Documente Academic
Documente Profesional
Documente Cultură
Bone
journal homepage: www.elsevier.com/locate/bone
Review
a r t i c l e
i n f o
Article history:
Received 27 November 2014
Revised 9 February 2015
Accepted 8 May 2015
Available online 27 June 2015
Keywords:
Bone
Healing
Remodeling
Microgravity
Kidney
Angiogenesis
Hypoxia
Apoptosis
a b s t r a c t
Osteopontin (OPN) and vascular endothelial growth factor (VEGF) are characterized by a convergence in function
for maintaining the homeostasis of the skeletal and renal systems (the bonerenalvascular axis regulates bone
metabolism). The two cytokines contribute to bone remodeling, dental healing, kidney function, and the adjustment to microgravity. Often, they are co-expressed or one molecule induces the other, however, in some settings
OPN-associated pathways and VEGF-associated pathways are distinct. In bone remodeling, OPN and VEGF
are regulated under the inuence of growth factors and hormones, hypoxia and inammation, the microenvironment, and various physical forces. Their abundance can be affected by drug treatment. OPN and VEGF
are variably associated with kidney disease. Their balanced levels are critical for restoring endothelial cell function and ameliorating the adverse effects of microgravity. Here, we review the relevant 83 papers of 257 articles
published, and listed in PubMed under the key words OPN and VEGF.
2015 Elsevier Inc. All rights reserved.
Contents
1.
2.
Introduction . . . . . . . . . . . . . . . . . . .
Skeletal healing and remodeling . . . . . . . . . .
2.1.
Growth factors and hormones . . . . . . .
2.2.
Hypoxia and Inammation . . . . . . . . .
2.3.
Micro-environment . . . . . . . . . . . .
2.3.1.
Three-dimensional scaffolds . . . .
2.3.2.
Porous scaffolds . . . . . . . . . .
2.3.3.
Inorganic scaffolds . . . . . . . .
2.3.4.
Biodegradable scaffolds . . . . . .
2.3.5.
Growth hormone-coated scaffolds .
2.4.
Mechanical, thermal or electromagnetic forces
2.5.
Drug treatment . . . . . . . . . . . . . .
3.
Dental remodeling . . . . . . . . . . . . . . . .
4.
Kidney disease . . . . . . . . . . . . . . . . . .
5.
Adjustment to microgravity . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
http://dx.doi.org/10.1016/j.bone.2015.05.047
8756-3282/ 2015 Elsevier Inc. All rights reserved.
For this comprehensive review, 257 articles with the key words
osteopontin or OPN and vascular endothelial growth factor or
VEGF in PubMed were screened (time frame from year 1996 to year
2014) (Fig. 1). After the exclusion of 37 papers, which did not focus on
Publications
30
25
20
15
10
2014
2013
2012
2011
2010
2009
2008
2007
2006
2005
2004
2003
2002
2001
2000
1999
1998
1997
1996
Year
Fig. 1. Publication statistics. Papers on OPN and VEGF by publication year.
Table 1
Functions of OPN and VEGF in bone. OPN and VEGF individually induce specic functions in various bone cell types.
Bone cell type
Function
Osteoprogenitor cells
Osteoblasts
Bone formation
Osteocytes
Maintenance of matrix
mineralization
Osteoclasts
without any change in the levels of VEGF in the calcied areas. This
increase does not match other types of lesions [41].
2.3. Micro-environment
Skeletal remodeling or regeneration is dependent on microenvironmental factors. Those include a 3-dimensional scaffold and perforations in the resident bone bed. The material used in tissue engineering is important and the performance of inorganic scaffolds needs to be
compared to biodegradable ones. Finally, the enhancement of healing
by growth factor coating of implant materials may provide substantial
support by combining structural and hormonal stimuli.
2.3.1. Three-dimensional scaffolds
Although conventional culture conditions grow cells on smooth
surfaces, the in situ micro-environment is 3-dimensional. Differential
responses between these settings, related to OPN and VEGF expression,
occur in articular chondrocytes [42], bone marrow stromal cells [43,44],
liposuction-derived stem cells [45] and osteo-progenitor cells [46].
Bone marrow stromal cells, when seeded onto collagen scaffolds in osteogenic media, undergo differentiation to form cells of osteogenic
and vascular lineages. In 3-dimensional scaffolds, they display a high expression of both OPN and VEGF, even without BMP-2. The VEGF receptor (VEGFR-2) is continuously expressed. On the other hand, when
stromal cells are cultured in 2D lms, mRNA expression of VEGF
becomes evident after a week, while OPN levels gradually increase
over 12 days, and may require treatment with BMP-2 [43,44]. Genetic
angiogenesis markers are enhanced prior to osteogenesis markers in
fat-derived stem cells in 3D scaffolds. VEGF is expressed as early as 1 h
after initiation of 3D culture and remains up-regulated by almost 7fold compared to 2D culture. Similarly, OPN shows a high baseline expression followed by a peak at day 10 in 3D, and continuously remains
up-regulated compared to 2D cultures. Thus, VEGF promotes early angiogenesis in 3D scaffolds followed by osteoblast differentiation [45].
Conventional monolayer culture of articular chondrocytes leads to a
loss of their chondrogenic phenotype and to their de-differentiation
into a broblast-like phenotype. Markers for hypertrophy, including
VEGF and OPN, are highly induced in monolayer and pellet cultures,
but have lower expression in 3D cultures. Conversely, chondrogenic
potential is present mostly in 3D cultures [42].
2.3.2. Porous scaffolds
The presence or absence of perforations in the resident bone bed affects vascularization and remodeling. Physical scaffold parameters, such
10
Table 2
Tissue engineering in bone healing. The composition of the scaffold provided profoundly impacts the process of bone healing. IL-6 = interleukin-6, BSP = bone sialoprotein, BMP = bone
morphogenic protein, AP = alkaline phosphatase, PGE2 = prostaglandin E2, OCN = osteocalcin, OPG = osteoprotegerin, FN = bronectin.
Scaffold
OPN
VEGF
Others
Comment
Reference
Inorganic
Titanium oxide, silicon dioxide, calcium monophosphide
Increase
Increase
IL-6, osteoprotegerin
[50]
Increase
Increase
Increase
Increase
Coated
ECM-coated titanium
Biomimetically-coated implant
Simvastatin-coated scaffolds
Osteostatin-coated mesoporous ceramics
Increase
Increase
Increase
Increase
Increase
Increase
OCN
OPG, OCN
PCNA, RUNX-2
Biodegradable
Hydroxyapatite/collagen
Increase
Increase
FN
Hydroxyapatite/poly(lactic-co-glycolytic acid)
Increase
Increase
AP
Hydroxyapatite ceramics
Autoclaved cancellous bone
Demineralized cancellous bone
(Increase)
(Increase)
Increase
Increase
Increase
Increase
Increase
(sustained)
Increase
(transient)
OCN, BMP-2, AP
[51]
[53]
[58]
[28]
[59]
[62]
[56]
[55]
[54]
[54]
[54]
[57]
co-glycolic acid) (PLG) composite scaffolds, those with higher hydroxyapatite (HA) content (HA:PLG ratio 2.5:1 or 5:1) are more efcacious
than scaffolds with lower HA:PLG ratios (1:1 or 0:1) in promoting osteogenic differentiation and bone tissue repair. As the percentage of
hydroxyapatite increases, there is more widespread vessel density
throughout the scaffolds, and mesenchymal stem cells form more mineralized tissue with more functional shape and size. This is matched by
increased VEGF secretion and an increase in early and late markers of
osteogenic differentiation, including alkaline phosphatase and OPN
[55]. An increasing apatite content on collagen substrates leads to a proportional increase in the deposition of VEGF-A, OPN and bronectin.
This matrix deposition is responsible for cell survival via VEGF and improved cell adhesion via OPN. Ultimately, a uniform matrix deposition
leads to increased cell migration on collagen-mineralized surfaces
[56]. Simple repeating units of amino acids assemble into nanober
scaffolds, such as RAD16, a biomaterial with potential for applications
in tissue engineering. RAD16 has osteogenic differentiation properties.
It increases OPN and VEGF levels in bone marrow cells within two
weeks. Although VEGF expression goes down thereafter, OPN expression continues to increase until week four [57].
2.3.5. Growth hormone-coated scaffolds
The interactions between cells and scaffolds constitute a very
important component in tissue engineering, which can be enhanced
by growth factor coating of the scaffold materials. An early presence of
OPN around titanium implant surfaces increases bone remodeling
after a fracture. Bone healing around the implant can be improved by
coating it with extracellular matrix (generated from cultured cells) or
growth factors such as BMP-2 or VEGF, either alone or in combination.
Bio-mimetically coated implant surfaces display increasing levels of
OPN and osteocalcin (expressed before matrix mineralization) over
two weeks. Therefore, matrix or BMP-2 plus VEGF improve the effectiveness of osteoblast differentiation and matrix mineralization via angiogenesis [28,58]. An alternative coating agent on scaffolds for tissue
engineering may be simvastatin, which promotes osteogenic differentiation via enhancing the gene expression and secretion of both VEGF-A
and OPN along with other osteoblastic markers including osteoprotegerin and osteocalcin [59,60]. According to genome wide association
studies, OPN and VEGF-A are among the top genes associated with osteoporosis and modications of the jawbone [61] (the jaw is the secondary target of osteoporosis), and therefore are likely to play a role in its
pathogenesis. Osteostatin-loaded mesoporous ceramics lead to an
increase in OPN, PCNA, VEGF and RUNX2, thus improving bone regeneration in osteoporosis [62].
2.4. Mechanical, thermal or electromagnetic forces
Processes such as distraction osteogenesis, hydrodynamic shear
stress, ultrasound, pulsed laser deposition, thermal stress, and electromagnetic elds impose forces that alter the rate of bone formation
and the expression of various proteins and growth factors associated
with the regeneration process.
Distraction osteogenesis is a surgical procedure used to reconstruct
skeletal deformities and elongate the long bones. Uniaxial mechanical
strain, the underlying force, acts on osteoblasts to stimulate cellular
and molecular factors that aid in decreasing the treatment time. During
the phase of active distraction, there is a higher expression of angiogenic
factors (VEGF-A and -D, VEGFR-2 and neuropilin, ANG1 and ANG2, and
both TIE receptors), along with the extracellular matrix protein OPN and
bone morphogenic proteins. The marker levels for angiogenesis and
osteogenesis correlate with each other, reecting a major role for
blood vessel formation in the process. The up-regulation of mRNA for
VEGF and OPN, along with broblast growth factor 2 and collagen I,
occurs via gradual distraction, which leads to complete bony union during healing, whereas acute lengthening leads to a brous non-union.
VEGF and OPN levels show an early up-regulation, peaking under
11
12
autocrine
survival
signal
VEGF
OPN
VEGF
OPN
X
mechanical stress
through
orthodontics
(reversal
of block)
NAC
apoptosis
(hypoxia)
blood
vessel
Fig. 2. Protection of dental cells by OPN and VEGF. Mechanical stress exerted by orthodontics may cause hypoxia and lead to cell death. The secretion of OPN and VEGF by pulp cells
or stromal cells protects from cell death in an autocrine fashion. N-acetylcysteine (NAC)
may restore OPN and VEGF production and anti-apoptosis under mechanical stress and
hypoxia.
Table 3
OPN and VEGF effects on the periodontal ligament. Various growth factors have distinct
effects on the secretion of OPN and VEGF, and they induce diverse functions.
VEGF
OPN
Biology
Reference
BDNF
EGF
Up
Up
Up
Unchanged
[82]
[81]
NGF
Down
Down
[81]
the levels of OPN and collagen IV, thus reducing macrophage inltration
and brosis to provide benecial effects [92].
Acute renal allograft rejection leads to an increased expression of
both OPN and VEGF. The perfusion of transplanted kidneys with a
monoclonal antibody against CD47 reduces ischemia-reperfusion injury
and lowers the levels of acute kidney injury biomarkers, including OPN,
VEGF, cystatin C, and TIMP-1. It thus improves transplantation outcomes [93].
Both OPN and VEGF may be markers of acute drug-induced or chronic nephrotoxicity. Various agents have distinct effects.
Gentamicin, ochratoxin A, sevourane, cisplatin, vancomycin and
bacitracin induce increased OPN expression [94].
Tacrolimus induces increased VEGF levels. Functionally, the induction
of VEGF by tacrolimus needs to be distinguished from VEGF increases
caused by lupus nephritis, kidney injury, or micro-albuminuric and
proteinuric diabetes [94].
Cyclosporin-mediated nephrotoxicity after transplantation leads to
an increased expression of both OPN and VEGF [94]. OPN levels rise
while VEGF levels are reduced. VEGF may have benet in the treatment of post-cyclosporine hypertension and nephropathy, because
it decreases OPN expression and reduces macrophage inltration
and collagen III deposition. Uric acid-lowering agents like the xanthine oxidase inhibitors allopurinol and benzbromarone decrease
OPN while restoring VEGF levels, thus limiting the severity of the
renal disease [95,96].
OPN, not VEGF, levels increase time- and dose-dependently in
aristolochic acid-induced renal injury, thus serving as an injury biomarker [97].
Long-term peritoneal dialysis may be employed in end-stage renal
disease. It can lead to encapsulating peritoneal sclerosis. The pathogenesis
of this complication is characterized by inammation, neoangiogenesis,
epithelialmesenchymal transition, and brosis. Matrix metalloproteinase 2 (MMP-2), which degrades type IV collagen, plays an important
role in the pathogenesis. The levels of the pro-angiogenic cytokines
OPN and VEGF, as well as transforming growth factor and monocyte
chemotactic protein 1, are correlated to MMP-2 [98].
5. Adjustment to microgravity
Extended space missions are associated with a prolonged exposure
to weightlessness (microgravity, very low g-forces). Their medical effects include muscle atrophy, osteopenia, slowing of the cardiovascular
system, anemia, balance disorders, and a weakening of the immune system, which in their sum lead to adverse health outcomes for astronauts.
Microgravity may have severe effects on various cellular features and
gene expression patterns by endothelial cells, which affect tissue remodeling. Balanced levels of OPN and VEGF are critical for restoring endothelial cell function and ameliorating the adverse effects of microgravity.
Endothelial cells are highly sensitive to conditions of weightlessness.
Their expression of various genes, including OPN, is up-regulated within
minutes of exposure to low g-forces and declines with time. Within a
week of microgravity, the endothelial cells display a delay in the formation of tubular structures of vascular intima, accompanied by a reduced
secretion of OPN, VEGF, broblast growth factor 2, soluble TNFRSF5,
TNFSF5, intercellular adhesion molecule-1 (ICAM-1), tumor necrosis
factor receptor 2 (TNFR-2), interleukin-18, complement C3, and von
Willebrand factor. There is an increase in necrotic cells. Consecutively,
the OPN protein levels slightly increase again over the ensuing week
and are higher than the OPN levels from cells under normal gravity.
By contrast, the levels of secreted VEGF are consistently lower in microgravity conditions than under normal gravity [99,100]. The introduction
of VEGF into endothelial cells in microgravity reduces cell death by suppressing the levels of FAS, PARP-116, PARP-85, NF-B, BAX and activated caspase-3, and it also counterbalances the increased levels of OPN
13
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