Molecular signaling mechanisms behind polyphenol-induced bone anabolism

44 Pages·2017·2.98 MB·English

by  Elisa Torre

PhytochemRev(2017)16:1183–1226
DOI10.1007/s11101-017-9529-x
Molecular signaling mechanisms behind polyphenol-induced
bone anabolism
Elisa Torre
Received:27January2017/Accepted:20August2017/Publishedonline:31August2017
(cid:2)TheAuthor(s)2017.Thisarticleisanopenaccesspublication
Abstract Formillennia, inthedifferent cultures all Keywords Anti-inflammation(cid:2)Antioxidant(cid:2)Bone
overtheworld,plantshavebeenextensivelyusedasa disease(cid:2)Pathway(cid:2)Polyphenols
source of therapeutic agents with wide-ranging
medicinal applications, thus becoming part of a
Abbreviations
rational clinical and pharmacological investigation
AD Adiposetissue-derived
overtheyears.Asbioactivemolecules,plant-derived
ALPL Alkalinephosphataseliver/bone/kidney
polyphenols have been demonstrated to exert many
AMPK Adenosinemonophosphateprotein
effects on human health by acting on different
kinase
biological systems, thus their therapeutic potential
AP1 Activatorprotein-1
would represent a novel approach on which natural
API Activepharmaceuticalingredient
product-baseddrugdiscoveryanddevelopmentcould
ARE/ Antioxidantresponse
be based in the future. Many reports have provided
EpRE element/electrophileresponsiveelement
evidence for the benefits derived from the dietary
Atf Activatingtranscriptionfactor
supplementationofpolyphenolsinthepreventionand
ATP Adenosinetriphosphate
treatment of osteoporosis. Polyphenols are able to
Bax Bcl-2-associatedX
protectthebone,thankstotheirantioxidantproperties,
Bcl-2 Bcelllymphoma2
aswellastheiranti-inflammatoryactionsbyinvolving
BMP-2 Bonemorphogeneticprotein-2
diverse signaling pathways, thus leading to bone
BMPs Bonemorphogeneticproteins
anabolic effects and decreased bone resorption. This
BSP Bonesialoprotein
review is meant to summarize the research works
Ca Calcium
performedsofar,byelucidatingthemolecularmech-
CADPE Caffeicacid3,4-dihydroxy-phenethyl
anismsofactionofpolyphenolsinaboneregeneration
ester
context,aimingatabetterunderstandingofapossible
CAFG Caviunin7-O-[b-D-apiofuranosyl-(1-6)-
applicationinthedevelopmentofmedicaldevicesfor
b-D-glucopyranoside]
bonetissueregeneration.
cAMP Cyclicadenosinemonophosphate
CCR2 C-Cchemokinereceptortype2
cGMP Cyclicguanosinemonophosphate
E.Torre(&) Col1 Collagentype1
NobilBioRicerchesrl,ViaValcastellana,26, GPR30 Gprotein-coupledreceptor30
14037Portacomaro,AT,Italy Gpx Glutathioneperoxidase
e-mail:[email protected]
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GTDF 6-C-b-D-glucopyranosyl-(2S,3S)-(?)- ERE Estrogenresponseelements
30,40,5,7-tetrahydroxyflavanol ERK Extracellularsignal-regulatedkinase
HCA P-hydroxycinnamicacid FGF-2 Basicfibroblastgrowthfactor2
HIF-1a Hypoxia-induciblefactor1-alpha FLICE FADD-likeIL-1b-convertingenzyme
HO Hemeoxygenase FLIP FLICE-inhibitoryprotein
HSP Heatshockprotein FoxO ForkheadboxO
ICAM Intercellularadhesionmolecule GM-CSF Granulocyte–macrophagecolony-
IFNc Interferonc stimulatingfactor
IGF Insulin-likegrowthfactor GPCR 7-TransmembraneGprotein-coupled
IKK Ijbkinase receptor
IL Interleukin GPER Gprotein-coupledestrogenreceptor1
iNOS Oxidesynthase PGE ProstaglandinE1
1
IP Inositoltrisphosphate PGE ProstaglandinE2
3 2
IP R IP3receptor PGF2a ProstaglandinF2a
3
JNK C-JunN-terminalkinase PI3K Phosphatidylinositol-4,5-bisphosphate
LPS Lipopolysaccharide 3-kinase
LRP Lipoproteinreceptor-relatedprotein PKA ProteinkinaseA
MAPKs Mitogen-activatedproteinkinases PKB/Akt ProteinkinaseB
MCP Monocytechemotacticprotein PKC ProteinkinaseC
MIP Macrophageinflammatoryprotein PGD ProstaglandinD2
2
MMP Matrixmetalloproteinase PLC PhospholipaseC
mPGES MicrosomalprostaglandinEsynthase PP2A Proteinphosphatase2A
MSCs Mesenchymalstemcells PPARc Peroxisomeproliferator-activated
mTORC Mammaliantargetofrapamycincomplex receptorgamma
NAD Nicotinamideadeninedinucleotide RANK Receptoractivatorofnuclearfactor
NCoR Nuclearreceptorco-repressor kappa-B
NFATc1 NuclearfactorofactivatedT-cells1 RANKL Receptoractivatorofnuclearfactor
NF-jB Nuclearfactorkappa-light-chain- kappa-Bligand
enhancerofactivatedBcells RANTES Regulatedonactivation,normalTcell
NO Nitricoxide expressedandsecreted
Nrf2 NuclearfactorE2-relatedfactor2 RNS Reactivenitrogenspecies
OCN Osteocalcin ROS Reactiveoxygenspecies
OPG Osteoprotegerin Runx2 Runt-relatedtranscriptionfactor2
OPN Osteopontin SAPK Stress-activatedproteinkinases
OSCAR Osteoclast-associatedimmunoglobulin- SERMs Selectiveestrogenreceptormodulators
likereceptor sGC Solubleguanylylcyclase
Osx Osterix Sir2 Silentinformationregulator2
COX2 Cyclooxygenase2 Sirt1 Sirtuin1
CREB Campresponseelementbindingprotein SMAD Smallmotheragainstdecapentaplegic
CREs Campresponseelements SOD-1 Superoxidedismutase1
CXCL Chemokine(C-X-Cmotif)ligand SOST Sclerostin
DP Driedplum SP1 Specificityprotein-1
E2 17b-estradiol TF Transcriptionfactor
EA Ellagicacid TGF-b1 Transforminggrowthfactor-b1
ECM Extracellularmatrix TNFR Tumornecrosisfactorreceptor
EGCG Epigallocatechingallate TNF-a Tumornecrosisfactor-a
eNOS EndothelialNOS TRAF TNFreceptorassociatedfactor
ER Estrogenreceptor TRAP Tartrate-resistantacidphosphatase
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TRKs Receptortyrosinekinases et al. 2010), that lead to anti-inflammatory, chemo-
VA Vanillicacid preventiveandchemotherapeuticactivities.
VCAM Vascularcelladhesionmolecule Depending on the number of phenol rings they
VEGF Vascularendothelialgrowthfactor contain and on the radicals bound to them, polyphe-
nols can be divided into different groups: phenolic
acids, flavonoids, stilbenes, tannins, coumarins and
lignans(Fig. 1–2)(D’Archivioetal.2007).Giventhat
Introduction thechemicalstructureofacompoundisrelatedtoits
biological/toxicological activity (McKinney et al.
Bonelossisaconsequenceofchangesthatoccurinthe 2000), polyphenols mode of action can be different,
bone cell activity during bone remodeling, which dependingalsoonwhichconcentrationandonwhich
causes an imbalance between bone resorption and biological system is used (Khlebnikov et al. 2007).
formation and leads to bone disorders, such as However,itisquitedifficulttoquantitativelyestablish
osteoporosis and increased fracture risk (Manolagas the benefits afforded by polyphenols, because of the
2000). During normal physiological remodeling, in limited understanding of their bioavailability; gener-
which the mature skeleton undergoes continuous ally,thesmallintestinecanabsorbpolyphenolsinthe
regeneration, bone formation follows resorption in a form of aglycones, but many of them in their native
‘‘coupled’’mechanismcontrolledbyvariedmolecular formareesters,glycosidesorpolymersthatcannotbe
factors.Unequaleffectsofthesefactorscouldleadto absorbed by the gut barrier (Crozier et al. 2009).
the imbalance responsible for the decrease of bone Hence, these compounds must be metabolized by
mass,inwhichextensionoftheworkinglifespanofthe intestinal enzymes or the gut microflora (D’Archivio
osteoclast coexists with shortening of the working et al. 2007). Many studies have found correlations
lifespanoftheosteoblast(Khoslaetal.2012).Various between intake of polyphenols and bone health
celltypesareinvolvedintheremodelingprocess,each (Henrotin et al. 2011; Shen et al. 2011; Rao et al.
type playing different roles in bone turnover: osteo- 2012;WelchandHardcastle2014),mainlyduetotheir
blastssupportingboneformation,osteoclastsinvolved antioxidant properties, because oxidative stress plays
in bone resorption and osteocytes playing a central an important role in the pathogenesis of osteoporosis
rolebyactingasmastersignalsensors,integratorsand with its promotion of an increase in bone resorption
transducersintheremodelingcompartment,withtheir linked to direct/indirect actions on the differentiation
multiple endocrine functions implicated in the regu- andactivityofosteoclasts(CallawayandJiang2015).
lation of both osteoclast and osteoblast activities Besides their scavenging properties, polyphenols can
(Bonewald2011). influencebonemetabolismthroughdownregulationof
Polyphenols are phytochemicals commonly found inflammatory mediators (Bodet et al. 2007), such as
in the plant kingdom, whose multiple biological cytokines, primarily implicated in sustaining osteo-
effects have been reported to be protective against clast differentiation and activity (Palmqvist et al.
chronic diseases, including neurodegenerative and 2002;ParkandPillinger2007;Yaoetal. 2008),thus
cardiovascular disease, cancer and osteoporosis contributingtoareductioninboneresorption.Another
(Scalbert et al. 2005). The beneficial actions of important aspect tobe taken into accountis the bone
phenolic compounds are mainly due to their antiox- anabolic effect exerted by polyphenols, shown by
idant properties, since they can act as scavengers of manyexperimentalevidencewhichhighlightedhowit
reactive oxygen species (ROS) (Procha´zkova´ et al. is promoted by effects on the osteoblast involving
2011), but also to their interaction with intracellular different signaling pathways such as Wnt/b-catenin
signaling cascades such as phosphatidylinositol-4,5- (Chen et al. 2010), insulin-like growth factor (IGF1)
bisphosphate 3-kinase (PI3K), protein kinase B (Buetal.2009),bonemorphogeneticproteins(BMPs)
(PKB)/Akt, tyrosine kinases, protein kinase C (PKC) (Trzeciakiewicz et al. 2010a),Runt-relatedtranscrip-
andmitogen-activatedproteinkinases(MAPKs)(No- tion factor 2 (Runx2) (Byun et al. 2014) and Osterix
mura et al. 2001; Lin 2002; Kern et al. 2007; Larsen (Osx) (Santiago-Mora et al. 2011). Furthermore,
because of a structural similarity to mammalian
estrogens, some polyphenols such as isoflavones are
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Fig.1 Polyphenolclassification.Principalclassesofpolyphenolsandtheirrelativemosteffectivecompounds(Rothwelletal.2013)
also called phytoestrogens and are able to bind to compounds (Chang and Jeong 2015; Rajesh et al.
estrogen receptors (ERs) a and b, thus acting as 2015; Farha and Brown 2016), still insufficient data
hormone analogs with different agonistic or antago- are available to establish the real value of these
nistic actions, depending on the tissue (Patisaul and compoundsinthe context of public healthorclinical
Jefferson2011). practice.Hence,itwillbenecessaryadeeperstudyof
Ascanbeseen,theirinvolvementinpathwaysthat the molecular mechanisms underlying polyphenol
can cross-talk to other multiple transduction signals modes of action, with an even more detailed knowl-
makes phenolic compounds a promising natural edge of the interaction of phenolic compounds with
source to be employed in the development of plant- theirmoleculartargets,tobetterclarifytheirpharma-
based therapeutics, with a wide application ranging cological activity and, subsequently, to properly
from bone diseases, to cancers (Chen et al. 2014b), optimize medicinal chemistry approaches and more
atherosclerosis(Lokeetal.2010),obesity(Tucakovic appropriate clinical trial designs, as well as the
et al. 2015), diabetes (Dragan et al. 2015) and development ofadvanced biomaterials and improved
neurodegenerative disorders (Ebrahimi and Schlue- tissue-engineeringapproaches.
sener 2012). However, despite the renewed scientific Here, we discuss the molecular mechanisms
interestindrugdiscoveryfromnaturalsourcesandthe involved in the anabolic effects induced by polyphe-
increasing demand in today’s society for natural nols, highlighting the signaling pathways shared
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betweenthediverseclassesofphenoliccompounds,in estrogens,sinceestrogensbindtobothERaandERb
terms of a better understanding of an even greater withalmostthesameaffinity(Moritoetal.2001),thus
application of these natural compounds in the bone triggeringdistinctER-mediatedtranscriptionalevents.
tissueregenerationfield. On the other hand, some polyphenols, such as
8-prenylnaringenin (8-isoprene-4,5-7-hydroxy fla-
vanone,isolatedfromthefemaleflowersofHumulus
Estrogensignalingpathway lupulus), have been shown to preferentially bind to
ERathantoERbandtopromoteosteoblastdifferen-
Amongsexualsteroids,estrogensarethemainfemale tiation and inhibition of bone resorption with a
hormones that, in addition to their action in the stronger effect, compared to genistein and daidzein,
development and maintenance of normal sexual and atadoseof10 lM(Luoetal.2014).
reproductive functions, play important roles in the Besides the predominant effects of ERb, a wide
control of different biological processes, with effects range of structural forms of the ligand-receptor
on the cardiovascular, musculoskeletal, immune and complex occur in generating a wider range of action
centralnervoussystem(Gustafsson2003). for phytoestrogens, thus recruiting different co-acti-
The biological effects of estrogens are mediated vatororco-repressorproteins(Routledgeetal.2000).
throughtwodistinctintracellularreceptorforms,ERa Furthermore, the potential hormonal effects of phy-
andERb,eachencodedbydifferentgeneslocatedon toestrogensonosteoblastsispertinentwiththediffer-
differentchromosomes(Gosdenetal.1986;Kousteni ent expression of the ER forms during the osteoblast
etal.2003). differentiationstages,sinceERbisfoundtobegreatly
Polyphenolic non-steroidal plant compounds with expressed during bone mineralization (Arts and
estrogen-like biological activity, estrogen receptor Kuiper 1997). Binding of the ER with different
binding, ER-transactivation and estrogen dependent compoundsinducesdifferentconformationalchanges
targetgeneexpressionareclassifiedasphytoestrogens inthereceptor.
(Cos and Apers 2003) or selective estrogen receptor Classical binding of estrogens to the ER in the
modulators(SERMs)and,assuch,theycanmodulate cytosol, leads to a conformational change within the
the estrogen-dependent pathway by acting as partial ER that promotes homodimerization, recruitment of
agonists and/or antagonists of the ER in a tissue the ER to the promoter region of transcription start
type and ligand concentration-dependent manner sites, high affinity binding to specific cis-acting
(Moutsatsou 2007). By activating the estrogen path- enhancers DNA response elements (ERE) located
way, polyphenolsare thus molecules able to regulate within the regulatory regions of target genes and
theexpressionofgeneswhich,inbone,areresponsible recruitment of coactivators that stimulate gene tran-
for the maintenance of bone mass, through a proper scription (O’Lone et al. 2004). In the case of genes
balancing between bone resorption and bone forma- whosepromotersdon’tharborEREs,ligand-boundER
tion(Cauley2015)(Fig. 3). can interact with transcription factor complexes like
Based on their chemical structure, they can be activator protein-1 (AP1) or specificity protein-1
classified into four main groups, which include (SP1), that tether the ER to the promoter, a process
isoflavonoids, flavonoids, stilbenes and lignans. referred to as ‘‘non-ERE’’ or ‘‘transcription factor
Because of the structural similarity between phytoe- cross-talk’’ (Gustafsson 2003). Thus, phytoestrogens
strogensand17b-estradiol(E2),basedonthephenolic canactaspureagonists,aspartialagonistsoraspure
ring required for binding to the ER, as well as the antagonists. Different results, in literature, are given
presenceoftwohydroxylgroups(Harrisetal.2005), about agonistic or antagonistic activities of polyphe-
phytoestrogens exert their estrogenic activities by nols, in fact coumestrol, apigenin, daidzein and
bindingtoERs(Moritoetal.2001),thusactivatingthe genistein exhibit a strong agonistic activity for ERs
ER-dependent gene transcription, with a higher rela- at concentrations ranging from 10 lM to 10 nM,
tive binding affinity for ERb than ERa (Kuiper et al. while resveratrol, naringenin (a flavonoid found in
1998; Casanova et al. 1999). This relative selective Citrus medica), kaempferol and quercetin have been
binding of phytoestrogens to ERb indicates that they shown tohave weak or even antagonistic activity for
may produce different effects from those exerted by bothERaandERb(Miodinietal.1999;Harris etal.
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Fig.2 Polyphenolclassification.Principalclassesofpolyphenolsandtheirrelativemosteffectivecompounds(Rothwelletal.2013)
2005; Tang et al. 2008b). Conversely, other authors conversely,stimulationofosteoblasticboneformation
found that quercetin mediates ERE-dependent trans- following a diet enriched with phlorizin (a flavonoid
activation with effects on stimulation of osteoblastic exclusively found in apple) 2.0 9 10-4 mol/day and
proliferation(VanDerWoudeetal.2005;Vepriketal. rutin 4.1 9 10-3 mol/kg have been postulated to be
2012). mediated through the ER (Horcajada-Molteni et al.
Otherphytoestrogens,followingbindingtotheER, 2000;Pueletal.2005).
have been observed to negatively target bone resorp- Apart from acting through EREs, phytoestrogens
tion through the classical ERE-mediated ligand- have been shown to interact, through the ERs, with
dependent pathway (Fig. 3). In fact, a possible inter- other response elements, such as the antioxidant
action for quercetin and kaempferol with the ER, at response element/electrophile responsive element
concentrationsof0.1–10 lM,hasbeenspeculatedon (ARE/EpRE), thus inducing the transcription of the
the basis of their inhibitory effects on bone resorp- phaseIIdetoxificationenzymes(Fig. 3).Evidencefor
tion—although the estrogenic potency of kaempferol phytoestrogen modulation of ARE-regulated tran-
is greater than quercetin—significantly reversed by scription is provided by Veprik et al., that report the
theuseoftheERantagonistICI182780(Watteletal. involvement of the nuclear factor E2-related factor 2
2003)andconfirmedinasubsequentreportshowing, (Nrf2)/ARE transcription system in the activation of
furthermore, that quercetin is able to act as selective estrogen signaling in two osteoblast-like cell lines
ERmodulatorbyupregulatingERbanddownregulat- (Veprik et al. 2012), while cyclic adenosine
ing ERa expression (Rassi et al. 2005). Similarly, monophosphate (cAMP) response elements (CREs)
inhibition of osteoclastic bone resorption in rats and, have been shown to be targeted by soy isoflavones,
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Fig.3 Influenceofpolyphenolsonbonemetabolismthrough protein,G Gproteinasubunit,G Gproteinbcsubunits.(1)
a bc
estrogensignaling.BindingofphenoliccompoundstoERsleads Resveratrol, curcumin, daidzein, genistein, kaempferol, puer-
to activation of the canonical and noncanonical estrogen arin,coumestrol,apigenin,quercetin.(2)Vanillicacid,icariin,
pathways, with a crosstalk with MAPKs and PI3K/Akt prunetin,resveratrol,daidzein,genistein,quercetin,kaempferol.
signaling.GRB2growthfactor receptor-boundprotein2,SOS (3) Daidzein, genistein, resveratrol, icariin, quercetin, kaemp-
sonofsevenless,RTKreceptortyrosinekinase,GDPguanosine ferol.(4)Resveratrol,genistein,daidzein,quercetin,rutin
diphosphate,OSE1/2osteoblast-specificelement(cid:2),MAFMAF
whichsuppressCRE-mediatedtranscriptionalactivity by diverse main signaling cascades: phospholipase C
through ERs and mRNA expression of genes that (PLC)/PKC, Ras/Raf/MAPK,PI3K/AKT and cAMP/
contain CRE/CRE-like elements in their promoter in protein kinase A (PKA) (Bjo¨rnstro¨m and Sjo¨berg
osteoblasticcells(Tangetal.2011). 2005).
Phytoestrogens not only target the classical ER Vanillic acid (VA), isolated from Sambucus
pathway,butalsotherapidnon-genomicsignaling,in williamsii, for example, differs from other phytoe-
a ligand-dependent or independent manner (Fig. 3). strogens like genistein, because it does not bind to
The ‘‘nongenomic’’ action differs from the genomic either ERa or ERb, nor induces ERE-dependent
one,sinceitinvolvesaseriesofrapideventsderiving transcription. In fact, VA has been shown to up-
from the interaction between cell-surface ER forms regulate the expression of osteoblastic differentiation
that are linked to intracellular signal transduction markers, such as Runx2, osteocalcin (OCN) and
proteins, such as the G protein-coupled receptor 30 osteoprotegerin (OPG), by activating the rapid non-
(GPR30).Thesenon-genomiceventsmaybemediated genomic ER pathway at concentrations of 0.01 lM
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Fig.4 SIRT1-mediated bone anabolic effects of resveratrol. osteoclastogenesis.GAB2GRB2-associated-bindingprotein2,
TheabilityofresveratroltobindtoSIRT1andtosubsequently TRADDtumornecrosisfactorreceptortype1-associateddeath
increase its enzymatic activity provides a reply aimed at domain,RIPreceptor-interactingproteinkinases,CIAPcellular
enhancing the osteoblast differentiation process, through the inhibitor of apoptosis, LUBAC linear ubiquitination assembly
parallel decrease of adipogenesis. Impairment of osteoclast complex, PGC-1a peroxisome proliferator-activated receptor
differentiationandfunctionisalsoachievedthroughdecreasing gamma coactivator-1 alpha, PPRE PPAR response element,
theDNAbindingactivityofNFjB,thusinhibitingRANKLand FREFOXOresponseelement,Qubiquitin,Pphosphorylation
TNF-a-induced transcription of genes involved in
and 0.1 nM, through phosphorylation of MEK1/2, activatingAP-1throughtheup-regulationofc-fosand
ERK1/2andERa(Xiaoetal.2014b).Alsoipriflavone c-jun via activation of extracellular signal–regulated
(7-isopropoxyisoflavon, isolated from Medicago kinase (ERK) and c-Jun N-terminal kinase (JNK)
sativa) has been shown not to bind to the ER, but to pathways (Song et al. 2013; Wu et al. 2015b). Thus,
a unique steroid receptor superfamily binding site in icariincouldhavetherapeuticeffectsonosteoporosis
thenucleusofpre-osteoblasticcellsandnottoinduce (Zhangetal.2009),byenhancingosteoblasticdiffer-
ERE-dependentgenetranscription(Petillietal.1995). entiation and suppressing osteoclastic differentiation
Furthermore,icariin,theprincipalflavonoidglycoside (Chen et al. 2007; Huang et al. 2007; Hsieh et al.
foundinHerbaEpimedii,alsoactslikeaphytoestro- 2011).
genthroughthenon-classicalER-dependentpathway Gprotein-coupledestrogenreceptor1(GPER),also
(Xiao et al. 2014a), because its effects on osteoblast known as GPR30, is a member of the 7-transmem-
proliferation, differentiation and mineralization, at brane G protein-coupled receptor (GPCR) family,
doses ranging from 5 to 40 lM, are reached by capable of mediating both transcriptional and
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Fig.5 Polyphenol beneficial effects on bone diseases are osteoclastogenesis,respectively.(1)Geraniin,daidzein,genis-
mediated through actions on the MAPKs cascade. Different tein, quercetin, curcumin, caffeic acid, CADPE, furosin,
effects are obtained on the basis of MAPKs phosphorylation coumestrol, EGCG, A-type proanthocyanidins, (2S)-20-
state, in fact polyphenols are able to either increase or to methoxykurarinone,icariin,apigenin,cajanin,isoformononetin,
decreasephosphorylation,thusdeterminingosteoblastprolifer- HCA,ugoninK,baicalein,quercitrin
ationanddifferentiationandinhibitionofinflammation-induced
nongenomiceventsinresponsetoestrogen(Prossnitz exert pleiotropic effects on bone metabolism on the
et al. 2008). An example of a positively acting basisofwhichcelltypetheytarget.
polyphenol on bone metabolism, through binding to Firstofall,phytoestrogensarecapableofinfluenc-
theGPR30,isgivenbyprunetinisoflavone(foundin ing MSCs, by enhancing osteogenic differentiation,
red clover and fruit of Prunus avium), which, at while suppressing the adipogenic one via a nonge-
0.01 lM, selectively binds to the GPR30, thus stim- nomic mechanism ER-mediated (Li et al. 2005). In
ulating osteoblast proliferation and differentiation this context, supplementation of 1 lM genistein has
throughtheproductionofcAMPandthroughactivat- beenreportedtoincreaseosteogenesisinhumanbone
ing ERK/MAPK, as well as leading to expression of marrowstromalcells(hBMSCs)atday18ofincuba-
Runx2inosteoblasts(Khanetal.2015)(Fig. 3). tion, by acting on gene expression markers, such as
Given the evidence that the ER is expressed by Runx2 and alkaline phosphatase liver/bone/kidney
mesenchymal stem cells (MSCs), osteoblasts and (ALPL),involvedintheearlystagesofdifferentiation
osteoclasts (Vidal et al. 1999; Windahl et al. 2000), ofhumanprimaryMSCs(Heimetal.2004).Abilityof
it is clear that estrogen and estrogenic compounds isoflavones to suppress adipogenic differentiation of
adipose tissue-derived (AD) MSCs has also been
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Fig.6 Anti-inflammatory properties of polyphenols in con- resveratrol, EA, geraniin, rutin, A-type pro-anthocyanidins,
trolling bone resorption. Inflammation-induced activation of CADPE, delphinidin, fisetin, peonidin, honokiol, rosmarinic
NF-jB is inhibited by polyphenols, which are effective in acid,arbutin,oleuropein,silibinin,luteolin,myricetin,EGCG,
triggeringosteoclastapoptosisandinhibitingosteoclastdiffer- (?)-catechin, naringenin, apigenin, kaempferol, quercetin,
entiation. Thus, theyplaya roleinshiftingtheRANKL/OPG quercitrin,formononetin,tyrosol
ratioinfavorofOPG.(1)HCA,curcumin,galangin,genistein,
investigatedinthecontestofWnt/b-cateninsignaling with resveratrol, which has been shown, at 1 lM, to
using an estrogen antagonist. The results show that directly stimulate cell proliferation, osteoblastic dif-
thesephytoestrogens,at0.01–100 lM,doinhibitAD- ferentiation and osteogenic gene expression through
MSCs differentiation in mature adipocytes through a inductionofERsignalingandMAPKactivation,with
stimulation of Wnt signaling mediated by both non- involvement of ERK1/2 and p38, playing a positive
genomic and genomic ER-dependent pathways (Kim andanegativeroleoncellproliferationandosteoblast
etal.2010).Theseoppositeeffectsonosteogenicand differentiation,respectively(Daietal.2007)(Fig. 3).
adipogenicdifferentiationarelikelyduetoadifferent The role of polyphenols in bone anabolism is
expressionoftheERsubtypesintheMSCsduringthe furthersupportedbyinvitrostudiesinvestigatingthe
developmental stages, implying cell-specific differ- effects of isoflavones on osteoblast activity, showing
ences in the estrogenic sensitivity. Indeed, all ERs increasedproteinsynthesis,DNAcontentandalkaline
already present in MSCs are up-regulated during phosphatase activity (Yamaguchi and Gao 1997);
osteogenesis, with the b5 splice variant strongly given that the presence of E2 caused a significant
expressedand,exceptforERa,downregulatedduring increase in protein content and alkaline phosphatase
adipogenesis (Heim et al. 2004). Effects on MSCs activity and that the anti-estrogen tamoxifen blocked
proliferationhavealsobeenseenfollowingtreatment the effects, the mechanism proposed by the authors
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