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Cartilage contains a variety of proteoglycans that are essential for its normal …


Biology Articles » Biochemistry » The Structure and Function of Cartilage Proteoglycans » SLRPs

SLRPs
- The Structure and Function of Cartilage Proteoglycans

The SLRPs are not structurally related to aggrecan, but belong to the large family of leucine-rich repeat proteins, which are characterized by multiple adjacent domains bearing a common leucine-rich motif (Hocking et al., 1998). They can be divided into several sub-families based on their gene organization, the number of leucine-rich repeats and the type of GAG chain substituent. In the case of decorin, biglycan, fibromodulin and lumican there are ten leucine-rich repeats, which are flanked by disulphidebonded domains (Fig. 7). Decorin and biglycan are part of one subfamily based on their 8 exon gene structure, whereas fibromodulin and lumican are part of a second subfamily based on their 3 exon gene structure. The genes for decorin and lumican reside close to one another at human chromosome 12q22 (Danielson et al., 1993; Grover et al., 1995), while the gene for fibromodulin is at 1q32 (Sztrolovics et al., 1994) and that for biglycan is at Xq28 (McBride et al., 1990). Decorin and biglycan can also be classified as dermatan sulphate (DS)-proteoglycans, whereas fibromodulin and lumican are keratan sulphate (KS)-proteoglycans. The mature forms of fibromodulin and lumican present in the cartilage matrix correspond to removal of only the signal peptide, whereas for decorin and biglycan an additional amino acid sequence of 14 and 21 amino acids, respectively, is removed (Roughley et al., 1996b; Scott et al., 2000). These additional sequences have been considered as propeptides, though it is not clear whether their removal has any functional consequence.

The four SLRPs all possess N-linked oligosaccharide chains within their central leucine-rich repeats (Neame et al., 1989; Plaas et al., 1990). In the case of fibromodulin and lumican, it is these N-linked oligosaccharides that may be modified to KS (Fig. 7). Decorin and biglycan possess attachment sites for CS/DS within the extreme amino terminus of their core proteins. In decorin, there is one such site at amino acid residue 4 of the mature core protein, whereas in biglycan there are two sites at amino acids 5 and 10 in the human (Roughley and White, 1989). In most connective tissues including cartilage the CS is modified to DS. Biglycan may also exist in non-glycanated forms devoid of DS chains, with the abundance of such forms accumulating with age (Roughley et al., 1993). These nonglycanated forms of biglycan appear to be the result of proteolysis within the amino terminal region of the core protein. Non-glycanated forms of fibromodulin and lumican can also accumulate with age (Grover et al., 1995; Roughley et al., 1996a), due to the absence of KS synthesis.

In vitro, decorin (Imai et al., 1997) and fibromodulin (Heathfield et al., 2004) have been shown to be degraded by matrix metalloproteinses, and it is predicted that such cleavages can occur in vivo. The function of the SLRPs depends on both their core protein and GAG chains. Their core proteins allow the SLRPs to interact with the fibrillar collagen that forms the framework of the tissue (Vogel et al., 1984). In so doing they help regulate fibril diameter during its formation and possibly fibril-fibril interaction in the extracellular matrix. They also appear to limit access of the collagenases to their unique cleavage site on each collagen molecule, and in so doing may help protect the fibrils from proteolytic damage (Fig. 8). While the interaction of decorin, fibromodulin and lumican with collagen fibrils is universally accepted, that of biglycan is not. At least in vitro, biglycan interaction depends upon the environmental conditions, and this might contribute to the different tissue locations that have been observed for decorin and biglycan. Fibromodulin and lumican interact with the same region of the collagen molecule (Svensson et al., 2000), which is distinct from the site at which decorin interacts (Hedbom and Heinegård, 1993). For decorin, interaction involves amino acid sequences present within the leucine-rich repeats (Svensson et al., 1995). Molecular modelling predicts that the SLRPs possess a “horse-shoe” conformation that is able to accommodate a single collagen molecule at the surface of the collagen fibrils within its concave face (Scott, 1996). However, X-ray diffraction analysis of decorin crystals indicate that it exists as a dimer with interlocking concave faces (Scott et al., 2004). It is not clear whether decorin dimers represent the functional form of the molecule in solution and how this impacts their interaction with other molecules.

Interaction of the SLRPs is not confined to the fibrillar collagens. Decorin, biglycan, fibromodulin and lumican have been reported to interact with many other macromolecules, including types VI, XII and XIV collagen, fibronectin and elastin, and growth factors such as EGF, TGFβ and TNFα. At least in the case of decorin, it appears that interaction with fibrinogen occurs in a zinc-dependent manner (Dugan et al., 2003), and it is possible that other family members also act as Zn-binding proteins, and that this influences their conformation and function. The GAG chains have been associated with the interaction with several growth factors, and enable the SLRPs to provide a sink for growth factor accumulation within the extracellular matrix. In this manner the SLRPs can help modulate chondrocyte metabolism by regulating growth factor access to the cells.

The level of SLRP synthesis varies with age, and may be influenced by growth factors. While the precise consequence of the age-related changes in SLRP abundance is unclear, it is clear that depletion in SLRP production can influence tissue properties. This is best illustrated by the abnormal phenotypes arising in “knockout” mice. Absence of decorin results in lax, fragile skin, in which collagen fibril morphology is irregular with fusion of adjacent fibrils appearing to have occurred (Danielson et al., 1997). Absence of biglycan results in an osteoporosis-like phenotype, with animals having a reduced growth rate and a decreased bone mass (Xu et al., 1998). Absence of lumican produces both skin laxity and corneal opacity, with an increased proportion of abnormally thick collagen fibrils, and delayed corneal epithelial wound healing (Chakravarti et al., 1998). Absence of fibromodulin produces no change in the appearance of the mice, but does result in an abnormal collagen fibril organization in tendons (Svensson et al., 1999). This work clearly shows that collagen fibril architecture is impaired in tissues in which SLRPs are deficient, and that the abnormal phenotype is specific for each proteoglycan. Of these SLRP genes, only that for decorin has currently been linked to a human disorder, with a frameshift mutation being reported in congenital stromal dystrophy of the cornea (Bredrup et al., 2005). It is also evident that the absence of GAG synthesis on the SLRPs can have detrimental consequences, as deficiency in CS/DS substitution of decorin due to mutation in a glycosyl transferase gene has been associated with the progeriod form of Ehlers-Danlos syndrome (Götte and Kresse, 2005).


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