Experimental Oncology 26, 179-184, 2004 (September)
Exp Oncol 2004
26, 3, 179-184
179
ROLE OF OSTEOPONTIN IN ADHESION, MIGRATION, CELL
SURVIVAL AND BONE REMODELING
Therese Standal*, Magne Borset, Anders Sundan
Department of Cancer Research and Molecular Medicine, Faculty of Medicine,
Norwegian University of Science and Technology, Trondheim, Norway
Osteopontin (OPN) is a secreted adhesive glycophosphoprotein expressed by several cell types. It is normally
produced in bone, teeth, kidney and epithelial lining tissues and is found in plasma and breast milk. It is involved
in a number of physiologic and pathologic events including angiogenesis, apoptosis, inflammation, wound healing
and tumor metastasis. In this review focus will be on OPN in bone and its role in adhesion, migration and cell
survival. These aspects of OPN biology are important in tumorigenesis.
OPN — general properties. OPN’s versatile functions are illustrated by early articles describing this protein. Initially, OPN was described as a major noncollagenous protein in bone and named bone sialoprotein I [1].
The paper by Senger and colleagues [2] describes a protein whose secretion was elevated in cultures of transformed cells, indicating a function of it in tumor biology. In
addition, OPN is important in immune activity and bacterial resistance and was named early T-lymphocyte activation 1 protein (Eta-1) by Patarca et al [3] in 1989. Today the protein is designated OPN and is known to be
involved in bone resorption, wound repair, immune function, angiogenesis, cell survival and cancer biology.
OPN is an acidic protein consisting of about 300 amino acids. The protein is highly phosphorylated and glycosylated and has an arginine-glycine-aspartic acid
(RGD)-binding domain as well as two heparin-binding
sites, one thrombin cleavage site and a putative calcium
binding site [4]. Matrix metalloproteases 3 and 7 also
cleave OPN [5]. Cleavage of OPN by proteases (most
notably thrombin) generates two functional fragments,
an RGD-containing N-terminal part that binds to integrin receptors and a C-terminal fragment which interacts with CD44 variants. The C-terminal fragment also
contains the two heparin-binding sites [4]. Both cleaved
and native OPN can bind integrins, although some cells
adhere more strongly to cleaved than native OPN [6–9].
Cleavage of OPN by thrombin unmasks epitopes that
are hidden in the native protein, and also makes the
RGD-motif more accessible in some cases.
OPN is encoded by a single gene, and its promoter
is responsive to a number of different transcription factors [10, 11].
Cell survival. Both soluble OPN, which works as a
cytokine, and immobilized OPN, which function as an
extracellular matrix protein, protect against apoptosis and
induce survival and proliferation in several cell types.
OPN has a pro-survival and/or proliferative function
in adherent cell types such as smooth muscle cells [12]
and epithelial cells [13]. Endothelial cells plated on OPNReceived: July 8, 2004.
*Correspondence:
Fax: +47 73 59 88 01
E-mail: [email protected]
Abbreviations used: OPN — osteopontin.
coated surfaces are protected against apoptosis induced
by serum deprivation or by TRAIL [14, 15]. OPN’s survival function on endothelial cells is mediated through avb3
integrin and nuclear factor kappa B (NF-kB) activation
[14]. Furthermore, it was recently shown that OPN-induced NF-kB activation in endothelial cells leads to enhanced expression of osteoprotegerin (OPG). OPG forms
a complex with TRAIL which subsequently blocks apoptosis [15, 16]. In another study, soluble OPN was found to
inhibit apoptosis of adherent endothelial cells deprived of
growth factors [17]. In contrast to the NF-kB pathway
probably involved in immobilized OPN’s anti-apoptotic
effect, stimulation by soluble OPN was shown to cause
an up-regulation and re-distribution of Bcl-XL. Although
both immobilized and soluble OPN seem to protect adherent endothelial cells, soluble OPN has no anti-apoptotic effects on endothelial cells held in suspension [18].
However, other cells grown in suspension are protected from apoptosis by OPN. An example of this is the
non-adherent IL-3-dependent pro-B cell line Ba/F3.
When these cells are stressed (deprived of IL-3), OPN
protects against apoptosis via CD44 interaction and seems
to involve PI 3K-Akt downstream signaling pathway [19,
20]. OPN thus seems to give pro-survival signals both
through integrins and through CD44, and the downstream
signaling pathways seem to differ and depend both on
which receptors are engaged and on cell type.
OPN is strongly associated with tumorigenesis. In patients with breast cancer [21–23], multiple myeloma [24]
and prostate cancer [25] high plasma levels or tumor expression of OPN are associated with poor prognosis. Thus,
not surprisingly, OPN is expressed by several types of cancer cells [26–29]. Some of them also respond to OPN with
enhanced survival and proliferation. A recent study [30] indicates that epidermal growth factor (EGF) dependent proliferation of prostate cancer cells is amplified by OPN. This
is probably due to an interaction of OPN with beta1 integrins on the surface of the cancer cells, leading to sustained activation of the epidermal growth factor receptor
(EGFR). Epidermal growth factor (EGF) is an important
growth factor for prostate cancer cells and this interaction
thereby promotes proliferation of the cancer cells. Similarly, IL-6 is an important growth promoting/survival factor for
myeloma cells, and OPN has been shown to promote my-
180
eloma cell growth in combination with IL-6. Receptors involved are a4b1 and avb3 [31] but the precise molecular
mechanisms are currently not known. Breast carcinoma
cells are protected against apoptosis when they adhere to
OPN via avb3 [32]. Although cancer cells often produce
OPN, they also give rise to enhanced OPN production by
host cells such as stromal cells/osteoblasts [29, 33] and
osteoclasts [31]. OPN effects on tumor cells can thus be
both autocrine and paracrine.
Adhesion and migration. OPN’s association with
cancer can partly be explained by its anti-apoptotic and
proliferative effect on tumor cells. However, OPN’s role
as an adhesive and migratory factor might be even more
important in tumorigenesis. Increased adhesion and migration may confer metastatic capacity and invasiveness to tumor cells.
Most cells adhere to OPN through integrins. Both
av (b1, b3, b5) and (a4, a8, a9)b1 on several cell types
bind to OPN [7, 34–36]. The binding of avb1, avb3, avb5
integrins to OPN is RGD-dependent [6, 37–39], whereas the binding of a4b1 and a9b1 involves other amino
acid sequences [40, 41]. Cells can also bind to OPN
via some splice forms of CD44. The binding of
CD44-variants to OPN is RGD-independent [42] but
seems to require b1 containing integrins [43].
The chemoattractant property of OPN has been demonstrated in the migration of monocytic cells/macrophages, T-cells, smooth muscle cells, endothelial cells, epithelial cells and several malignant cells [8, 39, 42, 44,
45]. Malignant cells often show an increased responsiveness to OPN as compared to their normal counterparts.
In cancer, integrin expression is often aberrant on malignant cells [46–48]. Tumorigenic and highly metastatic
mammary epithelial cells migrate toward OPN in an
avb3-dependent way whereas non-malignant and less
malignant epithelial cells do not express avb3. Migration of
the latter cells to OPN is dependent on avb5 and b1 [49,
50]. Transfection of the less malignant cells lacking avb3
with b3 leads to increased adherence, migration and invasiveness in vitro and also leads to increased tumorigenesis in vivo [50]. Cells expressing avb3 are more responsive to OPN than cells lacking this integrin and the
increased responsiveness may enhance the malignancy-inducing effect of OPN. Migration induced by OPN
via integrin is dependent on at least two different growth
factor/receptor pathways (HGF/Met and EGF ligands/
EGF) and multiple signaling pathways [49, 51, 52].
Increased motility in combination with increased
protease expression may lead to increased invasiveness. Breast cancer cells invade through basement
membrane in response to OPN [45] and the invasion
seems to be dependent on secretion of uPA [53]. This
important protease is secreted due to OPN signaling
via avb3, and further activating c-Src/EGFR/ERK/AP-1
and/or PI-3kinase/Akt/NF-kB [54, 55]. Also prostate
cancer cells respond to OPN in an avb3-dependent way
with increased chemotaxis, invasion and up-regulation of plasminogen activators [56].
The findings discussed above indicate that OPN and
in particular OPN interacting with avb3 is important for the
Experimental Oncology 26, 179-184, 2004 (September)
spread of breast and prostate cancer. OPN’s role as a
metastasis-enhancing protein is further emphasized by
the fact that OPN-deficient mice have reduced number
of metastases to bone and soft tissue [57] and other studies linking OPN expression and responsiveness to increased cancer risk [45, 58, 59]. Although OPN-avb3 interaction seem to be of particular importance in breast
and prostate cancer metastases other receptors, such as
CD44, may be of importance in the malignancy and spread
of other cancer cells [27, 43].
Recent findings indicate that an intracellular form of
OPN (iOPN) exists [60, 61]. In migrating fibroblasts,
macrophages, osteoclasts and metastatic breast cancer cell lines iOPN co-localizes with CD44 in cell processes and at the cell membrane. Furthermore, iOPN
and CD44 associate with ezrin-radixin-moesin proteins inducing cytoskeleton rearrangement and signaling involved in cell migration, indicating that iOPN plays
an important role in cell movement [61-63].
OPN in bone. Bone remodeling is a regulated process in which removal of old bone by osteoclasts is
followed by bone-formation by osteoblasts. OPN influences bone homeostasis both by inhibiting mineral
deposition, by promoting differentiation of osteoclasts
and by enhancing osteoclast activity.
Inhibition of mineral deposition. Bone matrix consists of an inorganic component in the form of hydroxyapatite (HA - [Ca10 (PO4)6 (OH)2]) and an organic component consisting of proteins and proteoglycans. OPN
is one of the major non-collagenous proteins in bone.
Its electronegative glutamic and aspartic acid residues
as well as the putative Ca2+ binding motif make it bind
tightly to HA. OPN is a potent inhibitor of the mineralization process, since binding of OPN to HA inhibits
growth of HA crystals [64–66].
Differentiation of osteoclasts. Osteoclasts develop from precursor cells in the monocyte/macrophage
family to become giant multinucleated cells capable of
resorbing bone. The maturation and differentiation of
macrophages to osteoclasts are dependent on two factors secreted or expressed by stromal cells/osteoblasts:
macrophage colony stimulating factor (M-CSF) and receptor for activation of NF-kB ligand (RANKL) [67]. Engagement of these cytokines with their receptors, c-fms
and RANK, on the osteoclast precursor cells induces
maturation of the osteoclast osteoprotegerin (OPG) is a
decay receptor for RANKL. It is secreted by osteoblasts/
stromal cells and inhibits interaction of RANKL with RANK
and thereby inhibits osteoclastogenesis.
OPN does not seem to be an essential factor in the
development of osteoclasts during normal bone development since osteoclast number and distribution are normal
in OPN knock-out mice [68, 69]. However, several studies
show that in pathological situations, OPN is of importance
in osteoclastogenesis. PTH-induced RANKL signaling
normally results in either an increase in osteoclast number
and/or activation, but this increase is disrupted in the absence of OPN [70]. Similarly, ovariectomy of normal mice
(as a model of postemenopausal osteoporosis) results in a
3-fold increase of TRAP+ cells whereas ovariectomized
Experimental Oncology 26, 179-184, 2004 (September)
OPN-/- mice lack the capability to increase osteoclast number [71]. Furthermore, loss of mechanical stress normally
leads to increased bone resorbtion and an increase in osteoclast number. This effect in not seen in OPN-/- mice,
and OPN thus seems to be required for the effects on mechanical stress on bone [72].
In vitro, neutralization of OPN suppresses osteoclastogenesis, whereas addition of OPN enhances osteoclastogenesis in OPN-/- cells [73, 74]. OPN has also been shown
to influence osteoclastogenesis by enhancing RANKL and
decreasing OPG expression on stromal cells [74].
Although both Rittling et al [68] and Liaw et al [69]
found that osteoclast number was normal in OPN-/- mouse,
the number of osteoclasts in OPN-/- mice was about 3fold higher than in normal mice in the study by Yoshitake
et al [71]. This is also reported by Chellaiah et al [75]. The
increase in number of osteoclasts may be compensatory
for the decreased activity of OPN-/- osteoclasts [75].
Osteoclast activity. In mineralized tissues, OPN is
secreted by both osteoblasts and osteoclasts [73, 76, 77].
OPN is highly concentrated in sites where preexisting and
newly formed bone meet (cement lines), and in bone surfaces interfacing with cells (laminae limitantes) [78–80].
Several studies suggest that OPN in laminea limitantes
mediate the attachment of osteoclasts to bone. avb3 integrin is located in the sealing zone of osteoclasts and interacts with OPN in the bone matrix underneath [78, 79, 81–
83]. OPN stimulate osteoclast migration through avb3 and
CD44 [84–86] and also increases CD44 expression on
osteoclasts. The expression of CD44 is necessary for osteoclast motility [75]. Osteoclasts deficient in OPN do not
migrate and are unable to resorb bone [86, 87]. The boneresorbing activity can only partially be restored by exogenous OPN, indicating that autocrine OPN is important to
osteoclast activity [75]. OPN secreted by the osteoclast is
present in the resorption lacunae in which exogenously
added OPN does not have access. The need for autocrine
OPN to get fully functional osteoclasts could also be due to
the need of the expression of intracellular OPN [62].
Osteolysis in myeloma and breast cancer. Breast
cancer cells frequently metastasize to bone and commonly give rise to osteolysis. Breast cancer patients
with metastases to the skeleton have higher levels of
OPN than patients without such metastases [21].
Breast cancer and prostate cancer cells that induce
osteolytic lesions are able to enhance expression of
OPN in osteoblasts, whereas cancer cells that induce
osteopetrotic effects have no effect on OPN expression [33]. This finding indicates that osteolysis induced
by tumor cells metastasizing to the skeleton could be
due to enhanced OPN expression by osteoblasts. On
the other hand, breast cancer cells themselves express
OPN [23, 26, 88], so enhanced osteoclast activity could
be due to both tumor cell and host cell OPN.
Osteolysis is also a common complication of multiple myeloma, and, similarly, myeloma cells express
OPN [24, 29, 89] and increases OPN expression in osteoblasts/stromal cells [29] and osteoclasts [31]. Levels of circulating OPN in myeloma patients have recently been shown to be increased as compared to lev-
181
els of OPN in healthy individuals [24, 29] and to correlate to bone disease and prognosis [24]. However, the
correlation to bone disease and prognosis is not confirmed, since Standal et al [29] found no such correlations in their patient material (although a significant
correlation to serum calcium could indicate a connection of OPN to bone disease). Both studies found that
MM patients had higher plasma concentration of OPN
than MGUS patients. A major difference between MM
and MGUS patients is the lack of bone affection in
MGUS patients. Taken together, this could indicate that
OPN is implicated in the bone destruction in MM although more studies are needed to confirm this hypothesis. During the last few years, several reports show
that bone homeostasis in patients with multiple myeloma is disrupted due to an imbalance in the RANKL/
RANK/OPG system [90–94]. OPN appears to be an
important downstream factor in RANKL-mediated bone
resorption [70] and deregulation of OPN could thus
contribute to the imbalance in bone homeostasis in this
disease.
Conclusion. OPN is a player in several processes
and functions in different ways in different cells in different
systems. In this review, OPN’s role in tumorigenesis has
been exemplified by giving a brief overview over its role in
cell survival, adhesion, migration and bone remodeling.
Other aspects of OPN biology that are important in malignancy are OPN’s role in angiogenesis and immune
function. A recent review covering these topics was published [95]. The transcriptional control of OPN has not been
mentioned her but are excellently reviewed in [11].
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