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(Howard and Isacke
2002
). Following uPARAP/Endo180-dependent internaliza-
tion, the collagen ligand is routed to the lysosome and degraded in a cysteine
cathepsin-dependent manner (Kjoller et al.
2004
).
uPARAP/Endo180 is predominantly expressed by mesenchymal cells.
Although the picture is far from being complete, various localization studies
have been performed in healthy tissues, using immunohistochemistry and/or in
situ hybridization. In the normal human breast, uPARAP/Endo180 is present in
some fibroblasts and myoepithelial cells (Wienke et al.
2007
). In mouse embryos
and the growing bones of young mice, strong uPARAP/Endo180 expression is
observed at primary ossification sites with prominent expression in osteoblasts,
proliferative chondrocytes, and resting zone chondrocytes (Wu et al.
1996
; Engelholm
et al.
2001
; Wagenaar-Miller et al.
2007
). Chondrocytes of articular cartilage are
also uPARAP/Endo180-positive (Howard et al.
2004
). Additional sites of expres-
sion include dermal macrophages (Sheikh et al.
2000
) and mesenchymal cells of
the villous stroma in the human placenta (Engelholm et al.
2001
). The latter study
of placenta also revealed expression of uPARAP/Endo180 in the endothelium of
the larger microvessels, although endothelial cells are in most cases uPARAP/
Endo180-negative. In marked contrast to the generally restricted expression pat-
tern of this receptor observed by most investigators, uPARAP/Endo180 in one
study was found to be expressed in several cell types in both normal and wounded
human gingiva, including epithelial cells (Honardoust et al.
2006
). However, an
independent study, in which the specificity of immunostaining was rigorously
controlled, did not observe staining in the epithelial compartment of the oral
cavity, in line with the general absence of uPARAP/Endo180 expression in the
epithelial compartment (Sulek et al.
2007
). A strongly altered expression pattern is
evident in cancer tissue. This will be discussed below.
uPARAP/Endo180-deficient mice have been generated in two independent studies
(East et al.
2003
; Engelholm et al.
2003
), and in both cases, the deficiency has been
found to have very limited consequences in unchallenged mice. Thus, mice were
born in the expected Mendelian ratio, had a normal weight gain and lifespan, and
were able to reproduce. The uPARAP/Endo180-deficient mice did, however, show
a reduced growth of the long bones in early postnatal life (Wagenaar-Miller et al.
2007
). This effect on bone growth is not unexpected in the light of the prominent
expression of the receptor in osteogenic cells and the importance of collagen
remodeling in the osteogenic process.
A recent independent work, which focused on the cause of a hereditary bone
defect in cattle, has shed additional light on the role of uPARAP/Endo180 in bone
growth. The defect in question had occurred spontaneously within a partially inbred
strain, “belgian blue” cattle, which are homozygous for a defective myostatin gene,
leading to oversized muscle tissue in otherwise healthy animals. The hereditary
bone defect was mapped in an unbiased search using chromosomal mapping, SNP
analysis, and gene sequencing, identifying a frameshift mutation in the uPARAP/
Endo180 gene as being the necessary and sufficient factor to explain all of the
observed cases of the defect (Fasquelle et al.
2009
).Thediseasedcondition,referred
