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conserved domain of tandem leucine-rich repeats
(LRRs), an N-terminal variable domain that contains
clusters of cysteine or sulfated tyrosines, “ear repeats”
and at least one GAG side chain.
24
The LRRs are partic-
ularly important for protein-protein interactions such
as binding to collagen fibrils25-30
25-30
and modulation of
BMP activity.
15
The collagen-binding property of some
SLRPs grants them a crucial role in the proper forma-
tion of extracellular matrices. Moreover, because they
are extracellular, they are upstream of multiple signal-
ing cascades, including those driven by TGFβ/BMP
superfamily members, receptor tyrosine kinases such as
ErbB family members, the insulin-like growth factor I
receptor and Toll-like receptors.
13-16,22,31
Based on their amino acid sequence and the intron-
exon organization, SLRPS are divided into five sub-
classes that are described in further detail below.
All class I SLRPs have a similar genomic organiza-
tion of eight exons and their N-termini have a charac-
teristic cluster of cysteine residues that each form two
disulfide bonds. Class I includes: decorin, biglycan,
asporin, ECM2 and ECMX.
Class II members have a similar genomic organi-
zation containing three exons. Their N-termini con-
tain clusters of tyrosine sulfate, which may also bind
ligands
32
and their GAG chains are principally kera-
tan sulfate. Class II includes: fibromodulin, lumican,
proline arginine-rich end leucine-rich repeat protein
(PRELP), keratocan and osteoadherin.
The SLPRs in class III have a genomic organization
comprised of seven exons. Class III includes: epiphy-
can, opticin and osteoglycan.
Based on their structure, class IV members are not
classically considered SLRPs; however, as these mol-
ecules share functional properties with class I SLRPs,
a separated subclass was created to include them. This
non-canonical class includes: chondroadherin, nyctalo-
pin and tsukushi.
Class V members have 20 LRRs and homology to
class I and II molecules. They too are not conventional
SLRPs. Members of class V include: podocan and
podocan-like protein I.
Throughout evolution some of the genes encod-
ing members of the SLRP family of PGs were retained
in clusters on their respective chromosomes, which
may, at least partially, explain their (functional) redun-
dancy.
33
Despite the fact that ablation of SLRP genes
usually results in increased expression of other mem-
bers of the same subclass, disruption of SLRP genes in
mice has revealed various clinical skeletal phenotypes,
which are mostly associated with abnormal collagen
fibril size and shape. Considering that the assembly of
proper, specialized collagen fibrils via the regulation
of intermolecular crosslinking is one major function of
SLRPs,
34
it is not surprising that the absence of SLRPs
leads to improper or impaired crosslinking and there-
fore affects the fibril diameter, alignment and aggre-
gation into thicker bundles. Since different stages of
fibril formation require different SLRPs, manipulation
of different SLRP family members has different conse-
quences.
1,34-38
Moreover, the continued presence of a
SLRP “coating” on the collagen fibrils, even after the
collagen fibers are assembled, prevents overgrowth
of the fiber beyond a certain diameter,
34
protects
against collagenase activity and enables proper matrix
function.
34,39
Decorin, a class I SLRP, is encoded by the
DCN
gene
located on human chromosome 12. The PG contains
only one GAG chain attached to the serine at position
4.
40
Decorin expression is high in the dermis, tendons
and bones.
41-43
The biglycan gene (
BGN
) is located on
the X (but not Y) chromosome. Biglycan is also a class I
SLRP containing two GAG chains, which in humans
are attached at amino acids 5 and 10. In tendon devel-
opment, the expression of biglycan decreases after early
fibril assembly.
44,45
Within mineralized matrices decorin
and biglycan are predominantly substituted with the
chondroitin sulfate GAGs, while those in soft connec-
tive tissues predominantly carry dermatan sulfate.
Though there is some controversy regarding
biglycan's ability to bind collagen (type I and II), most
reports indicate biglycan actually competes with deco-
rin in binding to type I collagen in the gap zone of the
fibrils.35-37,46
35-37,46
In addition, despite the fact that both deco-
rin and biglycan are capable of binding all three iso-
forms of TGF-β, analysis of bone cell extracts revealed
that TGF-β is mainly bound to decorin's core protein
and that the interaction between TGF-β and decorin
actually increases the affinity of TGF-β to its receptors
and, as a consequence, its activity.
13,47
Different spatial patterns of expression of decorin
and biglycan are found in mature and immature bones,
and these expression patterns dramatically change
during bone tissue development. The patterns point
to the different roles these two SLRPs play at specific
sites during specific developmental events such as ini-
tial osteoid formation and subsequent bone miner-
alization.
48
In immature bones, decorin is expressed
throughout the osteoid matrix and is associated with
osteogenic and non-osteogenic layers of the periosteum,
whereas in mature bone, decorin is present in specific
bone matrix areas. These areas include the perilacu-
nar matrix, the canaliculi of osteocytes, and the matrix
immediately adjacent to quiescent Haversian canals.
Biglycan, on the other hand, is localized to the walls
of the osteocyte lacunae and bone cell surface within
developing bone but appears to be evenly distributed
throughout the bone matrix in mature bone.
48,49
Studies in genetically altered animals show that con-
sistent with the high level of expression of decorin in
