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Osteoarthritis and (2001) 9, Supplement A, S23–S28 © 2001 Research Society International 1063–4584/01/0A0S23+06 $35.00/0 doi:10.1053/joca.2001.0440, available online at http://www.idealibrary.com on

Collagen binding L. Svensson, Ar. Oldberg and D. Heinega˚rd Department of Cell and Molecular Biology, Lund University, Lund, Sweden

Connective tissues—an introduction diversity of fibrils is accomplished. The solid strength of bone, another important structural entity of the The connective tissues are crucial for multicellular joint, is achieved by mineralization of the extracellular organisms, playing many diverse roles both structurally and matrix. Mineral crystals of hydroxyapatite comprise about mechanically as well as providing a protective function. two-thirds of the dry weight of bone and are formed in a They make up the frame of the mammalian body and add lattice of collagen type I fibrils. strength and elasticity, while their protective function is important both on the outside of the body and inside, where they surround and support the inner organs. Connective tissues consist mainly of (ECM) sur- rounding a sparse population of cells. The framework of the ECM consists of insoluble fibrils primarily of collagen. The Collagens are the most abundant proteins in the body, structure of the fibrils varies depending on the demands providing the necessary mechanical stability and protection the tissue has to meet. An important determinant is the from external physical stress. Defects in collagen or colla- proportion of different collagen types. However, the shape, gen metabolism have been connected to genetic defects organization and mechanical properties of the fibrils also and diseases such as , chondro- dysplasia, osteoarthritis, rheumatoid arthritis, osteoporosis, depend on the presence of other ECM glycoproteins and 1,2 . and fibrotic diseases . Distinct collagen families differ in Cartilage represents a specialized connective tissue that their ability to form fibrils as discussed below. is a major target in joint diseases affecting more than 10% of the population. To understand the biology and the pathology of events in the articular cartilage in repair and in -FORMING COLLAGENS disease leading to destruction, it is of essence to discern Fibril-forming collagens make up 90% of the total colla- key constituents in the matrix and their functions. Most of gens and represent a mjaor molecular constituents of fibrils the macromolecules in the cartilage are not unique to this with a specific banded pattern. The five members of this tissue and are present in other tissues where they have subfamily, collagen types I, II, III, V and XI, contain long similar functions. Thus the more general discussion on the triple helical domains with about 1000 amino acid residues constituents of the fibrillar networks very much applies to per chain. Collagen type I is by far the most abundant cartilage, where it contains a mixture of molecules specific collagen and found in skin, bone, tendon and many other to cartilage and others present in many tissues. tissues. Collagen type II is the major collagen of cartilage The major constituents of cartilage are collagen and the vitreous. Collagen type III is associated with type II, hyaluronan and the cartilage-specific collagen type I in skin fibrils3. Collagen types V and XI are . Aggrecan binds to hyaluronan to form large considered as minor collagens and are associated with aggregates, which due to their extensive charge, hydrate type I and type II collagen, respectively. the tissue resulting in a high osmotic swelling pressure. The fibril-forming collagens are synthesized as larger Collagen type II is by far the major constituent of a network precursors known as procollagen and contain both amino- of thin fibrils entrapping and interacting with the aggrecan/ and carboxy-terminal propeptides (N- and C-propeptides). hyaluronan aggregates thus endowing the cartilage with The propeptides are usually removed after secretion of the its ability to resist compressive load and providing both molecule, leaving a short, non-triple helical telopeptide at mechanical stiffness and resilience. each end of the molecule. In collagen types III, V and XI the The bulk collagen in banded fibrils in almost all tissues is N-propeptides or parts thereof can be retained in the . A notable exception from this rule is hyaline fibril4–6. cartilage, where type II collagen replaces type I collagen. However, the mode of aggregation of these collagens is to a significant extent determined by other matrix macro- NON FIBRIL-FORMING COLLAGENS molecules with which they are alloyed into D-periodically banded fibrils. In this way, structural and functional tissue Collagen types IX, XII and XIV do not form fibrils by themselves, but are essential constituents co-aggregating Address correspondence to: Dr Dick Heinega˚rd, Department with fibril forming collagens and modulate outside inter- of Cell and Molecular Biology, Lund University, BMC, Plan actions of fibrils by domains projecting from their surfaces. C12, SE-221 84 Lund, Sweden. Tel: +46 46 222 85 71; They have short triple helical domains interrupted by short Fax: +46 46 211 34 17; E-mail: [email protected] non-collagenous sequences. These characteristics gave

S23 S24 L. Svensson et al.: Collagen binding proteins the subfamily its name; FACIT collagens, for fibril- associated collagens with interrupted triple helices7. Colla- gen type IX is the most extensively studied collagen in this group. It is commonly found covalently linked to collagen type II in fibrils and often occurs in a proteoglycan form with a single glycosaminoglycan chain8,9. By rotary shadowing the amino-terminal (N-terminal) triple helical NC3- and the globular, cationic NC4-domains are seen protruding from the fibril surface. Collagen types XII and XIV show some structural similarities to collagen type IX10,11. Both colla- gens occur in different splice variants of which some may be substituted with glycosaminoglycan chains12. They are localized to collagen fibrils in skin and cartilage. Collagen type X forms hexagonal lattices and is found primarily in hypertrophic cartilage13. Collagen type VI is present in many tissues such as skin, cornea and cartilage14,15. Extensive disulphide cross- linking leads to the assembly of characteristically long, thin, beaded filamentous structures. Collagen type VI binds to many cell types and also interacts with other matrix proteins, such as hyaluronan, and biglycan16–18.

Leucine-rich repeat glycoproteins/proteoglycans Proteins containing leucine-rich repeats (LRRs) are found in mammals, birds, plants, insects, bacteria and yeast and are implicated in a variety of –protein interactions19. These interactions are involved in such diverse functions as signal transduction and assembly of the ECM. Each LRR consists of 20–29 amino acids con- Fig. 1. A. Schematic illustration of , decorin, fibromodulin taining leucine residues in conserved positions. The super- and lumican. B. Dendrogram illustrating the evolutionary relation- family of LRR proteins can be divided into subfamilies ship between the ten known members of the ECM LRR protein based on the lengths and consensus sequences of the family. repeated motif. The members of the ECM leucine-rich repeat (ECM LRR) glycoprotein/proteoglycan subfamily N-terminal domain of lumican contains tyrosine residues, have core proteins of about 40 kDa and characteristic 25 cysteine clusters flanking the LRR domain. which are also likely to be sulphated . Both fibromodulin and lumican contain asparagine (Asn) linked carbo- hydrates in the central LRR domain. In fibromodulin syn- STRUCTURE OF ECM LRR PROTEINS thesized by chondrocytes, tendon and scleral fibroblasts, Asn residues in the LRR region can serve as acceptor sites The family of ECM LRR proteins comprises at least ten for keratan sulphate30. Lumican exists as a keratan sul- members, all of which share the common feature of a phate proteoglycan primarily in the cornea, while being a prominent central domain consisting of LRRs, where each classical glycoprotein in tissues such as skin, tendon and LRR consists of about 24 amino acids (Fig. 1). The N- and cartilage29. C-terminal regions are less conserved but are recognized Keratocan and PRELP show 53% sequence identity. by specific patterns of cysteine residues involved in Keratocan is abundant in cornea and sclera, and found in intrachain disulphide bonds20. This family of ECM LRR lesser amounts in tissues such as skin, cartilage and proteins can be further divided into four subfamilies based ligaments26. Keratocan has at least one potential site for on similarities in gene organization and amino acid tyrosine sulphation in the N-terminal domain. Like lumican, sequences. corneal keratocan is a keratan sulphate proteoglycan. Decorin and biglycan belong to one subfamily showing PRELP (proline arginine-rich end leucine-rich repeat pro- 57% protein sequence identity21,22. Both have N-terminal tein) has a unique N-terminal domain with a high content of domains substituted with one (decorin) or two (biglycan) basic amino acid residues27. PRELP was originally purified chondroitin/dermatan-sulphate chains. Decorin and bi- from cartilage, but is also present in other connective glycan are ubiquitous components found in a wide variety tissues such as skin, tendon, cornea and sclera31. Osteo- of tissues such as skin, bone, tendon, aorta and adherin is a keratan sulphate proteoglycan in bovine bone cartilage22,23. with tyrosine sulphate residues and shows 42% amino acid Another subfamily includes fibromodulin, lumican, sequence identity to keratocan32. This proteoglycan is keratocan, PRELP and osteoadherin24–28. In this subfamily found in bone only and has been shown to bind to cells28. fibromodulin and lumican are closely related, showing 48% Chondroadherin has a very short amino-terminal region amino acid sequence identity. They are widespread and and an extra disulphide bond in the C-terminal domain33. have similar expression patterns in tissues like cartilage, Chondroadherin is a cell-binding protein prominently heart, placenta, skeletal muscle, kidney and pancreas29. expressed in cartilage34. Fibromodulin contains a cluster of sulphated tyrosine The LRR motif is known to be involved in protein– residues in the N-terminal domain30. Similarly, the protein interactions, e.g. between ribonuclease and the Osteoarthritis and Cartilage Vol. 9 Suppl. A S25 ribonuclease inhibitor (RNase inhibitor). The RNase inhibi- TGF- production. Decorin has been shown to neutralize tor contains 15 LRRs, which make up 90% of the molecule the effect of TGF- in cell cultures and may prevent fibrotic and possesses only short N- and C-terminal domains35. disease when used in the treatment of rats with experimen- The RNase inhibitor forms a horseshoe-shaped coil of tal glomerulonephritis56,59,60. Cell binding has also been alternating -helices and -sheets. The -helices are shown for chondroadherin and osteoadherin, which bind to located on the outer boundary of the arch and the parallel cells via integrins 21 and v3, respectively28,34. -sheets are situated on the inner concave surface. This structural motif appears to be specific for LRR-proteins. The ECM LRR proteins have fewer and shorter LRRs and in addition have more prominent domains flanking the Assembly and modifications of collagen internal repeated motif compared to the RNase inhibitor. Rotary shadowing and electron microscopy of decorin Collagen fibrillogenesis is a multistep process involving and fibromodulin/lumican indicate that these proteins both intracellular and extracellular assembly reactions2,61. also have a similar horseshoe-shaped three-dimensional The various steps are regulated by a number of factors, structure36. Computer modelling of decorin, based on largely not well characterized, and many of the details the ribonuclease inhibitor structure, suggests a similar remain to be elucidated. arch-shaped molecule37. During the fibril assembly process there are numerous stages where fibril characteristics, such as fibril diameter, may be regulated. Differences in glycosylation and pro- ECM LRR PROTEIN INTERACTIONS peptide processing have been suggested to be involved in the regulation of fibril diameter. Other possible mech- With the exception of osteoadherin, it appears that most anisms for regulation are the association of different colla- of 10-11 LRRP repeats proteins are present in cartilage, gen types into heterotypic fibrils and interactions with albeit at different concentrations. Decorin, fibromodulin and non-collagenous proteins, such as proteoglycans. Thus, PRELP appears most prominent followed by chondro- binding of non-collagenous proteins to collagen has been adherin, that has a much more restricted distribution than shown to influence the fibrillogenesis. Most extensively the others to primarily cartilage. studied are the interactions between collagen type I and Binding to collagen is a prominent feature of some ECM members of the ECM LRR glycoprotein/proteoglycan fam- LRR proteins. Decorin is the most extensively studied ily. Early studies showed that the binding of decorin, member of the family and binds to collagen types I, II, III, V, fibromodulin and lumican to collagen type I was able to VI, XII and XIV18,38–41. Binding of decorin to collagen type affect collagen fibrillogenesis in vitro38,42–44. The situation I was shown to affect fibrillogenesis in vitro, creating thinner in vivo is more complex with an interplay between a number than normal fibrils42. The interaction of decorin with colla- of factors enhancing and inhibiting the process of fibril gen depends on the core protein since the removal of the formation. glycosaminoglycan chain does not alter the binding prop- The role of these collagen-binding ECM LRR erties. Furthermore, isolated glycosaminoglycan chains do glycoproteins/proteoglycans in the assembly of the extra- not interfere with proteoglycan binding. Subsequently, fibro- cellular matrix has been further evaluated in vivo by the use modulin43 and lumican44 were also shown to possess of transgenic mice, where the expression of one specific collagen-binding properties in vitro. Decorin and fibromodu- protein is deleted by gene targeting techniques. The lin seem to bind to separate sites on the collagen fibril, phenotypes of the mice lacking one of these glycoproteins/ since they do not compete with each other for binding proteoglycans are relatively mild. The mice are born alive, to collagen type I45. Biglycan, which is closely related to they are fertile and have a normal lifespan, however, they decorin, does not show any significant binding in vitro to show defects involving connective tissues. The decorin-null fibres of collagen type I46 and does not co-localize with mice have fragile skin with reduced tensile strength62. collagen type I-containing fibrils in tissues47. Biglycan, as Collagen fibrils from both skin and tendon are abnormal in well as decorin and fibromodulin have been implied to bind size and shape. These results suggest that the assembly of to collagen type VI18. the collagen matrix is disturbed, leading to tissues lacking The binding site for collagen type I in the decorin core normal properties. Lumican-null mice have fragile skin with protein has been localized to repeats 4 to 5 in the LRR reduced tensile strength and show corneal opacity63. Col- domain46,48, with a glutamate residue within this region lagen fibrils from both skin and cornea are abnormal in a being suggested to play a critical role for the interaction similar way to the decorin-null mice. In tendon, mice lacking with the collagen49. The binding site for fibromodulin to fibromodulin also show a disorganized collagen matrix, with collagen appears to reside in the C-terminal part of the abnormalities in size and shape of their collagen fibrils64. proteoglycan50. The abnormal collagen fibrils from these different mouse The ECM LRR proteins are not only involved in collagen strains resemble the fibrils from patients with certain forms fibrillogenesis, but may also have functions in regulation of of Ehlers–Danlos Syndrome (EDS). The cause of the cell growth, migration and adhesion. Decorin binds to defect is known for some of the types of EDS, where fibronectin51, thrombospondin52, complement component mutations in the genes for the collagen -chains or in C1q53, membrane receptors prior to endocytosis54 and proteins involved in posttranslational modifications or epidermal growth factor receptor (EGFR)55. Decorin, processing of the collagen have been described. The biglycan and fibromodulin also bind transforming growth results from the ECM LRR glycoprotein/proteoglycan-null factor- (TGF-)56,57. The binding of decorin to EGFR and mice may give an indication as to the possible involvement TGF- is suggested to be involved in the regulation of cell of these proteins in EDS or related disorders affecting growth. Decorin binding to EGFR is associated with cell- collagen matrices. cycle arrest and causes suppression of the growth of The LRRP-proteins appear to also have roles in the various tumor cell lines58. Fibrotic diseases are character- function of the assembled fibrils. Thus, both decorin and ized by accumulation of collagen and involve increased fibromodulin have been identified bound to collagen fibres S26 L. Svensson et al.: Collagen binding proteins in the tissue, localized at the gap region65. Furthermore, a contains covalently bound glycosaminoglycans. Proc population comprising a few percent of banded fibres with Natl Acad Sci USA 1985;82:2608–12. collagen II has been possible to extract from young 10. Gordon MK, Gerecke D, Olsen BR. Type XII collagen: cartilage. A proportion of these fibres contained bound Distinct matrix component discovered by cDNA 66 decorin . Interestingly another subclass of the minor cloning. Proc Natl Acad Sci USA 1987;84:6040–4. population of the total tissue collagen II-containing fibres 11. Dublet B, van der Rest M. Type XIV collagen, a that could be extracted contained collagen IX. 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