesis concomitant with the onset of angiogenesis, have led us to propose that HA may interact with collagens and that this interaction may be the initiating factor in angiogenesis. The models currently in use to study angiogenesis in vivo generally involve the growth of new vessels from existing vessels; we are interested in the growth of blood vessels where none previously existed. Consequently we are ex- amining a model of vascularisation in cartilaginous long bone rudiments where the avascular, cartilage rapidly becomes angiogenic, becomes vascularised and is eroded by bone marrow. Figure4 is a hypothetical model involving HA, type X and type VIII collagens, which could account for this vascularisation.

The biological functions of type VIII and type X collagens are unknown. Type VIII collagen is very similar in size and chemical characteristics to type X collagen [85, 981, which is a gene product unique to hypertrophic chondrocytes [40, 501. Several reports have linked the production of type X collagen with the process of mineralisation and have suggested that type X collagen may in some way initiate calcification [St]. However, in the developing cartilage long bone rudiment, particularly of the chick embryo, type X collagen is synthesised in the tibia at 8-9 days of incubation [76] whilst mineralisation does not begin until at least 1 week later [25]. It is inter-

6

Diagrammatic representation of vascularisation of a chick embryo cartilage rudiment

L

7-8 days incubation

R F H F R R Rounded chondrocyte F Flattened chondrocyte H Hypertrophic chondrocyte

-Direction of spread of cell hypertrophy and maior axis of growth

9 days

7 Point of entry of first blood vessels

10-12 days

Erosion of hypertrophic cartilage - Migration and invasion of Mood vessels but always within the hypertrophic cell zone

15- 16 days

Areas of cartilage erosion 0 and replacement by bone marrow

Leading front of blood vessel invasion

There IS 00 mineralisation of the carti\age at this time

Fig. 4. Hypothetical model outlining possible interactions between hyaluronan and collagen during vascularisation of long bone rudiments. A cartilaginous long bone rudiment is produced containing the three zones of chondrocytes and an extracellular matrix (ECM) consisting of collagens, proteoglycans, hyaluronan and glycoproteins (7-8 duys). The hypertrophic chondrocytes synthesise and secrete type X collagen which may induce ECM conformational changes resulting in hyaluronan breakdown, perhaps by activating hyaluronidase. Hyaluronan breakdown may attract vascular tissue to the cartilage/perichondrium junction where endothelial cells di- vide, synthesise type VIII collagen and migrate into the cartilage (9 d u p ) . Erosion of the cartilage ECM occurs producing more hyaluronan oligosaccharides, self-perpetuating the erosion (1 0-12 days). The direction of the erosion is controlled by the continued synthesis of type X collagen by hypertrophic chondrocytes. The leading endothelial cells continue to produce type VIII collagen facilitating further cellular infiltration (15-16 duys). Erosion and vascular invasion ceases when hypertrophic chondrocytes are re- moved and no more type X collagen can be synthesised

esting to note that vascular invasion and bone marrow cavity formation also begin in the centre of the hypertrophic zone at 8-9 days [ l l , 251. In addition, type X collagen is known to produce a hexagonal structure which is remarkably similar to the hexagonal structure formed by type VIII collagen in the Descemet’s membrane of the eye 152, 75, 771. The formation of a regular network in the ECM of hypertrophic cartilage may rep- resent part of a modification process which changes an existing anti-angiogenic ECM into an angiogenic matrix.

We would suggest that the production of type X collagen may influence angiogenesis rather than mineralisation and by altering the existing cartilage ECM, may influence the proliferation and migration of endothelial cells within the well vascularised perichondrium/periosteum. It is important to note that type X collagen selectively binds to HA but not to collagens type TI, VI, IX and XI (A.P.L. Kwan, personal communication). If this is the case then it is possible that type VIII collagen and type X collagen may play a similar role in non-skeletal and skeletal tissues respectively.

In conclusion, cell-cell and cell-matrix interactions are prerequisites for normal tissue development and function. Alterations in these interactions can lead to changes in the nature of the tissue. Most studies on these interactions have focused on collagens, in combination with either proteogiycans or glycoproteins such as fibronectin. Little information is available on the interactions between collagens and free giycosaminoglycans such as HA. This is surprising since reports often show an inverse relationship between collagens and HA synthesis both during development and in pathological states. This review draws together these diverse reports and demonstrates that the regulation of synthesis of HA and collagens are intimately related, with enhanced HA synthesis as collagen is broken down and vice versa. In addition, it demonstrates that following tissue damage, HA may act as a temporary ECM, allowing the incorpo- ration into the provisional matrix of instructive moie- cules (e.g. fibronectin, tenascin, thrombospondin etc.), until the arrival of appropriate collagen forming cells. Once collagen synthesis begins, HA is broken down and the angiogenic oligosaccharides produced may facilitate the supply of blood and nutrients to the repairing tissue. In this way, HA is involved in the migration of cells, the nutrition of these cells and in the deposition of the final remodelled ECM.

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