REFERATE GENERALE

ACTUALITI N GENETICA OSTEOPOROZEI

New insights in the genetics of osteoporosis
Nicoleta Baculescu1, Ctlina Poian1, 2
1
Universitatea de Medicin i Farmacie Carol Davila, Bucureti
2
Institutul Naional de Endocrinologie C.I. Parhon, Bucureti

Rezumat
Osteoporoza primar este o boal comun legat de vrst, caracterizat prin afectarea homeostaziei osoase i
risc crescut de fractur. Studiile familiale au artat c variaia densitii minerale osoase (BMD) este condiionat
genetic, fractura osteoporotic avnd, de asemenea, o component genetic. Rezultatele studiilor GWAS (genome-
wide association studies) i meta-analizele acestora publicate n ultimii ani au evideniat o serie de locusuri
asociate semnificativ cu BMD, aparinnd cilor RANK-RANKL-OPG i WNT, dar i sistemelor de difereniere
a celulelor stem mezenchimale sau de osificare encondral. O parte a locusurilor asociate BMD s-a asociat
semnificativ i cu riscul de fractur, ca de exemplu 17q21.31 (SOST), 11q13.2 (LRP5), 10q21.1 (DKK1), 1p36.12
(WNT4) i 7q31.31 (WNT16), spre deosebire de SNP-urile genelor sistemului RANK-RANKL-OPG (TNFRSF11A,
TNFSF11, TNFRSF11B), ce au prezentat asocieri doar cu BMD. Aceste date contribuie la o nelegere mai bun
a mecanismelor fiziopatologice din osteoporoz i la descoperirea unor noi metode terapeutice.

Cuvinte cheie: osteoporoz, BMD, riscul de fractur, gene, SNP-uri

Abstract
Primary osteoporosis is a common age-related disease characterized by an imbalance in bone homeostasis,
increasing the risk of fractures. Twin and family studies have shown that bone mineral density (BMD) variance is
in part genetically determined and osteoporotic fractures have also a heritable component. Over the last years,
a series of genome-wide association studies (GWAS) and meta-analysises evidenced several loci associated
with BMD at genome-wide significance, clustering within the RANK-RANKL-OPG and WNT signaling pathways
but also in the mesenchymal stem cell differentiation or endochondral ossification systems. Some of these BMD-
associated loci were also significantly associated with risk of fracture, including 17q21.31 (SOST), 11q13.2
(LRP5), 10q21.1 (DKK1), 1p36.12 (WNT4) and 7q31.31 (WNT16), whereas SNPs in genes of the RANK-RANKL-
OPG pathway (TNFRSF11A, TNFSF11, TNFRSF11B) were associated with BMD only. These data provide key
insights into the pathophysiological mechanisms of the disease and may contribute to the identification of new
drug targets for the treatment of osteoporosis, beyond previously available therapy.

Key words: osteoporosis, BMD, risk of fracture, genes, SNPs

INTRODUCERE antiresorbtive bazate pe blocarea cii RANK ligand

Osteoporoza primar se caracterizeaz prin sc-
derea masei osoase i deteriorarea microarhitecturii
osului, ambele prezente n general la persoane vrst-
nice i specific la femeile post-menopauz, avnd
drept consecin creterea riscului de fractur (1).
Cercetrile iniiale n domeniul osteoporozei,
centrate pe studiul sistemului RANK-RANKL-OPG,
factori cu rol cheie n activarea resorbiei osoase, au
condus la descoperirea unor noi formule terapeutice
(Receptor Activator of NF-kB), implicat n promo-
varea osteoclastogenezei i apariia osteoclatelor
mature (1,2).
Prin contrast, studiul formrii osoase, mecanism
cel puin la fel de important ca i resorbia osoas, a
fost mult timp neglijat, ns n ultimii ani au fost
publicate tot mai multe date legate de impactul re-
ducerii activitii osteoblastelor i creterii apoptozei
acestora, ambele componente n fiziopatologia osteo-
porozei (3-5).

Adres de coresponden:
Dr. Ctlina Poian, Institutul Naional de Endocrinologie C.I. Parhon, B-dul. Aviatorilor Nr. 34-36, Bucureti
e-mail: endoparhon@gmail.com

30 REVISTA ROMN DE REUMATOLOGIE VOL. XXII NR. 1, An 2013

REVISTA ROMN DE REUMATOLOGIE VOL. XXII NR. 1, AN 2013
Au fost descrise trei ci majore ce condiioneaz
regenerarea osoas, reprezentate de: a) calea BMP
(bone morphogenetic protein), b) calea WNT i c)
calea mediat de activarea PTH1R (parathyroid hor-
mone receptor). Acestea sunt caracterizate de co-
nexiuni semnificative la nivel intracelular, iar studii
recente au evideniat semnificaia blocrii lor pentru
normalizarea masei osoase, sugernd noi inte tera-
peutice n osteoporoz (6).
Proteinele BMP aparin superfamiliei factorilor
de cretere TGF-, activarea receptorilor BMP avnd
drept consecin iniierea procesului de transcriere la
nivel nuclear, fie prin intermediul semnalului intra-
celular MAP-kinazic, fie prin fosforilarea proteinelor
SMAD1/5/8 (6;7) (Fig.1).
Calea WNT este format din semnalele canonic
i respectiv non-canonic, n funcie de tipul corecep-
torilor. Semnalul canonic este indus de liganzi WNT
la nivelul proteinelor transmembranare Frizzled (FZD
family proteins) i la nivelul coreceptorilor mem-
branari LRP5/6, cu activarea transcrierii genelor
WNT-dependente prin translocarea la nivel nuclear a
-Cateninei. Semnalul non-canonic WNT este me-
diat de proteinele FZD i coreceptorii ROR2/RYK,
avnd drept rezultat activarea proteinelor G i a cas-
cadei intracelulare Ca2+ dependente (8). La nivelul
celulelor stem mezenchimale (MSC), celule de ori-
gine ale osteoblatelor (dar i ale altor tipuri de celule
mezodermale precum adipocitele, condrocitele sau
fibroblatii) (9), semnalul canonic mediat de WNT2,
WNT3 sau WNT3a induce proliferare i meninerea
ntr-un status nedifereniat, n timp ce semnalul non-
canonic, mediat de WNT5a, WNT5b sau WNT11,
induce osteogeneza (6;10-12) (Fig. 1).
PTH (parathyroid hormone) activeaz cea de-a
treia cale major a regenerrii osoase. Astfel, ad-
ministrarea intermitent de PTH stimuleaz formarea
osoas att la nivel periostal, ct i trabecular (13)
(Fig. 1), reprezentnd o metod terapeutic alterna-
tiv n osteoporoz. Pe de alt parte, activarea con-
tinu a receptorilor PTH are un efect nociv la nivelul
homeostaziei osoase prin amplificarea expresiei
RANKL de ctre osteoblastele n maturare, ulterior
cu stimulare a formrii osteoclatelor i resorbie
osoas (6;14).
Studiile efectuate pe numere limitate de pacieni
dar i cele ample, GWAS (genome-wide association
studies), au evideniat c polimorfismele unor gene
ce codeaz diferii factori implicai att n formarea,
ct i n resorbia osoas se asociaz semnificativ cu
osteoporoza primar, susinnd natura poligenic a
bolii (15-18).
31
FIGURA 1. Rolul cilor BMP, WNT i PTH intermitent
n formarea osoas. Semnalul BMP, mediat de
fosforilarea proteinelor SMAD1/5/8. Semnalul WNT
canonic, mediat de -catenin. Semnalul WNT
noncanonic, mediat de c-jun NH2-terminal kinase (JNK),
dar i de hidroliza fosfatidilinozitol 4,5-bifosfatului (PIP2)
via fosfolipaze C (PLC) specifice, cu activarea unor
izoforme particulare ale protein kinazei C (PKC) i a
cascadei intracelulare Ca2+ dependente. PTH
intermitent, via semnal APMc/PKA are efect antiapoptotic
i/sau prodifereniere la nivelul preosteoblatelor (pre-Ob)
post-mitotice n osul periostal i efect antiapoptotic la
nivelul Ob mature n osul trabecular, rezultnd creterea
numrului de Ob i creterea formrii osoase.
SNP-uri (single-nucleotide polymorphisms) asociate
semnificativ cu osteoporoza primar i fractura
osteoporotic
ESR1
Receptorii estrogenici de tip 1 au reprezentat un
candidat semnificativ pentru studiul reglrii genetice
a masei osoase, iar rezultatele studiilor GWAS au
confirmat asocieri semnificative ale unor SNP-uri
ESR1 precum rs9479055, rs4870044, rs1038304 i
rs692913 cu BMD, att la nivel lombar, ct i la ni-
velul colului femural (19-22). Mecanismele mole-
culare prin care polimorfismele ESR1 influeneaz
masa osoas nu sunt foarte clare, dar sunt evidene
pentru stimularea transcrierii genice (22).
TNFRSF11A
Gena TNFRSF11A (18q21), codeaz RANK,
membru al superfamiliei receptorilor TNF. RANK
este exprimat la nivelul osteoclastelor i precursorilor
acestora, avnd rol critic n reglarea diferenierii i
funciei acestui tip de celule. Unele studii au con-
firmat asocierea RANK-BMD (23,24), rs3018362
aparinnd genei RANK fiind primul SNP raportat
ca asociindu-se semnificativ cu BMD (19,20). Stu-
diile GWAS efectuate att n populaii europene, ct
i asiatice au confirmat asocierea dintre rs3018362 si
BMD (21,22).
32
TNFRSF11B
Gena TNFRSF11B (8q24) codeaz osteopro-
tegerina (OPG) sintetizat de osteoblaste. Aceasta
blocheaz competitiv receptorii RANK, conducnd
la inhibarea proliferrii i diferenierii osteoclastelor,
cu blocare consecutiv a resorbiei osoase. Astfel,
OPG are un rol critic n metabolismul osos, fiind
gen candidat n numeroasele studii de asociere
genetic n osteoporoza. Variantele A163-G, T245-G
i G1181-C se numr printre cele mai importante
dintre primele polimorfisme ale OPG descrise ca
asociate cu osteoporoza (24;25). Au fost raportate i
SNP-uri noi n populaia european: rs4355801,
rs6993813, respectiv rs6469804 (19;20;26), toate
asociate cu BMD att la nivel lombar, ct i la nivelul
colului femural. Mai mult, asocierile rs6469804 i
rs6993813 cu BMD lombar i/sau femural, s-au re-
plicat i n alte grupuri etnice (21).
TNFSF11
Gena TNFSF11 (13q14) codeaz RANKL, mem-
bru al superfamiliei factorilor de cretere TNF, cu rol
n stimularea resorbiei osoase prin activarea recep-
torilor RANK. Gena TNFSF11 a fost studiat ca
gen candidat n reglarea BMD i susceptibilitatea la
osteoproroz. Cu toate c exist date contradictorii,
de-CODE GWAS a confirmat c RANKL este o gen
de susceptibilitate pentru osteoporoz, evideniind
mai multe polimorfisme TNFSF11 asociate cu BMD
lombar (19;20). Aceste asocieri au fost ulterior con-
firmate i n metaanaliza GEFOS (18). Rezultatele
provenite din populaiile europene nu s-au replicat
ns i n alte grupuri etnice (21).
O metaanaliz recent, publicat n 2012 (27), a
descris noi SNP-uri asociate semnificativ cu BMD,
aparinnd cii de difereniere a celulelor stem
mezenchimale, precum RUNX2 (runt-related trans-
cription factor 2), SP7 sau SOX9, sistemului de osi-
ficare encondral format din procese eseniale pentru
dezvoltarea scheletic n etapa fetal precum SPP1
(osteopontina), MEF2C (myocite-specific enhancer
factor 2C), RUNX2, SOX6, PTHLH (PTHrP), SP7
i SOX9, dar i sistemului WNT - LRP5, CTNNB1
(-catenina), SFRP4 (secreted frizzled-related pro-
tein 4), WNT3, WNT4, WNT5B, WNT16, DKK1
(Dickkopf-1) i AXIN1 (axin-1).
Spre deosebire de ESR1 i de sistemul RANK-
RANKL-OPG, asociate doar cu BMD, o parte a
SNP-urilor menionate mai sus s-au asociat semni-
ficativ i cu riscul de fractur vertebral sau non-ver-
tebral. Printre acestea amintim SNP-uri ale siste-
mului WNT, format din LRP5 (11q13.2), WNT4
REVISTA ROMN DE REUMATOLOGIE VOL. XXII NR. 1, AN 2013
(1p36.12), WNT16 (7q31.31), SOST (17q21.31) i
DKK1 (10q21.1) (27).
LRP5
Studiile efectuate n sindromul osteoporoz -
pseudogliom (28) sau sindroamele de mas osoas
crescut (29) au evideniat faptul c gena LRP5
(low-density lipoprotein receptorrelated protein 5)
(11q13.4) are un rol cheie n reglarea masei osoase.
Primele studii de asociere genetic efectuate n
populaia general au evideniat c variantele comune
LRP5 se asociaz cu variaii BMD (30-33). ntr-un
studiu efectuat pe 45.000 de subieci ai consoriului
GENOMOS, van Meurs et al. (34) au raportat c
polimorfisme de la nivelul exonilor 9 i 18 ai genei
LRP5 se asociaz semnificativ cu BMD i riscul de
fractur. Mai mult, LRP5 s-a evideniat drept deter-
minant semnificativ al BMD att n unele studii
GWAS (26), ct i n metaanalizele GEFOS (18) i
cea publicat de Richards et al. (35). Studiile funcio-
nale LRP5 au fost centrate n special pe mutaiile
rare prezente la acest nivel. Analiza osoas efectuat
la oareci cu inactivare intit LRP5 a artat c masa
osoas redus a acestora este mai degrab consecina
scderii formrii dect a creterii resorbiei (36). Pe
de alt parte, exist evidene pentru faptul c anumite
mutaii LRP5 asociate cu creterea masei osoase
(G171V, G171R, A214T, A214V, A242T, T253I i
D111Y) inhib interaciunea dintre LRP5 i DKK1
(Dickkopf-1), proteine inhibitorii ale semnalului
WNT (37). Aceste date susin faptul c, n populaia
general, mutaiile rare de la nivelul genei LRP5 au
un impact major pe BMD, n timp ce polimorfismele
au rol att n modularea densitii minerale osoase,
ct i n determinarea riscului de fractur (22).
Semnalul WNT are un rol crucial n fiziopatologia
osoas. Astfel, n absena liganzilor WNT, -catenina
formeaz structuri complexe cu APC (adenomatous
polyposis coli), Axina, GSK3 (glycogen synthase
kinase 3) i CK1 (casein kinase I), acestea facilitnd
fosforilarea i degradarea ulterioar a -cateninei la
livelul proteozomilor. n prezena liganzilor WNT,
complexele disociaz iar -catenina translocheaz la
nivel nuclear, unde formeaz alt tip de complexe cu
factorii de transcriere TCF/Lef1, iniiind procesele
de transcriere genic. n acest context, diversele
polimorfisme descrise, WNT3, WNT4, WNT5B,
WNT16, pot fi semnificative n modularea variaiilor
BMD i/sau riscului de fractur.
Sclerostina (gena SOST, 17q12-q21) aparine
familei glicoproteinelor secretorii DAN, este sinteti-
zat aproape exclusiv de osteocite (ce constituie
REVISTA ROMN DE REUMATOLOGIE VOL. XXII NR. 1, AN 2013
peste 90 % din celulele osoase adulte) i are rol n
inhibarea formrii osoase, reprezentnd, mpreun
cu proteinele Dickkopf-1, principalii antagoniti ai
semnalului canonic WNT la nivel extracelular prin
legare competitiv la coreceptorii LRP5 i LRP6
(38-42). Asocierile mutaiilor inactivatoare SOST cu
sindroamele de mas osoas crescut sclerosteoza
i boala van Buchem susin gena SOST ca excelent
candidat pentru studiul reglrii BMD. Iniial a fost
evideniat asocierea semnificativ ntre polimorfis-
mele SOST SRP-3 i SRP-9 (SOST promoter re-
gion) i BMD, att la femei, ct i la brbai, efect pro-
gresiv cu vrsta (43). Ulterior, studiul de-CODE GWAS
a descris alte trei SNP-uri apropiate genei ca semni-
ficativ asociate cu BMD la nivelul oldului (20).
Gena SOST s-a asociat cu BMD i riscul de fractur
i n metaanaliza publicat de Richards et al (35).
Metaanaliza GEFOS a evideniat, de asemenea, aso-
cierea cu BMD, dar aceasta nu a atins semnificaia
statistic (18,22). Astfel, studiile de asociere genetic
susin contribuia polimorfismului SOST la reglarea
genetic a BMD, mecanismele ce stau la baza acestei
asocieri fiind n continu explorare.
Studiile efectuate pe oareci KO pentru sclerostin
au demonstrat efectul inhibitor al acesteia la nivelul
semnalului BMP7 n osteocite, sugernd c sclero-
stina nu inhib formarea osoas doar prin blocare
WNT la nivelul osteoblastelor i osteocitelor, ci i
reglnd inhibitor semnalul BMP n osteocitele ce
exprim sclerostina. Experimentele in vitro pe culturi
celulare de osteocite au confirmat interaciunea
sclerostinei cu pro-BMP7 i BMP7 la nivel intra-
celular, conducnd la degradarea proteozomal i
blocarea secreiei BMP7 la nivelul acestor celule
(44) (Fig. 2).
Mai mult, studiile genetice i (pre)clinice, efec-
tuate att pe modele animale, ct i la om, au de-
monstrat rolul cheie al sclerostinei n reglarea formrii
osoase (45-47), aceasta fiind sintetizat i secretat de
osteocitele mature prin mecanisme sensibile la
variaiile de ncrcare mecanic. Exist evidene ce
susin c expresia sclerostinei este reglat negativ de
stresul mecanic n cadrul sistemului mecanosenzorial
format de osteocite, explicnd astfel creterea masei
osoase simultan cu exerciiul fizic i scderea acesteia
n repaus (48). Pe lng stresul mecanic, au fost des-
crii i ali factori ce pot modifica secreia sclerostinei,
precum vrsta, estrogenii, prostaglandinele, PTH sau
cortizolul, explicnd parial variaia BMD din post-
menopauz, bolile inflamatorii, administrarea de PTH
sau sindromul Cushing (49).
33
FIGURA 2. Efectul inhibitor al sclerostinei la nivelul
cilor formrii osoase BMP i WNT. Sclerostina leag
BMP7 la nivel intracelular, cu sechestrare i degradare
proteozomal a BMP7. Blocarea cii WNT / beta-
catenin se produce la nivel extracelular, prin legarea
sclerostinei secretate la coreceptorii WNT, LRP5/6
(adaptat dup Krause et al. Ref 44).
Astfel, o serie de studii efectuate la om au evi-
deniat c valorile sclerostinei cresc progresiv cu
vrsta, n paralel cu scderea masei osoase (50,51).
Valorile serice ale sclerostinei au fost semnificativ
mai mari la brbai fa de femei i semnificativ mai
mari la femeile postmenopauz comparativ cu cele
premenopauz (51). Creterea sclerostinei serice s-a
corelat negativ cu BMD la nivelul colului femural i
cu indexul de estradiol liber, n alt populaie post-
menopauz (52). Alte studii au evideniat impactul
terapiei cu estrogeni asupra nivelului sclerostinei
serice, femeile postmenopauz substituite estrogenic
pentru 4 sptmni nregistrnd o scdere semni-
ficativ a valorilor sclerostinei serice, comparativ cu
grupul control (49,53,54).
Sclerostina este reglat i de mediatori ai infla-
maiei, acest mecanism putnd explica pierderea de
mas osoas n context inflamator. Prostaglandinele
E2 au avut un efect de down-reglare pe expresia
SOST i au activat calea WNT n celulele osteoblastice
UMR106.01 (55), n timp ce expresia SOST a fost
up-reglat n osteoblastele umane dup expunere la
TNF- (49,56,57).
Impactul analogului PTH, teriparatide PTH (1-34),
i al activrii receptorilor PTH pe expresia scle-
rostinei a fost studiat att n culturi celulare i modele
animale, ct i la om. Administrarea de PTH n cul-
turi celulare i modele experimentale conduse la oa-
rece s-a asociat cu scderea expresiei i secreiei scle-
rostinei (58). Mai mult, administrarea intermitent
34
de PTH la femei postmenopauz, n cadrul unui
studiu clinic prospectiv, a demonstrat o scdere sem-
nificativ (12,7%) a valorilor serice ale sclerostinei
(59). Pe de alt parte, ntr-un alt studiu clinic, admi-
nistrarea de teriparatide pentru un interval mai mare
de 6 luni nu s-a asociat cu modificarea valorilor scle-
rostinei serice (60). Alte evidene ale asocierii PTH
sclerostin vin de la pacienii cu osteodistrofie
renal ce prezint att valori crescute ale PTH ct i
valori reduse ale sclerostinei serice (49,61).
Glucocorticoizii au impact pe metabolismul osos
att prin creterea resorbiei, ct i prin scderea for-
mrii osoase, conducnd la pierdere osoas trabecu-
lar, dar i cortical. RANKL s-a evideniat ca
responsabil de creterea resorbiei osoase gluco-
corticoid-indus, n timp ce sclerostina este unul din
factorii responsabili de scderea formrii post-ex-
punere la glucocorticoizi. oarecii tratai cu pre-
dnisolon timp de 56 zile au prezentat o cretere sem-
nificativ a expresiei sclerostinei i DKK1 la nivel
osos, urmat de efectul negativ semnificativ pe osul
trabecular. Interesant este faptul c dac tratamentul
administrat acestor oareci a asociat i hPTH (1-34)
(zilele 28-56), pierderea osoas indus de prednisolon
a fost recuperat, iar expresia sclerostinei i DKK1 a
fost semnificativ redus, comparativ cu monoterapia
cortizonic sau cu placebo (62). La femeile postme-
nopauzale tratate cu glucocorticoizi, sclerostina
seric a fost semnificativ mai mare comparativ cu
cele fr terapie cortizonic, sugernd c, la om,
glucocorticoizii au rol n modularea inhibitorilor
serici ai cii WNT (49).
Valori crescute ale sclerostinei serice au fost evi-
deniate i la pacienii cu diagnostic de DZ tip 2,
comparativ cu subiecii control (49;63).
Astfel, sclerostina apare ca un modulator sem-
nificativ n reglarea masei osoase, mai mult, un im-
portant studiu recent publicat, demonstrnd c la
femeile vrstnice, valorile serice crescute de sclero-
stin s-au asociat cu un risc crescut de fractur de
old, independent de BMD (64).
Studiile preclinice efectuate pe modele animale
au artat c administrarea de anticorpi monoclonali
neutralizani ai sclerostinei a dus la creterea global
a formrii osoase (la nivel trabecular, periostal, endo-
cortical i intracortical), fr creterea resorbiei (si-
milar cu terapia cu teriparatide sau PTH full length),
n final nregistrndu-se creterea grosimii trabe-
culare, a BMD i a rezistenei osoase (65,66). Ad-
ministrarea subcutan n doz unic a AMG 785
(anticorp uman recombinant antisclerostin), la br-
bai sntoi sau femei post-menopauzale, a avut
REVISTA ROMN DE REUMATOLOGIE VOL. XXII NR. 1, AN 2013
drept rezultat o cretere dependent de doza a marke-
rilor de formare osoas i o scdere dependent de
doz a markerilor de resorbie (telopeptidul C, Ctx
seric), sugernd prezena unei ferestre largi de tip
anabolic. Evaluarea efectuat la 85 de zile postadmi-
nistrare a evideniat creterea BMD att la nivel
lombar, ct i la nivelul colului femural (67). n
prezent sunt n derulare alte dou studii clinice de
faz II, evalund vindecarea fracturilor post-adminis-
trare AMG 785 (la nivelul diafizei tibiale, colului
femural sau intertrohanterian). De asemenea, este n
plin desfurare recrutarea femeilor post-menopauz
pentru studiile clinice de faz III. Astfel, anticorpii
antisclerostin reprezint o terapie promitoare n
osteoporoz, nu numai prin creterea BMD, dar mai
ales prin reducerea riscului de fractur.
Toate aceste date genetice, experimentale i cli-
nice, susin importana sclerostinei i a genei SOST
n etiopatogenia osteoporozei i a fracturii osteo-
porotice.
HTR1E
Gena HTR1E (6 q14-q15) codeaz unul dintre
receptorii 5-hidroxitriptaminei (serotonina), bine-
cunoscut neurotransmitor cu proprieti promito-
genice. Exist dovezi c serotonina intestinal acio-
neaz pe receptorii Htr1b prezeni la nivelul osteo-
blastelor, inhibnd proliferarea acestor celule (68),
n timp ce serotonina sintetizat cerebral se leag la
nivelul receptorilor Htr2c exprimai de neuronii
nucleilor hipotalamici ventromediali, favoriznd
acumularea de mas osoas via inhibare a activitii
neuronilor simpatici (69).
Recent, s-a demonstrat c rs9351097 i rs9362321,
dou SNP-uri ale genei HTR1E aflate n dezechilibru
de legtur, se asociaz semnificativ cu un model in-
tegrat al parametrilor geometriei colului femural i,
mai mult, un alt SNP al aceleiai gene, rs6919366,
s-a asociat semnificativ cu riscul de fractur non-
vertebral (70).
Ca i n cazul sclerostinei, demonstrarea asocierii
cu riscul de fractur este deosebit de important, de-
terminarea precoce a factorilor de risc avnd rol n
predicia fracturii osteoporotice n etapa vrstnic.
AKAP6
O alt gen asociat semnificativ cu geometria
integrat a colului femural este AKAP6, situat pe
cromozomul 14, codnd protein kinase A (PRKA)
anchor protein 6 (70). Aceast protein este exprimat
n variate esuturi creier, cord, muchi scheletic att
AKAP6, ct i 5-HT fiind asociate cu semnalul in-
tracelular AMPc (cyclic adenosine monophosphate).
REVISTA ROMN DE REUMATOLOGIE VOL. XXII NR. 1, AN 2013
Deoarece 5-HT acioneaz intracelular prin semnalul
AMPc (71) coordonat de AKAP6 (72), interaciunea
AKAP6 HTR1E reprezint un alt mecanism al me-
tabolismului osos, important de investigat pe viitor.
Concluzionnd, genele evideniate ca semnifica-
tive n studiile de asociere genetic efectuate n
BIBLIOGRAFIE
1. Rachner T.D., Khosla S., Hofbauer L.C. Osteoporosis: now and the
future. Lancet 2011; 377(9773):1276-1287.
2. Khosla S. Minireview: The OPG/RANKL/RANK system. Endocrinology
2001; 142(12):5050-5055.
3. Misof B. Bone material properties in premenopausal women with
idiopathic osteoporosis. J Bone Miner Res 2012.
4. Jilka R.L. Biology of the basic multicellular unit and the pathophysiology
of osteoporosis. Medical and Pediatric Oncology 2003; 41(3):182-185.
5. Duque G. Bone and fat connection in aging bone. Current Opinion in
Rheumatology 2008; 20(4):429-434.
6. Benisch P., Schilling T., Klein-Hitpass L. et al. The Transcriptional
Profile of Mesenchymal Stem Cell Populations in Primary Osteoporosis
Is Distinct and Shows Overexpression of Osteogenic Inhibitors. Plos One
2012; 7(9).
7. Canalis E. Growth Factor Control of Bone Mass. Journal of Cellular
Biochemistry 2009; 108(4):769-777.
8. Katoh M., Katoh M. WNT signaling pathway and stem cell signaling
network. Clinical Cancer Research 2007; 13(14):4042-4045.
9. Valtieri M., Sorrentino A. The mesenchymal stromal cell contribution to
homeostasis. Journal of Cellular Physiology 2008; 217(2):296-300.
10. Boland G.M., Perkins G., Hall D,J,, Tuan R.S. Wnt 3a promotes
proliferation and suppresses osteogenic differentiation of adult human
mesenchymal stem cells. Journal of Cellular Biochemistry 2004;
93(6):1210-1230.
11. Ling L., Nurcombe V., Cool S.M. Wnt signaling controls the fate of
mesenchymal stem cells. Gene 2009; 433(1-2):1-7.
12. Cho H.H., Kim Y.J.. Kim S,J, et al. Endogenous Wnt signaling
promotes proliferation and suppresses osteogenic differentiation in human
adipose derived stromal cells. Tissue Engineering 2006; 12(1):111-121.
13. Jilka R.L., OBrien C.A., Ali A.A., Roberson P.K., Weinstein R.S.,
Manolagas S.C. Intermittent PTH stimulates periosteal bone formation
by actions on post-mitotic preosteoblasts. Bone 2009; 44(2):275-286.
14. Potts J.T. Parathyroid hormone: past and present. Journal of
Endocrinology 2005; 187(3):311-325.
15. Li W.F., Hou S.X., Yu B., Li M.M., Ferec C., Chen J.M. Genetics of
osteoporosis: accelerating pace in gene identification and validation.
Human Genetics 2010; 127(3):249-285.
16. Koller D.L., Ichikawa S., Lai D.B. et al. Genome-Wide Association
Study of Bone Mineral Density in Premenopausal European-American
Women and Replication in African-American Women. Journal of Clinical
Endocrinology & Metabolism 2010; 95(4):1802-1809.
17. Duncan E.L., Danoy P., Kemp J.P. et al. Genome-Wide Association
Study Using Extreme Truncate Selection Identifies Novel Genes Affecting
Bone Mineral Density and Fracture Risk. Plos Genetics 2011; 7(4).
18. Rivadeneira F., Styrkarsdottir U., Estrada K. et al. Twenty bone-
mineral-density loci identified by large-scale meta-analysis of genome-
wide association studies. Nature Genetics 2009; 41(11):1199-1U58.
19. Styrkarsdottir U., Halldorsson B.V., Gretarsdottir S. et al. Multiple
genetic loci for bone mineral density and fractures. New England Journal
of Medicine 2008; 358(22):2355-2365.
20. Styrkarsdottir U., Halldorsson B.V., Gretarsdottir S. et al. New
sequence variants associated with bone mineral density. Nature Genetics
2009; 41(1):15-17.
21. Liu J.M., Zhang M.J., Zhao L. et al. Analysis of Recently Identified
Osteoporosis Susceptibility Genes in Han Chinese Women. Journal of
Clinical Endocrinology & Metabolism 2010; 95(9):E112-E120.
35
osteoporoz reflect att natura poligenic a variaiei
densitii minerale osoase, ct i complexitatea me-
canismelor fiziopatologice ale riscului de fractur,
fiecare dintre aceste gene reprezentnd i un posibil
candidat pentru descoperirea unor noi formule tera-
peutice n osteoporoz.
22. Ralston S.H., Uitterlinden A.G. Genetics of Osteoporosis. Endocrine
Reviews 2010; 31(5):629-662.
23. Choi JY, Shin A, Park SK et al. Genetic polymorphisms of OPG, RANK,
and ESR1, and bone mineral density in Korean postmenopausal women.
Calcified Tissue International 2005; 77(3):152-159.
24. Kim JG, Kim JH, Kim JY et al. Association between osteoprotegerin
(OPG), receptor activator of nuclear factor-kappa B (RANK), and RANK
ligand (RANKL) gene polymorphisms and circulating OPG, soluble
RANKL levels, and bone mineral density in Korean postmenopausal
women. Menopause-the Journal of the North American Menopause
Society 2007; 14(5):913-918.
25. Zhao HY, Liu JM, Ning G et al. The influence of Lys3Asn polymorphism
in the osteoprotegerin gene on bone mineral density in Chinese
postmenopausal women. Osteoporosis International 2005; 16(12):1519-
1524.
26. Richards JB, Rivadeneira F, Inouye M et al. Bone mineral density,
osteoporosis, and osteoporotic fractures: a genome-wide association
study. Lancet 2008; 371(9623):1505-1512.
27. Estrada K, Styrkarsdottir U, Evangelou E et al. Genome-wide
meta-analysis identifies 56 bone mineral density loci and reveals 14 loci
associated with risk of fracture. Nature Genetics 2012; 44(5):491-501.
28. Gong YQ, Vikkula M, Boon L et al. Osteoporosis-pseudoglioma
syndrome, a disorder affecting skeletal strength and vision, is assigned
to chromosome region 11q12-13. American Journal of Human Genetics
1996; 59(1):146-151.
29. Johnson ML, Gong GD, Kimberling W, Recker SM, Kimmel DB,
Recker RR. Linkage of a gene causing high bone mass to human
chromosome 11 (11q12-13). American Journal of Human Genetics 1997;
60(6):1326-1332.
30. Urano T, Shiraki M, Ezura Y et al. Association of a single-nucleotide
polymorphism in low-density lipoprotein receptor-related protein 5 gene
with bone mineral density. Journal of Bone and Mineral Metabolism 2004;
22(4):341-345.
31. Koh JM, Jung MH, Hong JS et al. Association between bone mineral
density and LDL receptor-related protein 5 gene polymorphisms in young
Korean men. Journal of Korean Medical Science 2004; 19(3):407-412.
32. Ferrari SL, Deutsch S, Choudhury U et al. Polymorphisms in the low-
density lipoprotein receptor-related protein 5 (LRP5) gene are associated
with variation in vertebral bone mass, vertebral bone size, and stature in
whites. American Journal of Human Genetics 2004; 74(5):866-875.
33. van Meurs JBJ, Rivadeneira F, Jhamai M et al. Common genetic
variation of the low-density lipoprotein receptor-related protein 5 and 6
genes determines fracture risk in elderly white men. Journal of Bone and
Mineral Research 2006; 21(1):141-150.
34. van Meurs JBJ, Trikalinos TA, Ralston SH et al. Large-scale analysis
of association between LRP5 and LRP6 variants and osteoporosis. Jama-
Journal of the American Medical Association 2008; 299(11):1277-1290.
35. Richards JB, Kavvoura FK, Rivadeneira F et al. Collaborative Meta-
analysis: Associations of 150 Candidate Genes With Osteoporosis and
Osteoporotic Fracture. Annals of Internal Medicine 2009; 151(8):528-U32.
36. Kato M, Patel MS, Levasseur R et al. Cbfa1-independent decrease
in osteoblast proliferation, osteopenia, and persistent embryonic eye
vascularization in mice deficient in Lrp5, a Wnt coreceptor. Journal of Cell
Biology 2002; 157(2):303-314.
37. Ai M, Holmen SL, Van Hul W, Williams BO, Warman ML. Reduced
affinity to and inhibition by DKK1 form a common mechanism by which
36
high bone mass-associated missense mutations in LRP5 affect canonical
Wnt signaling. Molecular and Cellular Biology 2005; 25(12):4946-4955.
38. Avsian-Kretchmer O, Hsueh AJW. Comparative genomic analysis of the
eight-membered ring cystine knot-containing bone morphogenetic protein
antagonists. Molecular Endocrinology 2004; 18(1):1-12.
39. Bell E., Munoz-Sanjuan I., Altmann C.R., Vonica A., Brivanlou A.H.
Cell fate specification and competence by Coco, a maternal BMP, TGF
beta and Wnt inhibitor. Development 2003; 130(7):1381-1389.
40. Itasaki N., Jones C.M., Mercurio S. et al. Wise, a context-dependent
activator and inhibitor of Wnt signalling. Development 2003;
130(18):4295-4305.
41. Piccolo S., Agius E., Leyns L. et al. The head inducer Cerberus is a
multifunctional antagonist of Nodal, BMP and Wnt signals. Nature 1999;
397(6721):707-710.
42. ten Dijke P., Krause C., de Gorter D.J.J., Lowik C.W.G.M., van
Bezooijen RL. Osteocyte-derived sclerostin inhibits bone formation: Its
role in bone morphogenetic protein and Wnt signaling. Journal of Bone
and Joint Surgery-American Volume 2008; 90A:31-35.
43. Uitterlinden A.G., Arp P.P., Paeper B.W. et al. Polymorphisms in the
sclerosteosis/van Buchem disease gene (SOST) region are associated
with bone-mineral density in elderly whites. American Journal of Human
Genetics 2004; 75(6):1032-1045.
44. Krause C., Korchynskyi O., de Rooij K. et al. Distinct Modes of
Inhibition by Sclerostin on Bone Morphogenetic Protein and Wnt Signaling
Pathways. Journal of Biological Chemistry 2010; 285(53):41614-41626.
45. Noble B.S. The osteocyte lineage. Archives of Biochemistry and
Biophysics 2008; 473(2):106-111.
46. Bellido T., Ali AA, Gubrij I et al. Chronic elevation of parathyroid
hormone in mice reduces expression of sclerostin by osteocytes: A novel
mechanism for hormonal control of osteoblastogenesis. Endocrinology
2005; 146(11):4577-4583.
47. Li XF, Zhang YZ, Kang HS et al. Sclerostin binds to LRP5/6 and
antagonizes canonical Wnt signaling. Journal of Biological Chemistry
2005; 280(20):19883-19887.
48. Moriishi T, Fukuyama R, Ito M et al. Osteocyte Network; a Negative
Regulatory System for Bone Mass Augmented by the Induction of Rankl in
Osteoblasts and Sost in Osteocytes at Unloading. Plos One 2012; 7(6).
49. Ke HZ, Richards WG, Li XD, Ominsky MS. Sclerostin and Dickkopf-1 as
therapeutic targets in bone diseases. Endocrine Reviews 2012; 33(5):747-
783.
50. Ardawi MSM, Al Kadi HA, Rouzi AA, Qari MH. Determinants of Serum
Sclerostin in Healthy Pre- and Postmenopausal Women. Journal of Bone
and Mineral Research 2011; 26(12):2812-2822.
51. Modder UI, Hoey KA, Amin S et al. Relation of Age, Gender, and Bone
Mass to Circulating Sclerostin Levels in Women and Men. Journal of Bone
and Mineral Research 2011; 26(2):373-379.
52. Mirza FS, Padhi ID, Raisz LG, Lorenzo JA. Serum Sclerostin Levels
Negatively Correlate with Parathyroid Hormone Levels and Free Estrogen
Index in Postmenopausal Women. Journal of Clinical Endocrinology &
Metabolism 2010; 95(4):1991-1997.
53. Modder UI, Roforth MM, Hoey K et al. Effects of estrogen on
osteoprogenitor cells and cytokines/bone-regulatory factors in
postmenopausal women. Bone 2011; 49(2):202-207.
54. Il Modder U, Clowes JA, Hoey K et al. Regulation of Circulating
Sclerostin Levels by Sex Steroids in Women and in Men. Journal of Bone
and Mineral Research 2011; 26(1):27-34.
55. Genetos DC, Yellowley CE, Loots GG. Prostaglandin E-2 Signals
Through PTGER2 to Regulate Sclerostin Expression. Plos One 2011;
6(3).
56. Findlay DM, Atkins GJ. TWEAK and TNF Regulation of Sclerostin: A
Novel Pathway for the Regulation of Bone Remodelling. Advances in Tnf
Family Research 2011; 691:337-348.
REVISTA ROMN DE REUMATOLOGIE VOL. XXII NR. 1, AN 2013
57. Vincent C, Findlay DM, Welldon KJ et al. Pro-Inflammatory Cytokines
TNF-Related Weak Inducer of Apoptosis (TWEAK) and TNF alpha Induce
the Mitogen-Activated Protein Kinase (MAPK)-Dependent Expression of
Sclerostin in Human Osteoblasts. Journal of Bone and Mineral Research
2009; 24(8):1434-1449.
58. Keller H, Kneissel M. SOST is a target gene for PTH in bone. Bone
2005; 37(2):148-158.
59. Drake MT, Srinivasan B, Modder UI et al. Effects of Parathyroid
Hormone Treatment on Circulating Sclerostin Levels in Postmenopausal
Women. Journal of Clinical Endocrinology & Metabolism 2010;
95(11):5056-5062.
60. Gatti D, Viapiana O, Idolazzi L, Fracassi E, Rossini M, Adami S.
The Waning of Teriparatide Effect on Bone Formation Markers in
Postmenopausal Osteoporosis Is Associated with Increasing Serum
Levels of DKK1. Journal of Clinical Endocrinology & Metabolism 2011;
96(5):1555-1559.
61. Cejka D, Herberth J, Branscum AJ et al. Sclerostin and Dickkopf-1
in Renal Osteodystrophy. Clinical Journal of the American Society of
Nephrology 2011; 6(4):877-882.
62. Yao W, Cheng ZQ, Pham A et al. Glucocorticoid-Induced Bone Loss
in Mice Can Be Reversed by the Actions of Parathyroid Hormone
and Risedronate on Different Pathways for Bone Formation and
Mineralization. Arthritis and Rheumatism 2008; 58(11):3485-3497.
63. Garcia-Martin A et al. Circulating levels of sclerostin are increased in
patients with type 2 diabetes mellitus. Proc 33rd Annual Meeting of the
American Society for Bone and Mineral Research, San Diego, CA , p
S142. 2011.
64. Arasu A, Cawthon PM, Lui LY et al. Serum Sclerostin and Risk of Hip
Fracture in Older Caucasian Women. Journal of Clinical Endocrinology &
Metabolism 2012; 97(6):2027-2032.
65. Ominsky MS, Vlasseros F, Jolette J et al. Two Doses of Sclerostin
Antibody in Cynomolgus Monkeys Increases Bone Formation, Bone
Mineral Density, and Bone Strength. Journal of Bone and Mineral
Research 2010; 25(5):948-959.
66. Li XD, Warmington KS, Niu QT et al. Inhibition of Sclerostin by
Monoclonal Antibody Increases Bone Formation, Bone Mass, and Bone
Strength in Aged Male Rats. Journal of Bone and Mineral Research 2010;
25(12):2371-2380.
67. Padhi D, Jang G, Stouch B, Fang LA, Posvar E. Single-Dose, Placebo-
Controlled, Randomized Study of AMG 785, a Sclerostin Monoclonal
Antibody. Journal of Bone and Mineral Research 2011; 26(1):19-26.
68. Yadav VK, Ryu JH, Suda N et al. Lrp5 Controls Bone Formation by
Inhibiting Serotonin Synthesis in the Duodenum. Cell 2008; 135(5):825-
837.
69. Oury F, Yadav VK, Wang Y et al. CREB mediates brain serotonin
regulation of bone mass through its expression in ventromedial
hypothalamic neurons. Genes & Development 2010; 24(20):2330-2342.
70. Karasik D, Cheung CL, Zhou YH, Cupples LA, Kiel DP, Demissie
S. Genome-wide association of an integrated osteoporosis-related
phenotype: Is there evidence for pleiotropic genes? Journal of Bone and
Mineral Research 2012; 27(2):319-330.
71. Tsutsui Y, Ikeda M, Takeda M, Matsumoto S. Excitability of Small-
Diameter Trigeminal Ganglion Neurons by 5-Ht Is Mediated by
Enhancement of the Tetrodotoxin-Resistant Sodium Current Due to the
Activation of 5-Ht(4) Receptors And/Or by the Inhibition of the Transient
Potassium Current. Neuroscience 2008; 157(3):683-696.
72. Dodge-Kafka KL, Soughayer J, Pare GC et al. The protein kinase A
anchoring protein mAKAP coordinates two integrated cAMP effector
pathways. Nature 2005; 437(7058):574-578.