Role of osteopontin in bone remodeling and orthodontic tooth movement: a review

Abstract

In this review, most of the known and postulated mechanisms of osteopontin (OPN) and its role in bone remodeling and orthodontic tooth movement are discussed based on available literature. OPN, a multifunctional protein, is considered crucial for bone remodeling, biomineralization, and periodontal remodeling during mechanical tension and stress (orthodontic tooth movement). It contributes to bone remodeling by promoting osteoclastogenesis and osteoclast activity through CD44- and αvβ3-mediated cell signaling. Further, it has a definitive role in bone remodeling by the formation of podosomes, osteoclast survival, and osteoclast motility. OPN has been shown to have a regulatory effect on hydroxyapatite crystal (HAP) growth and potently inhibits the mineralization of osteoblast cultures in a phosphate-dependent manner. Bone remodeling is vital for orthodontic tooth movement. Significant compressive and tensional forces on the periodontium induce the signaling pathways mediated by various osteogenic genes including OPN, bone sialoprotein, Osterix, and osteocalcin. The signaling pathways involved in the regulation of OPN and its effect on the periodontal tissues during orthodontic tooth movement are further discussed in this review. A limited number of studies have suggested the use of OPN as a biomarker to assess orthodontic treatment. Furthermore, the association of single nucleotide polymorphisms (SNPs) in OPN coding gene Spp1 with orthodontically induced root resorption remains largely unexplored. Accordingly, future research directions for OPN are outlined in this review.

Full text

R E V I E W Open Access
Role of osteopontin in bone remodeling
and orthodontic tooth movement: a review
Amarjot Singh
1*
, Gurveen Gill
1,3
, Harsimrat Kaur
1,3
, Mohamed Amhmed
1,3
and Harpal Jakhu
2,4
Abstract
In this review, most of the known and postulated mechanisms of osteopontin (OPN) and its role in bone
remodeling and orthodontic tooth movement are discussed based on available literature. OPN, a multifunctional
protein, is considered crucial for bone remodeling, biomineralization, and periodontal remodeling during
mechanical tension and stress (orthodontic tooth movement). It contributes to bone remodeling by promoting
osteoclastogenesis and osteoclast activity through CD44- and αvβ3-mediated cell signaling. Further, it has a
definitive role in bone remodeling by the formation of podosomes, osteoclast survival, and osteoclast motility.
OPN has been shown to have a regulatory effect on hydroxyapatite crystal (HAP) growth and potently inhibits the
mineralization of osteoblast cultures in a phosphate-dependent manner. Bone remodeling is vital for orthodontic
tooth movement. Significant compressive and tensional forces on the periodontium induce the signaling pathways
mediated by various osteogenic genes including OPN, bone sialoprotein, Osterix, and osteocalcin. The signaling
pathways involved in the regulation of OPN and its effect on the periodontal tissues during orthodontic tooth
movement are further discussed in this review. A limited number of studies have suggested the use of OPN as a
biomarker to assess orthodontic treatment. Furthermore, the association of single nucleotide polymorphisms (SNPs)
in OPN coding gene Spp1 with orthodontically induced root resorption remains largely unexplored. Accordingly,
future research directions for OPN are outlined in this review.
Keywords: Osteopontin, Bone remodeling, Biomarkers, Root resorption, Orthodontic tooth movement
Background
Osteopontin (OPN) is a highly phosphorylated and gly-
cosylated sialoprotein that is expressed by several cell
types including osteoblasts, osteocytes, and odontoblasts.
OPN belongs to the family of non-collagenous proteins
known as SIBLING (small integrin-binding ligand,
N-linked glycoprotein) [1]. In humans, OPN is encoded
by Spp1 gene located on the long arm of chromosome 4
region 22 (4q1322.1). OPN is a prominent component of
mineralized extracellular matrices of bones and teeth
[2]. It has been found to be involved in a number of
pathologic and physiological events including bone re-
modeling, biomineralization, wound healing, apoptosis,
and tumor metastasis [2].
Bone remodeling is crucial for maintaining the normal
skeletal structure as well as a key factor for orthodontic
tooth movement. Orthodontic forces exert a significant
amount of compressive [3–9] and tensional [7,10–13]
forces on the periodontium to induce the signaling path-
ways mediated by various osteogenic genes including
OPN, bone sialoprotein, Osterix, and osteocalcin. The
signaling pathways and response of the periodontium
differ on both tension and compression sides; however,
OPN is ubiquitously expressed in bone remodeling on
both sides [13].
In this review, our focus will be on the events con-
trolled by OPN in bone remodeling and orthodontic
tooth movement. In addition, the prospects of OPN in
accelerating tooth movement and root resorption and as
a biomarker will be outlined. In our knowledge, no study
till date has reviewed the mechanisms involved in
OPN-mediated bone remodeling during orthodontic
tooth movement.
OPN structure and its expression and regulation
OPN is multifunctional protein owing to its structure.
OPN molecule comprises unique conserved regions
* Correspondence: amarjot.singh@mail.mcgill.ca
1
Faculty of Dentistry, McGill University, Montreal, Quebec, Canada
Full list of author information is available at the end of the article
© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made.
Singh et al. Progress in Orthodontics (2018) 19:18
https://doi.org/10.1186/s40510-018-0216-2

which involve (RG)-binding domain, serine/threonine
phosphorylation site, two heparin-binding sites, one
thrombin cleavage site, and a putative calcium-
binding site [14]. The cell interacting domains include
arginine-glycine-aspartic acid (RGD) cell-binding se-
quence and serine-valine-valine-tyrosine-glutamate-
leucine-arginine (SVVYGLR) motif [15]. The cleavage
sites include thrombin and matrix metalloprotinase’s
(MMP’s) cleavage sites [14]. In response to cleavage
by thrombin, SVVYGLR site is revealed and leads to the
formation of two segments: N-terminal fragment and
C-terminal fragment (Fig. 1). The pro-inflammatory
N-terminal segment includes two integrin-binding sites:
RGD and SVVYGLR motifs [15]. However, the C-terminal
fragment is devoid of an integrin-binding site. MMP’s
cleave both fragments by binding to MMP’s cleavage sites:
cleaving N-terminal fragment leads to inactivation of
integrin-binding domain of SVVYGLR motifs [15].
The expression of OPN is regulated by a large number
of cytokines, hormones, and growth factors, which affects
gene transcription, translation, and post-translational
modifications (Table 1)[16]. Also, expression of OPN in-
creases in response to mechanical stress [17–19]. There-
fore, it is a critical factor in regulating bone remodeling in
responses to mechanical stimuli.
OPN in bone remodeling
OPN is considered to play important role in bone forma-
tion and resorption [20–22]. It is highly concentrated at
cement lines where pre-existing and newly formed bone
meet and at bone surfaces interfacing with cells called as
laminae limitantes [23]. There are various levels of medi-
ation of OPN in bone remodeling. For example, OPN is
demonstrated to have chemotactic activity [24]onthe
precursor of osteoclasts, at a concentration from 10 nM
to 1 μM[17]. Also, OPN-dependent intracellular signaling
is seen in sealing zone formation in osteoclastic resorption
(Fig. 2a,b). Broadly, various authors described the follow-
ing pathways in OPN-mediated bone remodeling.
Integrin αvβ3-mediated signaling
OPN binds to several integrins including αvβ3, αvβ5,
αvβ1, α4β1, α5, and α9β1. OPN binding to αvβ3iscrucial
for major post-receptor signal responses, which involves
regulation of osteoclastic activity and activation of osteo-
protegerin expression [24,25]. Further, OPN binding to
integrin αvβ3 plays a major role in the formation of
sealing zone in osteoclast activity. OPN-αvβ3bindingon
the surface of osteoclasts induces integrin clustering and
leads to intracellular signaling by phosphorylation of pro-
tein tyrosine kinase 2 (PYK2) [25,26]thatfacilitatebind-
ing of proto-oncogene tyrosine-protein kinase (Src) via its
SH2 domain. This Src-PYK2 binding leads to further
phosphorylation of PYK2 at other sites which amplifies
the signals activating cellular functions including cell
adhesion such as sealing zone formation (Fig. 2b)[25,26].
It has also been suggested that integrin αvβ3, Src, and Fms
(the receptor for M-CSF) stimulate Spleen tyrosine kinase
(Syk) which further mediates GTP loading on Rac1 via Vav3
in osteoclasts [27]. GTP loading on Rac 1 drives cytoskeletal
remodeling leading to bone resorption. Certain proteins
including Wiskott-Aldrich syndrome protein (WASP) and
gelsolin are also regulated by integrin αvβ3. This process is
vital for the podosome formation on osteoclasts [27].
In addition, OPN binding to integrin αvβ3 has been sug-
gested to modulate intracellular Ca
2+
through stimulation
of Ca
2+
release from intracellular compartments and regu-
lating extracellular calcium influx via Ca
2+
-ATPase pump
[28,29]. The induction of cytosolic Ca
2+
further modu-
lates osteoclast activity by translocation of transcription
factor NFATc1 (nuclear factor of activated T cells,
cytoplasmic 1) through the Ca
2+
-NFAT pathway (Fig. 2b)
[30,31]. This NFATc1 has been shown to be imperative
for osteoclastogenesis [32–34], leading to the increased re-
sorptive activity of mature osteoclasts [30,31].
CD44-associated cell signaling
Osteoclasts deficient in OPN show no migratory activity
and do not resorb bone [35]. It has been demonstrated
Fig. 1 A schematic representation of osteopontin structure and thrombin cleavage site. RGD (arginine-glycine-aspartic acid) and SVVYGLR
(serine-valine-valine-tyrosine-glutamate-leucine-arginine) binding domains are indicated
Singh et al. Progress in Orthodontics (2018) 19:18 Page 2 of 8

that OPN-deficient osteoclasts, when treated with
exogenous OPN, result in an enhanced CD44 expres-
sion [36]. CD44-induced cell signaling enhances
osteoclast motility [35], which partially restores bone
resorption, by activation of αvβ3integrin[36,37].
OPN stimulate osteoclast migration through αvβ3-
and CD44-mediated cell signaling, which further in-
creases CD44 expression on osteoclasts [35,36].
Addition of exogenous OPN partially restores the
resorptive activity of osteoclasts, which indicates
autocrine OPN is important to osteoclast activity
[36]. However, exogenously added OPN does not
have access to OPN secreted by osteoclasts, which
are present in resorption lacuna [36]. The intracellu-
lar form of OPN (iOPN), an integral component of
the CD44-ERM complex, is seen to be involved in
migrating fibroblasts, macrophages, osteoclasts, and
metastatic breast cancer lines [2,38]. A hypothetical
pathway was described in which iOPN with components
of CD44-ERM is involved in cell migration [2,38].
Further, it has been demonstrated that overexpression of
phosphatase and tensin homolog (PTEN) restricts
PI3-kinase signaling, suppresses receptor activator of
nuclear kappa-B ligand (RANKL) and OPN-induced Akt
activation, and ultimately results in the downregulation of
osteoclast differentiation and cell motility [39].
Table 1 Factors affecting the expression and regulation of osteopontin
Expression and upregulation of OPN Downregulation of OPN
Transcription factors—Runx2 and Osterix [68] cGMP-dependent protein kinase [2]
Inorganic phosphate [69] Bisphosphonates [2]
Systematic conditions—hypophosphatemia, hypocalcemia [2]
Hormones—glucocorticoids, [70]
1,25-dihydroxyvitamin D3, [70] parathyroid hormone [14]
ERK inhibitor
Vitamins—retinoic acid [70]
Inflammatory mediators—TNFα, IL-1β, TGFβ[14]
Mechanical stress
ab
Fig. 2 A schematic representation of bone resorption occurring at cellular and molecular level. aRANKL/RANK/OPG pathway and osteopontin in
podosome formation. bOsteopontin binding to integrin αvβ3 leads to podosome formation and osteoclastic activity via Rac and NFAT pathway
respectively. M-CSF (macrophage colony-stimulating factor), CSF-R (colony-stimulating factor receptor), RANKL (receptor activator of nuclear
kappa-B ligand), RANK (receptor activator of nuclear kappa-B), OPG (osteoprotegerin), Src (proto-oncogene tyrosine-protein kinase), Syk (Spleen
tyrosine kinase), Vav3 (vav guanine nucleotide exchange factor 3), Rac1 (Ras-related C3 botulinum toxin substrate 1), NFAT (nuclear factor of
activated T cells)
Singh et al. Progress in Orthodontics (2018) 19:18 Page 3 of 8

Inhibition of mineral deposition
The bone matrix consists of the inorganic component, hy-
droxyapatite (HA), and organic component, proteins and
proteoglycans [2]. OPN protein along with other SIBLING
proteins contain acidic, serine-, and aspartate-rich motif
(ASARM) which are the potential phosphorylation sites
[1]. Phosphorylated OPN inhibits mineralization via phos-
phate residues [40]. Contrary to it, OPN dephosphoryla-
tion by tissue-non-specific alkaline phosphatase (TNAP)
prevents much of its mineral binding and crystal growth
activity [40]. Both pyrophosphate (PPi) and OPN contains
highly negative charge phosphate residues which inhibit
mineralization after binding to HA crystals [40]. It has
been shown that peptide phosphorylated MEPE ASARM
(pASARM) has a greater affinity for HA than nonpho-
sphorylated ASARM (npASARM). OPN can act inde-
pendently of PPi as well as a mediator of PPi effects. High
levels of extracellular PPi lead to increased OPN expres-
sion and secretion by osteoblasts [40].
Pyrophosphate prevents mineralization by three pro-
posed mechanisms. Firstly, there is direct binding of PPi
to growing HA crystals. Secondly, there is the induction
of OPN expression by osteoblasts through MAPK path-
way, enabling the coordinated action of both PPi and
OPN [40]. Thirdly, there is a feedback mechanism in
which Pi/PPi ratio inhibits TNAP activity [40]. Even
though OPN is considered as mineralization inhibitor, it
has been shown that OPN can serve as an agent for
intra-fibrillar mineralization in collagen [41], thus pointing
towards the multifunctional role of OPN.
Potential role of OPN in orthodontic tooth
movement
Various knockout studies have demonstrated that bone
remodeling is impaired in OPN-deficient mice [42]in
response to mechanical stress [8,43,44]. An animal
study [44], by Walker et al., has revealed that OPN is
required for osteoclast recruitment through RANKL
expression in unloaded mechanical stress (unopposed
molar model). Further, it has been suggested that OPN
mediates osteoclast activity, RANKL expression, and
bone resorption at unloaded alveolar bone walls using a
PI3K- and ERK-dependent mechanism [44]. No distal
drifting was reported in the OPN-deficient mice [44].
In the initial stages of orthodontic tooth movement,
OPN is observed in the osteocytes [13]. A study [17]
suggested the change in the number of OPN mRNA
expressing osteocytes on the pressure side after 48 h of
mechanical stress and reached a maximum value at 72 h
[8], coinciding with bone resorption. However, in the
later stages of OTM, OPN is ubiquitously expressed in
PDL cells, osteoclasts, cementocytes, cementoblasts, and
osteoblasts as well as the cement line of alveolar bone
and cementum [13,45,46]. The potential signaling
pathways involved in the OPN regulation during the
orthodontic tooth movement on compression as well as
on tension side are summarized in Fig. 3.
OPN and RANKL regulation on compression side
Wongkhantee and coworkers first studied the OPN ex-
pression in human periodontal ligament cell (HPDL) via
Rho kinase pathway (Fig. 3)[4] and analyzed that
stress-induced ATP activates Rho kinase pathway via the
purinoreceptor 1 (P2Y1) receptor [5]. They proposed
that RANKL upregulation during mechanical compres-
sion may be further induced via activation of NFκB
pathway-mediated release of cyclooxygenase and prosta-
glandin E2 (PGE2) production [3]. Later, various re-
search groups analyzed the Rho kinase-mediated OPN
induction. Hong et al. reported that OPN induction dur-
ing compression is mediated by RhoA-controlled focal
adhesion kinase (FAK) and extracellular signal-regulated
kinase (ERK) pathways in human periodontal ligament
fibroblasts (Fig. 3). ERK further phosphorylates ETS
domain-containing protein (Elk-1) which results in the
transcription of OPN [47].
OPN and RANKL collectively work to induce the bone
resorption in response to compressive forces (Fig. 3).
Osteoblasts and stromal stem cells express receptor
activator RANKL which binds to its receptor, receptor
activator of nuclear kappa-B (RANK), on the surface of
osteoclasts and their precursors. This regulates the
differentiation of precursors into multinucleated osteo-
clasts [48,49]. In addition, a study by Walker and
coworkers suggested that increased OPN expression
enhances RANKL expression via extracellular matrix sig-
naling pathway in unloaded distal drift [44]. Nevertheless,
no study has assessed the influence of OPN expression on
RANKL in mechanically stressed condition viz. orthodon-
tic tooth movement and need further investigation.
OPN regulation on tension side
Su et al. first reported the expression of a gap junction
alpha-1 protein, connexin 43, on tension side during
orthodontic tooth movement in rat periodontal ligament
cells [10]. Later, Shengnan et al. confirmed the involve-
ment of connexin 43 and ERK in tension-induced signal
transduction human periodontal ligament fibroblasts
(Fig. 3)[7]. It was reported that ERK further induces the
transcription of osteogenic proteins, runt-related tran-
scription factor 2 (RUNX2), osteoprotegerin (OPG), and
Osterix [7]. In a recent study, the upregulation of OPN
along with alkaline phosphatase, collagen I, osteocalcin,
and bone sialoprotein was reported via ERK and p38
MAPK-mediated pathway during orthodontic tooth
movement in response to tension stress [11]. Thus, both
ERK and p38 were proposed to be significantly involved
Singh et al. Progress in Orthodontics (2018) 19:18 Page 4 of 8

in periodontal remodeling during orthodontic tooth
movement [11].
Wnt/βcatenin pathway has been shown to be signifi-
cantly involved in the matrix formation in response to
mechanical strain [50–54]. Whether this pathway is in-
volved in the tension forces created during the ortho-
dontic tooth movement is not yet known. Thus, we
hypothesize that strain-induced transduction of Wnt/β
catenin could be involved in the upregulation of osteo-
genic proteins including Osterix and OPN (Fig. 3).
OPN-mediated tooth root resorption and repair
Root resorption is one of the side effects of the ortho-
dontic treatment and is the result of activity of odonto-
clasts [45]. A mice study showed odontoclast expressing
OPN mRNA appeared on the surface of the active root
resorption 5 days after orthodontic movement [45].
Similarly, Chung et al. demonstrated that OPN defi-
ciency has much more enhanced effect on the decrease
in the odontoclastic activity than osteoclastic activity
[43]. They proposed that abundance of inflammatory
regulators in the alveolar bone might overwhelm the
deficiency of OPN, thereby having little effect on the bone
resorption [43]. In contrast to the alveolar bone, cementum
and root surface of the tooth is deficient in the inflamma-
tory mediators, thereby enhanced odontoclastic activity
may be the one reason in OPN-deficient mice [43]. Thus,
OPN is a crucial factor in force-induced root resorption of
tooth [43]. Jimenez-Pellegrin et al. demonstrated that OPN
plays a key role in both cementum resorption and repair
after orthodontic rotation movement [55].
On the other hand, the role of OPN in cementogenesis
followed by mechanical injury was also studied in the
epithelial cell rests of Malassez (ECRM) [56,57]. It has
been suggested that ECRM express various osteogenic
genes including OPG and OPN [56]. Also, immunohis-
tochemical characteristics of ECRM suggested that it
may be significantly involved in the secretion of matrix
proteins including OPN to further induce cementum
repair followed by mechanical injury [57].
Various research groups studied the single nucleotide
polymorphisms (SNPs) in the OPN coding gene Spp1
and its effect on the tooth root resorption [58–60].
Iglesias-Linares and coworkers first reported that OPN
Fig. 3 A schematic representation of osteopontin regulation and osteopontin-mediated periodontal remodeling during orthodontic tooth movement
at tension side and compression side. ECM (extra-cellular matrix), PDL (periodontal ligament), Cx43 (connexin 43), ERK1/2 (extra-cellular signal-regulated
kinase 1,2), RUNX2 (runt-related transcription factor 2), IL-1/IL-8 (interleukin 1/8), MMP’s (matrix metalloproteinases), VEGF (vascular endothelial growth
factor), TIMP’s (tissue inhibitors of metalloproteinases), ATP (adenosine triphosphate), PGE2 (prostaglandin E2), EP, RANKL (receptor activator of nuclear
kappa-B ligand), RANK (receptor activator of nuclear kappa-B), OPG (osteoprotegerin), P2Y1 (purinoreceptor 1), Pka (protein kinase A), NFkB (nuclear
factor kappa B), COX (cyclooxygenase), ROCK (Rho-associated protein kinase), FAK (focal adhesion kinase), ELK1 (ETS domain containing protein), AP1
(activator protein 1)
Singh et al. Progress in Orthodontics (2018) 19:18 Page 5 of 8

gene SNPs (rs9138, rs11730582) are involved in the sus-
ceptibility of external root resorption in patients under-
going orthodontic treatment [58]. However, in another
study, OPN gene SNPs and its effect on external apical
root resorption (EARR) were not confirmed in Czech
children [60]. However, the association between individual
variability in purinoreceptor (P2X7) and EARR was sug-
gested to be an important factor in the etiopathogenesis of
EARR [60]. Iglesias-Linares et al. later implicated the Spp1
gene SNPs to assess the orthodontically induced external
apical root resorption (OIEARR) in patients with remov-
able appliances versus fixed appliances [59]. No any pre-
disposition to OIEARR was reported with response to
fixed and removable appliances [59].
Future directions
Since OPN is ubiquitously expressed in periodontal re-
modeling during orthodontic tooth movement, various
research groups have implicated OPN as a biomarker to
assess the tissue response with respect to orthodontic
treatment [61]. The samples were collected from GCF
and a protein levels were assessed [61–65]. DNA methy-
lation biomarkers of Spp1 gene and other osteogenic
genes may also be helpful to understand the individual
variability in response to orthodontic treatment [66].
Thus, a more tailored and personalized approach [66]
can be drawn to treat patients with an increased predis-
position to OIEARR via targeting the epigenetic mecha-
nisms. Similarly, micro RNAs targeting the osteogenic
genes can be assessed.
Alveolar decortication has been shown to induce the
rate of tooth movement via the coupled mechanism of
bone resorption and formation in early stages of ortho-
dontic tooth movement [67]. The underlying biomarkers
(OPN, osteocalcin, bone sialoprotein) demonstrated in-
creased anabolic activity. Whether the orthodontic tooth
movement can be accelerated via targeting the under-
lying signaling pathways warrants further investigation.
Conclusions
OPN has a definitive role in the formation of podo-
somes, osteoclast survival, and osteoclast motility. Vari-
ous OPN-mediated signaling pathways involved in the
periodontal remodeling facilitate orthodontic tooth
movement. There is a need to pharmacologically target
these signaling pathways in order to decrease the side ef-
fects of orthodontic treatment including tooth root re-
sorption in patients with an increased predisposition to
OIEARR. In addition, the application of OPN bio-
markers should be assessed and compared at proteomic,
genomic, and epigenomic levels in order to gain a more
tailored orthodontic approach. Nonetheless, there is dire
need of validated studies to further translate the rele-
vance of OPN in orthodontic treatment.
Abbreviations
AP1: Activator protein 1; ATP: Adenosine triphosphate; COX: Cyclooxygenase;
CSF-R: Colony-stimulating factor receptor; Cx43: Connexin 43;
ECM: Extracellular matrix; ELK1: ETS domain containing protein; EP,
P2Y1: Purinoreceptor 1; ERK1/2: Extracellular signal-regulated kinase 1,2;
FAK: Focal adhesion kinase; IL-1/IL-8: Interleukin 1/8; M-CSF: Macrophage
colony-stimulating factor; MMP’s: Matrix metalloproteinases; NFAT: Nuclear
factor of activated T cells; NFkB: Nuclear factor kappa B;
OPG: Osteoprotegerin; PDL: Periodontal ligament; PGE2: Prostaglandin E2;
Pka: Protein kinase A; Rac1: Ras-related C3 botulinum toxin substrate 1;
RANK: Receptor activator of nuclear kappa-B; RANKL: Receptor activator of
nuclear kappa-B ligand; RGD: Arginine-glycine-aspartic acid; ROCK: Rho-
associated protein kinase; RUNX2: Runt related transcription factor 2;
Src: Proto-oncogene tyrosine-protein kinase; SVVYGLR: Serine-valine-valine-
tyrosine-glutamate-leucine-arginine; Syk: Spleen tyrosine kinase; TIMP’s: Tissue
inhibitors of metalloproteinases; Vav3: Vav guanine nucleotide exchange
factor 3; VEGF: Vascular endothelial growth factor
Authors’contributions
AS made a substantial contribution to the conception, design, and revision
of the manuscript. GG, HK, MA, and HJ made contributions in the revision of
the manuscript. AS and HK designed the figures. All authors read and
approved the final manuscript.
Ethics approval and consent to participate
Ethical approval was not required.
Competing interests
The authors declare that they have no competing interests.
Publisher’sNote
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1
Faculty of Dentistry, McGill University, Montreal, Quebec, Canada.
2
Department of Endodontics, Government Dental College, Amritsar, Punjab,
India.
3
Lady Davis Institute, Jewish General Hospital, Montreal, Quebec,
Canada.
4
Sandalwood Smiles, Private Dental Practice, Brampton, Ontario,
Canada.
Received: 27 February 2018 Accepted: 24 May 2018
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