o stec las to genesis

8/13/2019 o Stec Las to Genesis

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J Musculoskelet Neuronal Interact 2008; 8(3):204-216

Original Article Hylonome

Osteoclastogenesis - Current knowledge and future

perspectivesM.P. Yavropoulou and J.G. Yovos

r!stotle "n!#ers!ty o$ %&essalon!k!' H "n!#ers!ty Hos*!tal' +reece

Abstract

%&e stren,t& an !nte,r!ty o$ t&e &uman skeleton e*ens on a el!cate e.u!l!/r!um /eteen /one resor*t!on /y osteoclasts an /one $ormat!on /y osteo/lasts %&!s e.u!l!/r!um !s cont!nuously com*rom!se /y a #ar!ety o$ ,enet!c' &umoral' an mec&an!calalterat!ons In osteo*oros!s' t&!s /alance s&!$ts !n $a#or o$ osteoclasts' an /one resor*t!on ecees /one $ormat!on More eta!le

knole,e o$ t&e /!olo,y o$ osteoclasts an osteoclasto,enes!s &as s&on t&at t&e !n#ol#e *roceures can *ro#!e o**ortun!t!es $ore#elo*!n, t&era*eut!c a,ents steoclasto,enes!s !s a mult!-com*le *roceure t&at !nclues many sta,es' an eac& one o$ t&em

*resents as a *otent!al tar,et $or t&era*eut!c !nter#ent!on' ece*t $or t&e sta,e o$ comm!tment o$ *re-osteoclasts' at least $or t&e t!me /e!n, ecause t&e osteoclast !s er!#e $rom t&e *lur!*otent &emato*o!et!c stem cell' any !nter#ent!on !n t&!s sta,e coul result !nser!ous a#erse e$$ects $rom t&e &emato*o!et!c system n t&e contrary' !nter#ent!on !n t&e later sta,es o$ !$$erent!at!on' mult!-nucleat!on' an act!#at!on' &as *ro#e to /e #ery *rom!s!n, !n t&e e#elo*ment o$ no#el *otent ant!-resor*t!#e a,ents In t&e *resentre#!e e summar!5e t&e current knole,e relate to osteoclast !$$erent!at!on an t&e ne e#elo*!n, tar,ets o$ *&armacolo,!cal!nter#ent!on !n eac& sta,e o$ t&!s etremely com*l!cate an not com*letely eluc!ate *rocess

Kewords! steoclasts' steo*oros!s' %reatment' !$$erent!at!on' 7omm!tment

"ntroduction

s &umans l!#e lon,er' e,enerat!#e skeletal !seases' suc&as osteo*oros!s' /ecome !ncreas!n,ly *re#alent e,arless o$cause' osteo*oros!s re$lects a relat!#e *re*onerance o$ osteo-clast act!#!ty %&e osteoclast !s a un!.ue /one-resor/!n, celler!#!n, $rom t&e cells o$ monocyte-macro*&a,e l!nea,eur!n, t&e last ecae' a more eta!le knole,e o$ t&emolecular mec&an!sms !n#ol#e !n osteoclasto,enes!s &as r!#-en researc& e$$ort !n ,enerat!n, ne *&armacolo,!cal a,entst&at select!#ely !n&!/!t t&e !$$erent!at!on or t&e act!#!ty o$

t&ese cells steoclasto,enes!s !s a com*l!cate *roceure t&at!nclues many sta,es' suc& as comm!tment' !$$erent!at!on'mult!nucleat!on' an act!#at!on o$ !mmature osteoclasts #ar!ety o$ /ot& system!c &ormones an cytok!nes locally *ro-uce !n t&e /one m!croen#!ronment re,ulate osteoclast !$-$erent!at!on an $unct!on In a!t!on' t&e osteoclast !tsel$ !s a

%&e aut&ors &a#e no con$l!ct o$ !nterest

Corresponding aut#or! Jo#n G. Yovos$ A%&PA 'niversit #ospital$ (.Kriakidi )$ *#essaloniki$ Greece&-+ail! giovos,+ed.aut#.gr

Accepted June //0

/1

secretory cell an can *rouce cytok!nes' &!c& st!mulate or !n&!/!t !ts on act!#!ty 9!nally' ot&er cells !n t&e /one marrom!croen#!ronment' l!ke % an lym*&ocytes' marro stromalcells' osteo/lasts an osteocytes' can !n$luence osteoclast !$-$erent!at!on %&e *resent re#!e !s $ocuse on t&e currentknole,e o$ t&e molecular mec&an!sms re,ulat!n, osteoclas-to,enes!s' as ell as on t&e creat!on o$ ne *otent!al ru,s t&at!nter#ene !n !$$erent sta,es o$ osteoclasto,enes!s 9or escr!*-t!#e *ur*oses t&!s re#!e !s !#!e !nto 4 *artssta,es; com-m!tment' !$$erent!at!on' mult!nucleat!on' an maturat!on

Co++it+ent

%&e osteoclast !s er!#e $rom t&e *lur!*otent &emato*o!-et!c stem cell' &!c& ,!#es r!se to a myelo! stem cell t&at can$urt&er !$$erent!ate !nto me,akaryocytes' ,ranulocytes'monocytesmacro*&a,es an osteoclasts (9!,ure 1) %&e ear-l!est !ent!$!a/le &emato*o!et!c *recursor a/le to $ormosteoclasts !s t&e ,ranulocyte-macro*&a,e colony $orm!n,un!t (79"-+M)' &!le 79"-M' t&e more !$$erent!atemonocyte *recursor' $orms osteoclasts at a muc& loer e$$!-c!ency1 t t&!s sta,e t&e *r!nc!*al transcr!*t!on $actors t&at are!n#ol#e are t&e "1' t&e MI%9' an t&e c-9; %&ecytok!ne M-7;9' st!mulates t&e *rol!$erat!on an *re#ents t&ea*o*tos!s o$ early osteoclast *recursors



M <a#ro*oulou an J+ <o#os: steoclasto,enes!s

2igure ). %&e cell $ate o$ t&e *lur!*otent &emato*o!et!c stem cell %&e *lur!*otent stem cell ,!#es r!se to a myelo! stem cell &!c& can$urt&er !$$erent!ate to me,akaryocytes' ,ranulocytes' monocytesmacro*&a,es an osteoclasts

Abbreviations

%&e "1 transcr!*t!on $actor

%&e "1 /elon,s to t&e ts $am!ly o$ transcr!*t!on $actorsan !s res*ons!/le $or t&e earl!est esta/l!s&e e#ent !n osteo-clasto,enes!s "1 null m!ce lack not only osteoclasts' /utalso macro*&a,es' &!le *reser#!n, t&e a/!l!ty to *rouceearly monocyt!c cells2 Macro*&a,e an neutro*&!l cell $ate

s*ec!$!cat!on re.u!re t&e *r!mary cell $ate eterm!nants "1an 7a' res*ect!#ely3 ot& $actors are &!,&ly e*resse!n macro*&a,es an neutro*&!ls u/-t&res&ol le#els o$ "1act!#ate a m!e l!nea,e *attern o$ ,ene e*ress!on !t&!n!n!#!ual myelo! *ro,en!tors n !ncrease !n "1 act!#!ty

/eyon t&e t&res&ol !nuces resolut!on o$ t&e m!e l!nea,e *attern lea!n, to an o#ert !$$erent!at!on !nto macro*&a,es%&e re*ress!on o$ neutro*&!l ,enes ur!n, macro*&a,e !$$er-ent!at!on !s !n!rectly me!ate /y "1 #!a t&e !nuct!on o$ne,at!#e re,ulators (9!,ure 2) %&e 5!nc $!n,er $am!ly tran-scr!*t!on $actors ,r-1 an r,-2 &a#e /een !m*l!cate !n re,-ulat!n, macro*&a,e !$$erent!at!on4 "1 !n!t!ally act!#ates a

79"-+M ,ranulocyte-macro*&a,e colony $orm!n, un!t

M-79 macro*&a,e colony st!mulat!n, $actor I3= *&os*&o!nos!tol 3 k!nase= etracellular s!,nal-re,ulate k!nases)>7? *&os*&ol!*ase ?+=3@ ,lyco,en synt&ase k!nase 3@7t 7-term!nal /!n!n, *rote!n

M)A m!tB,en act!#ate *rote!n k!nasestm osteo*etros!s-assoc!ate transmem/rane *rote!n 1JN= Canus l!ke k!naseD9 6 %N9 rece*tor-assoc!ate $actor 6%N *&os*&atase an tens!n &omolo,ue elete $rom

c&romosome 10HI rc &omolo,y (H) 2-conta!n!n, !nos!tol-E-

*&os*&ataseI7M-1 !ntercellular a&es!on molecule-1>9-1 >ym*&ocyte $unct!on-assoc!ate ant!,en-1

N9% nuclear $actor o$ act!#ate %-cellsM7-1 monocyte c&emotact!c *rote!n-1

/3




2igure . %&e comm!tment o$ *re-osteoclasts Macro*&a,e an neutro*&!l cell $ate s*ec!$!cat!on re.u!res t&e *r!mary cell $ate eterm!nants"1 an 7a' res*ect!#ely ,r-1'2Na/-2 an +$!-1 re*resent l!nea,e s*ec!$!c counteract!n, re*ressors +$!-1 !s u*-re,ulate /y7a' re*resses "1' an counter-re*resses t&e ,r-1 an ,r-2 Interact!on o$ "1 an MI%9 !t& t&e 5!nc $!n,er *rote!n os results !nre*ress!on o$ t&e transcr!*t!on o$ s*ec!$!c macro*&a,e ,enes t&rou,& recru!tment o$ t&e co-re*ressors !n3 an 7t M-79-N=>s!,nal!n, results !n recru!tment o$ co-act!#ators' 7*300 an +1 an t&us act!#at!on o$ transcr!*t!on o$ t&e macro*&a,e ,enes cat&e*s!n= (7tsk) an ac! *&os*&atase E (c*E)' M+ - Macro*&a,e *ec!$!c +enes

m!e l!nea,e *attern o$ ,ene e*ress!on !n myelo! *ro,en!-tors' an t&en ut!l!5es ,r-2 to resol#e t&!s *attern !nto amacro*&a,e-s*ec!$!c out*utE ,r-2' !n colla/orat!on !t& t&eco-re*ressor Na/-2' re!n$orces macro*&a,e ,ene act!#!ty&!le anta,on!5!n, neutro*&!l-s*ec!$!c ,ene e*ress!on

,r-1'2Na/-2 an +$!-1 re*resent l!nea,e s*ec!$!c counter-act!n, re*ressors Inuct!on o$ ,r-2 an Na/-2 /y "1 results!n t&e!r cross-l!nk!n, to t&e +$!-1 *romoter re,!on' an !n t&e

!rect re*ress!on o$ t&e +$!-1 ,ene In turn +$!-1' &!c& !s u*-re,ulate /y 7a' *&ys!cally !nteracts !t& "1' re*ress!n,"1-e*enent transcr!*t!on6 an also counter-re*ress!n, t&e,r-1 an ,r-2 ,enes !n to !$$erent cellular contets 4 "1also re,ulates t&e N= ,ene transcr!*t!on !n myelo! *ro,en-!tors' t&e rece*tor $or N=>' &!c& !s t&e key osteoclasto,en!ccytok!ne !n osteoclast !$$erent!at!onF' as escr!/e /elo

%&e M-79 s!,nal!n,

%ranscr!*t!on o$ t&e macro*&a,e c-9M; ,ene' t&e solerece*tor o$ M-79' !s e*enent on /ot& "1 an ,r-1' 24

/4

(9!,ure 3) M-7;9 can !nuce !ts on rece*tor e*ress!on$orm!n, an autocr!ne loo* to am*l!$y M-79-me!ate s!,-nals' &!le !t &as also /een re*orte to st!mulate "1 8ct!#at!on o$ c-9M /y M-79 !s necessary $or t&e *rol!$er-at!on an sur#!#al o$ macro*&a,eosteoclast *ro,en!tor cells>oss o$ $unct!on mutat!on !n t&e M-7;9 ,ene (op5op m!ce)results !n a marke ecrease o$ t!ssue macro*&a,e anosteo*etrot!c *&enoty*e ue to t&e lack o$ osteoclastsG M-

79 !s *rouce const!tut!#ely !n t&e /one m!croen#!roment /y a ran,e o$ cells' !nclu!n, stromal cellsosteo/lasts' an %-lym*&ocytes' !n res*onse to ele#ate serum %H le#els an!n$lammatory molecules suc& as %N9- an I>-110 ecente#!ence su,,ests t&at %N9- can also !rectly !nuce c-9M e*ress!on t&rou,& /ot& M-79-e*enent an -!ne-

*enent mec&an!sms8 !n!n, o$ M-7;9 to c-9M; results!n !mer!5at!on an &ence act!#at!on o$ t&e rece*tor tyros!nek!nase' lea!n, to auto-*&os*&orylat!on on selecte tyros!neres!ues #a!la/le ata !n!cate t&at t&e onstream s!,nalsI3=' *4244 =' t&e *roto-onco,ene c-7/1 an >7? aret&e key transucers o$ M-7;9 s!,nal!n,11 (9!,ure 3)




2igure 6. %&e M-79-s!,nal!n, !n!n, o$ -79 results !n t&e !mer!5at!on an *&os*&orylat!on o$ t&e rece*tor c-$ms on selecte tyro-s!ne res!ues ac& *&os*&orylate res!ue acts as a /!n!n, s!te $or H-2 an % oma!n-conta!n!n, *rote!ns %&e aa*tor *rote!n com-

*le +r/2os !s recru!te to t&e rece*tor an st!mulates t&e asa$=M= *at&ay I3=kt *&os*&orylates an !nact!#ates +=3@an 9 +=3@ *&os*&orylates cycl!n-1 9 also *&os*&orylates cycl!n-1 an !ncreases t&e cell cycle !n&!/!tors *2F an *130"*on /!n!n, o$ M-79' -ty*e cycl!ns $orm a cycl!n ck4 com*le' &!c& &y*er*&os*&orylates t&e *ocket *rote!n /2' allo!n, entryto t&e cell cycle

I3==% re,ulates cell *rol!$erat!on #!a +;=3@ an9 %&e *&os*&orylat!on o$ +;=3@ an 9 su*-

*resses t&e!r ca*ac!ty to !n&!/!t entry !nto t&e cell cycle

%&e MI%9 transcr!*t!on $actor

MI%9 (m!cro*&t&alm!a-assoc!ate transcr!*t!on $actor) !s a /as!c &el!-loo*-&el!-leuc!ne 5!**er *rote!n' &!c& &as /een!m*l!cate !n t&e !$$erent!at!on an sur#!#al o$ e#elo*men-tally unrelate cell ty*es' !nclu!n, osteoclasts12 MI%9' l!ke"1' !s e*resse !n macro*&a,es' osteoclasts an !n t&ecommon mononuclear *recursor o$ t&ese cell ty*es12Interact!on !t& "1' at least *artly' account $or t&e a/!l!ty o$MI%9 to select!#ely re,ulate tar,et ,enes' l!ke cat&e*s!n =

(7tsk)' ac! *&os*&atase E (c*E)' an osteoclast-assoc!aterece*tor (;7) ur!n, osteoclast !$$erent!at!on13-14 In

cells e*r!#e o$ M-79' MI%9 !s se.uestere to t&e cell cyto- *lasm t&rou,& !nteract!ons !t& 14-3-3 *rote!ns1E ecent e#!-ence emonstrate t&at !nteract!on o$ "1 an MI%9 !t&t&e 5!nc $!n,er *rote!n os results !n re*ress!n, transcr!*t!on$rom s*ec!$!c *romoters' t&rou,& recru!tment o$ t&e co-re*ressors ;!n3 an 7t13 (9!,ure 2) M-7;9-N=>s!,nal!n, act!#ate e*ress!on o$ osteoclast s*ec!$!c tar,et ,enes

/y to mec&an!sms: 1) on-re,ulates os e*ress!on at t&ele#el o$ mN an *rote!n' lea!n, to !ssoc!at!on o$ t&e co-re*ressors $rom tar,et ,enes' an 2) &os*&orylates an act!-#ates MI%9 /y /ot& = an *38 M= *at&ays' lea!n,to recru!tment o$ t&e co-act!#ators 7*300 an +113-16

/




2igure 1. %&e N=>N= s!,nal!n, N=> act!#ates t&e rece*tor N= !n a tr!mer!c symmetr!c com*le !t& %96 onstreams!,nal!n, !nclues act!#at!on o$ I== an N9- ' an M== an su/se.uent st!mulat!on o$ *38 M=' =' an JN= ct!#at!on o$ t&eM=s leas to act!#at!on an nuclear translocat!on o$ t&e transcr!*t!on $actors' c-9os' c-Jun' an N9%c1' %&e c-src-e*enent act!#a t!on o$I3= results !n !ncrease tIns(3'4'E)3 an su/se.uent act!#at!on o$ kt' &!c& t&en *&os*&orylates an !nact!#ates t&e *ro-a*o*tot!c *rote!na %&!s *at&ay can /e !nact!#ate /y %N an HI' e*resse /y osteoclasts an t&e!r *ro,en!tor cells

n !m*ortant !st!nct!on !s t&at t&e e$$ect o$ os !s s*ec!$!c $or t&e MI%9"1 com*le t&er "1 an MI%9 tar,et ,enes'!n /ot& macro*&a,es an osteoclasts' l!ke c-9M' N=' ancl-2' are not a$$ecte /y os o#er-e*ress!on12 %&us' osoes not re,ulate t&e ent!re osteoclast ,ene e*ress!on nt&e ot&er &an' t&e *resence o$ MI%9 an "1 at *romoterso$ tar,et ,enes allos comm!tte *recursors to res*on ra*-!ly to M-7;9N=> s!,nal!n, an to re*ro,ram ,enee*ress!on ecently' no#el MI%9 tar,et ,enes &a#e /een

!ent!$!e' !nclu!n, c&lor!e c&annel F (7lcnF)' &!c& !s nec-essary $or t&e ac!!$!cat!on an /one resor/!n, act!#!ty o$osteoclasts an stm1' a mem/rane *rote!n o$ unknon $unc-t!on !m*ortant $or 7lcnF *rote!n sta/!l!ty1F Mutat!ons !n 7lcn-F or !n t&e stm1 ,ene cause osteo*etros!s !n &umans18

%&e c-9 transcr!*t!on $actor

%&e transcr!*ton $actor -1 !s a &etero!mer!c *rote!ncons!st!n, o$ 9 *rote!ns (c-9' 9-' 9-1' 9-2)an J"N *rote!ns (c-J"N' J"N-' J"N-) M!ce e$!c!ent!n c-9 e&!/!t osteo*etros!s ue to an osteoclast !$$eren-

/0

t!at!on e$ect' &!le t&e num/er o$ macro*&a,es !ncreases1G'!n!cat!n, t&at !n&!/!t!on o$ !$$erent!at!on occurs later t&an!n "1-e$!c!ent m!ce N=> an M-7;9 s!,nal!n,!nuce c-9-e*enent transcr!*t!on o$ 9-1' &!c& !s atar,et o$ c-920 rolon,e = act!#at!on /y /ot& M-79an K@3 !nte,r!n s!,nal!n, !s re.u!re $or sta/le e*ress!ono$ c-921 In *&ys!olo,!cal c!rcumstances' &ere concentra-t!ons o$ M-7;9 !s l!m!te' s!,nals er!#e $rom t&e #@3!nte,r!n are l!kely to /e !n!s*ensa/le $or transcr!*t!onalact!#at!on o$ c-9;22 re#!ous stu!es &a#e s&on t&at c-

9; !s a key me!ator o$ t&e l!nea,e comm!tment /eteenosteoclasts an enr!t!c cells' &!c& are also er!#e $rommonocytemacro*&a,e *recursor cells23 %&e !$$erent!at!on!nto an osteoclast or a enr!t!c cell l!nea,e !s rec!*rocally!n&!/!te /y +M-7;9 an M-7;9 res*ect!#ely L&!le M-79 an sN=> !nuce osteoclasto,enes!s' +M-79 ansN=> !nuce enr!t!c cell !$$erent!at!on $rom s!n,lecommon *recursors an N=> &as *ro#e to /e an act!-#at!n, $actor o$ enr!t!c cells24 Hoe#er' a$ter t&e trans-uct!on o$ t&e !$$erent!at!on s!,nal /y M-79 an N=>'an c-9; e*ress!on' cells are no lon,er com*etent tores*on to +M-7923




%&era*eut!c !nter#ent!ons

"* to no' t&ere are no researc& ata a#a!la/le concern-!n, any *oss!/le t&era*eut!c !nter#ent!on !n t&!s sta,e o$osteoclast e#elo*ment %&!s !s *ro/a/ly /ecause t&e tran-scr!*t!on $actors an t&e cytok!nes !n#ol#e are u/!.u!tously

e*resse an re,ulate many !$$erent cell l!nea,es' ant&ere$ore any !nter#ent!on coul lea to un*re!cta/le an *ro/a/ly ser!ous s!e e$$ects $rom ot&er cell l!nes' ma!nly t&e&emato*oet!c l!nea,e

7ifferentiation

%&e N=N=> s!,nal!n,

N=>' a mem/er o$ t&e %N9 su*er$am!ly' !s a mem- /rane-res!!n, *rote!n on osteo/lasts an t&e!r *recursors'&!c& act!#ates rece*tor N=' on osteoclast *recursors In

*&ys!olo,!cal con!t!ons' N=> !s *r!nc!*ally e*resse /y

stromal cells !n /one marro an osteo/lasts !n t&e *er!os-teum Hoe#er' !n states o$ skeletal !n$lammat!on' suc& asr&eumato! art&r!t!s' N=> !s *rouce !n a/unance /y %-lym*&ocytes2E n t&!s occas!on' N=> may /e clea#e $romt&e cell mem/rane an t&en !nteract !t& N= as a solu/lel!,an elet!ons o$ t&e N=> ( *nfsf))) or N= ( *nfrsf))a) ,enes result !n t&e a/sence o$ osteoclasts ue to

arreste !$$erent!at!on o$ M-7;9 e*ane osteoclast *ro-,en!tor cells %&e ecoy rece*tor' osteo*rote,er!n (+)' !salso *rouce /y osteo/lasts' an acts t&rou,& /!n!n, toN=> an *re#ent!n, !ts !nteract!on !t& N= ecent

e#!ence emonstrates t&at osteo*rote,er!n !s a cr!t!cal re,u-lator o$ *ostnatal skeletal e#elo*ment an &omeostas!s !n&umans Homo5y,ous elet!on o$ t&e %N9911 ,ene onc&romosome 8.242 t&at encoes osteo*rote,er!n' !s assoc!at-e !t& Cu#en!le a,ets !sease26 N=> e*ress!on !s re,u-late /y a #ar!ety o$ &ormones suc& as %H' +2' an$orskol!n' all act!n, #!a t&e cycl!c M*rote!n k!nase (=)

*at&ay' an /y 3' act!n, #!a t&e -me!ate *at&ay2FIn a!t!on %N9-a' s!,nal!n, t&rou,& *38 M=' !nucesstromal cell e*ress!on o$ I>-1' &!c& !n turn u*-re,ulates !tson rece*tor an *romotes N=> *rouct!on Hoe#er'&ereas I>-1 !s onstream o$ %N9 !n t&e osteoclasto,en!c

*rocess' t&e rec!*rocal oes not occur 28 N=> act!#ates t&e

rece*tor N= on osteoclast *ro,en!tor cells !n a tr!mer!csymmetr!c com*le (9!,ure 4)' !nteract!n, !t& an aa*tormolecule %N9 rece*tor-assoc!ate $actor 6 (%96) ;!%9s (%91-%96) &a#e /een re*orte so $ar on t&e

/as!s o$ t&e!r s!m!lar!t!es !n t&e car/oy-term!nal %9oma!n /ut only %96 seems to &a#e a cr!t!cal role !n osteo-clasto,enes!s %96-e$!c!ent m!ce s&o se#ere osteo*etro-s!s ue to !m*a!re osteoclasto,enes!s2G es*!te t&e act!#at!ono$ a**arently o#erla**!n, %96-e*enent s!,nal!n, cas-caes /y ot&er rece*tors' suc& as 740 an t&e I>-1%oll-l!ke rece*tor $am!ly mem/ers (%>)' only N=> can !nuceosteoclasto,enes!s30-31 ecent stu!es su,,est t&at t&e .uant!-

tat!#e !$$erence !n %96-act!#at!on' man!$este /y t&e

e,ree o$ !ts recru!tment to t&e sur$ace rece*tor an *38k!nase act!#at!on' !s *ro/a/ly t&e key mec&an!sm t&at !st!n-,u!s&es N=> $rom ot&er rece*tors !n terms o$ osteoclasto-,en!c *otent!al32 %&e onstream !ntracellular s!,nal!n, *at&-ays !nclue %96-e*enent act!#at!on o$ Ik k!nases(I==) a an /' an M k!nases (M==)' *38 M=' ='

an JN= ct!#at!on o$ Ik k!nase !nuces *&os*&orylat!on o$t&e !n&!/!tory *rote!n Ik' &!c& $orms a com*le !t& t&e!nact!#e $orm o$ N9-k !n t&e cyto*lasm nce *&os*&oryla-t!on occurs t&e N9-kIk com*le !ssoc!ates N9-k !srelease an translocates to t&e nucleus &ere !t /!ns to s*e-c!$!c N se.uences tr!,,er!n, transcr!*t!on o$ s*ec!$!c ,enes%&e Ik !s ta,,e /y u/!.u!t!n an !s e,rae /y t&e *rotea-some %&e !m*ortance o$ t&e N9-O *at&ay $or osteoclast$ormat!on !s emonstrate /y t&e $!n!n, t&at m!ce e$!c!ent !n

/ot& N9-O su/un!ts *E0 an *E2 are osteo*etrot!c' !t& mar-ro ca#!t!es $!lle !t& unremoele osteocart!la,!nousmatr!33 Nuclear translocat!on o$ N9-k !s also accelerate /yN=-!nuce ele#at!ons o$ !ntracellular 7a2P #!a >734

%&e !n#ol#ement o$ t&e JN= *at&ay !n osteoclasto,enes!s!s !n!cate /y t&e o/ser#at!ons t&at N= o#er-e*ress!onleas to en&ance act!#at!on o$ JN= an N9-k 3E&os*&orylat!on an act!#at!on o$ t&e M=s /y N=>36

leas to act!#at!on an nuclear translocat!on o$ t&e %92' c-9' c-J"N' an N9%c1' result!n, !n transcr!*t!on o$ ,enes'mostly unknon' /ut o$ #!tal !m*ortance $or osteoclast !$$er-ent!at!on an act!#at!on !,nal!n, *at&ays onstream o$N= (s!m!lar to t&at o$ M-79) also !nclue act!#at!on o$I3=' me!ate /y %96c-73F I3= ,enerates t&e l!*!secon messen,er *&os*&at!yl!nos!tol 3'4'E-tr!s*&os*&ateQtIns(3'4'E)3R an su/se.uently act!#ates t&e ant!-a*o*tot-

!c ser!net&reon!ne k!nase =% (=) In turn' =% *&os- *&orylates an !nact!#ates ' a *ro-a*o*tot!c *rote!nmem/er o$ t&e 7>-2 $am!ly %&e I3==%a *at&ay !s!n&!/!te /y t&e tumor su**ressor ,ene %N /y to mec&a-n!sms %N e*&os*&orylates tIns(3'4'E)3 to t&e !nac-t!#e tIns(4'E)2' an can also act as a *rote!n *&os*&atase /y e*&os*&orylat!n, act!#e =% In a!t!on' !t &as /eenemonstrate t&at N= may re,ulate t&e e*ress!on o$%N !n osteoclasts' !n!cat!n, t&at %N *lays a role !n re,-ulat!n, t&e /alance /eteen act!#e an non-act!#e =%3Ges!es %N' ;HI' anot&er E-*&os*&atase can alsoe*&os*&orylate tIns(3'4'E)3 an =% %&e *&enoty*e o$HI -- m!ce' !nclues lar,e &y*er-resor*t!#e osteoclasts' an !s

#ery s!m!lar to t&at o$ *at!ents !t& a,ets !sease3G 7ell to cellcontact /eteen osteo/lastsstromal cells an *re-osteo-clasts !s necessary $or t&e act!#at!on o$ N=N=> s!,-nal!n, It &as /een emonstrate t&at t&e eos!no*&!l c&emo-tact!c $actor-> (79>)' an autocr!ne $actor *rouce /yosteoclast *recursors' !ncreases t&e e*ress!on o$ t&e cella&es!on molecules I7M-1 an >9-1 t&at are alsoe*resse !n osteo/lasts40 I7M-1 !s one o$ t&e l!,ans $or>9-1' an !nteract!ons /eteen t&em are !n#ol#e !n a cell tocell contact /eteen osteoclast *recursors anosteo/last!cstromal cells or /eteen osteoclast *recursors !n t&e$us!on sta,e o$ osteoclast $ormat!on41

/8




%&e transcr!*t!on $actor N9%

%&e N9% $am!ly o$ transcr!*t!on $actors !nclues $!#e mem- /ers %&e necessary an su$$!c!ent role o$ N9%c1 !n osteoclasto-,enes!s as su,,este /y in vitro o/ser#at!ons t&at N9%c1(--)em/ryon!c stem cells o not !$$erent!ate !nto osteoclasts' an

t&at ecto*!c e*ress!on o$ N9%c1 causes /one marro-er!#e *recursor cells to uner,o osteoclast !$$erent!at!on !n t&ea/sence o$ N=>42 9urt&ermore' loss o$ $unct!on mutat!on !nt&e N9%c1 ,ene' leas to a/ol!s!on o$ t&e ca*ac!ty to $ormosteoclasts a$ter N=> st!mulat!on' &ereas M-79 st!mula-t!on o$ monocytemacro*&a,e *recursors !s normal42 re-e!st-!n, N9%c2 !s recru!te to t&e N9%c1 *romoter at t&e #eryearly *&ase' /ut t&!s !s not enou,& to act!#ate t&e N9%c1 *ro-moter N9%c2 co-o*erates !t& N9-k to act!#ate t&e !n!t!al!nuct!on o$ N9%c1' $olloe /y an auto-am*l!$!cat!on *&aseo$ N9%c143' &ere c-9' *lays a cr!t!cal role as !t !s recru!teselect!#ely to t&e N9%c1 *romoter 44 %ranslocat!on o$

N9%c1 to t&e nucleus !n#ol#es N=-!nuce 7a2P osc!lla-

t!ons an act!#at!on o$ 7a2Pcalmoul!n-e*enent calc!neur!n'a ser!net&reon!ne *&os*&atase4E N9%c1 re,ulates manyosteoclast-s*ec!$!c ,enes' suc& as cat&e*s!n =' %' calc!ton!nrece*tor (7%) an osteoclast-assoc!ate rece*tor (7)46-

4F' $orm!n, com*lees !t& ot&er transcr!*t!on $actors l!ke "1'

MI%9 an c-9' alt&ou,& t&e com*onents o$ t&e transcr!*-t!onal com*le are not alays t&e same

utocr!ne an *aracr!ne s!,nal!n,

%&e osteoclast' !s !tsel$ a secretory cell I>-6 as t&e $!rstautocr!ne $actor !ent!$!e &!c& st!mulate osteoclast $or-

mat!on steoclasts $rom *at!ents $rom a,ets !sease *ro-uce &!,& le#els o$ I>-648 nne!n II !s anot&er &eterote-tramer autocr!ne $actor *rouce /y osteoclasts &!c& st!mu-lates osteoclast $ormat!on !n!rectly /y !ncreas!n, *rouct!ono$ N=> an +M-7;9 on marro stromal cells4Gecently t&e $!rst sur$ace rece*tor $or anne!n II as !ent!-$!eE0 M8 me!ates !ts e$$ects at late sta,es o$ osteoclast

*recursors #!a !ts rece*tor G@1 !nte,r!nE1 steoclasts $rom Gknockout m!ce are small an contracte' o not $orm act!nr!n,s an t&ere$ore resor/ /one *oorly' s!m!lar to osteoclastst&at lack @3 !nte,r!nE2 73 com*onent o$ com*lement !s *ro-uce /y stromal cells !n res*onse to 1'2E-(H) 23 an !s!n#ol#e !n osteoclast e#elo*ment /y *otent!at!n, M-79-

e*enent *rol!$erat!on o$ *re-osteoclastsE3 %o no#elautocr!ne-*aracr!ne !n&!/!tors o$ osteoclast $ormat!on &a#ealso /een !ent!$!e %&e osteoclast !n&!/!tory *e*t!e-1(I-1)' a +I-l!nke *rote!n t&at can /e clea#e $rom t&ecell sur$ace to !n&!/!t osteoclast $ormat!onE4 an t&e 7-term!-nal *e*t!e o$ I-2' &!c& !s clea#e /y autocatalys!s &ent&e *rote!n !s secrete' an also !n&!/!ts osteclasto,enes!sEE


ecom/!nant + as *ro#en e$$ect!#e !n *re#ent!n, t&e /one loss result!n, $rom a lack o$ estro,enE6 Hoe#er' t&e

)/

$ormat!on o$ s!,n!$!cant ant!/oy t!ters !n a *at!ent ,!#en+ /rou,&t t&at e#elo*ment to an en ecently' eno-suma/' a &uman monoclonal ant!/oy t&at /!ns !t& &!,&a$$!n!ty an s*ec!$!c!ty to N=>' &as /een teste !n t&etreatment o$ osteo*oros!s !n *ostmeno*ausal omenEFecause t&e !nteract!ons /eteen N=> an + are

also !n#ol#e !n !mmune re,ulat!ons' /lock!n, N=> *ro-#!es an a!t!onal r!sk $or a#erse system!c e$$ects o$ t&e!mmune systemE8 No#el *otent !n&!/!tors o$ N9-=/' l!ke,u,,ulsterone' use to treat osteoart&r!t!s' are also uner!ntense researc& $or t&e e#elo*ment o$ ne t&era*eut!ca,ents a,a!nst /one lossEG In a!t!on' N9%' &!c& !s amaCor osteoclasto,en!c transcr!*t!on $actor' also re,ulatesne,at!#ely osteo/last !$$erent!at!on /y re,ulat!n, 9-2e*ress!on ecent analyses &a#e emonstrate t&at !n&!/!-t!on o$ t&e calc!neur!nN9% s!,nal!n, /y cyclos*or!ne!ncreases t&e e*ress!on o$ alkal!ne *&os*&atase an osteo-calc!n60 %&ese ata *ro#!e t&e mec&an!sm $or t&e *oss!/lee#elo*ment o$ a no#el ana/ol!c t&era*eut!c tar,et $or

osteo*oros!s' a!m!n, at N9% s!,nal!n,

Multinucleation of pre-osteoclasts

Mult!-nucleat!on !s an essent!al ste* !n t&e !$$erent!at!ono$ osteoclasts' as mono-nucleate macro*&a,es cannotresor/ /one e$$!c!ently Mult!-nucleate osteoclasts are$orme /y t&e $us!on o$ N=Pmononuclear *recursorsa$ter contact !t& a cell e*ress!n, N=> n osteoclast

*recursor cell !n contact !t& a N=> *resent!n, cell !llrece!#e t&e N=> s!,nal an !n!t!ate a cascae o$ ,enee*ress!on t&at !nclues t&e *rouct!on o$ t&e c&emok!nes

M7-1' an N%;' &!c& are c&emotact!c s!,nals $ormonocytes61 7&emok!ne-me!ate $us!on !ncreases t&e s!5eo$ t&e osteoclast' an also trans$ers t&e N=> s!,nal to t&ea!t!onal nucle! t&at are no !n t&e mult!-nucleate cell sment!one a/o#e' +M-79 an N=> re*resent to com- *et!n, !$$erent!at!on s!,nals: N=> to osteoclasts an+M-79 to enr!t!c-l!ke cells M7-1 o#ercomes +M-79me!ate re*ress!on o$ osteoclast !$$erent!at!on' *erm!tt!n,t&e cells to *ass t&rou,& mult!nucleat!on' to aut&ent!c /oneresor/!n, osteoclasts62 N=> also !nuces t&e M7-1rece*tors (772 an 774)' + *rote!n-cou*le rece*torst&at st!mulate t&e I3= s!,nal!n, *at&ays63 %&us' N=>!nuct!on o$ M7-1 sets u* /ot& autocr!ne' a$$ect!n, t&e

osteoclast *rouc!n, M7-1' an *aracr!ne *at&ays' a$$ect-!n, cells est!ne to $use !t& t&e N=>-st!mulate osteo-clast ne o$ t&e reasons t&at !n$lammatory !seases' suc& asr&eumato! art&r!t!s' are assoc!ate !t& !ncrease osteoclastact!#!ty !s /ecause t&ey !s*lay !ncrease c&emok!ne act!#!ty64M7-1 st!mulates % an 7% t&rou,& !nuct!on o$

N9%c164 Hoe#er' t&ese mult!nuclear cells cannot resor/ /one e$$!c!ently' !n!cat!n, t&at a !$$erent N=> s!,nal!n, *at&ay !s re.u!re $or act!#at!on o$ /one resor*t!on e#en !nt&e *resence o$ nuclear N9%c164 9urt&ermore' N=>#!a N9%c1 !nuces t&e e*ress!on o$ $us!on-me!at!n, mol-ecules suc& as t&e 2 !so$orm o$ #acuolar %ase o oma!n




2igure 3. %&e $us!on o$ mononuclear *re-osteoclasts N=> !nuces t&e e*ress!on o$ 7-;%M an t*6#0 2 %&e 7-%Me*ress!n, osteoclast /ecomes t&e master-$us!n, cell' &!c& can $use !t& a 7-%M-ne,at!#e $olloer cell %&e l!,an $or 7-%M may /e mem/rane-/oun or solu/le

(t*6#02) an t&e enr!t!c cell-s*ec!$!c transmem/rane *rote!n (7-%M)' /y /!n!n, !rectly to t&e!r *romoterre,!ons6E 7-;%M-e$!c!ent m!ce e#elo*e m!losteo*etros!s' attr!/ute to t&e e$ect !n t&e $us!on o$ osteo-clasts6E In t&e same ay #-%ase o su/un!t 2-e$!c!entm!ce e&!/!t !m*a!re osteoclast $us!on an !ncrease /one$ormat!on66 %&e 7-%M-e*ress!n, osteoclast /ecomest&e master-$us!n, cell' &!c& takes t&e lea !n Scellocytos!n,Sanot&er one' an $uses !t& a 7-%M-ne,at!#e $olloercell nce $us!on o$ to cells !s com*lete t&e to cells $orma /!nucleate cell' &!c& t&en /ecomes t&e SmasterS $user an

can $use !t& ot&er mono- or mult!nucleate cells6F (9!,ureE) %&e l!,an $or 7-%M may /e mem/rane /oun orsolu/le' &!c& coul /e release /y e!t&er o$ t&e $us!on *art-ners It !s *oss!/le t&at t&e !nuct!on o$ M9 (macro*&a,e$us!on rece*tor) !s also !n#ol#e !n t&!s *rocess 68 M9

/elon,s to t&e $am!ly o$ s!,nal re,ulatory *rote!ns (Is)'&!c& &a#e !ntr!ns!c s!,nal!n, $unct!ons !ctate mostly /y atransmem/rane re,!on t&at assoc!ates !t& aa*tor mole-cules conta!n!n, an !mmunorece*tor act!#at!n, mot!$(I%M) 12' an 9c? ;t!mulat!on o$ t&ese aa*tor

*rote!ns &a#e also /een *ro*ose to *lay a s!,n!$!cant role !nt&e $ormat!on o$ mult!nuclear osteoclasts6G


It !s knon t&at calc!ton!n !n&!/!ts c&emok!ne-st!mulatecell $us!on' *resuma/ly t&rou,& t&e M7-1-!nuce 7%' an

/locks osteoclast /one resor*t!on act!#!ty' act!n, at to sta,eso$ osteoclast !$$erent!at!on %&!s e*la!ns t&e /ene$!c!al e$$ecto$ calc!ton!n !n !n$lammatory /one loss' &ere &!,& c&emok!ne

*rouct!on !s o/ser#e In a!t!on' recent stu!es &a#eemonstrate t&at no#el -%ase !n&!/!tors' &!c& &a#e!n&!/!t!on select!#!ty' can /e system!cally am!n!stere to an!-mals an *ro#en to /e &!,&ly e$$!cac!ous a,a!nst /one loss F0

Activation of i++ature +ulti-nucleated osteoclas

%&e $!nal ste* to t&e mature /one-resor/!n, mult!nucleat-e osteoclast !n#ol#es t&e *olar!5at!on o$ t&e cell mem/rane!t& t&e ,enerat!on o$ to *olar!5e structures #!llousor,anelle un!.ue to t&e resor/!n, osteoclast' knon as t&e ruf-

fled +e+brane' an an act!n r!n,-l!ke structure' t&esealing

9one' &!c& !solates t&e resor*t!#e m!croen#!ronment $romt&e ,eneral etracellular s*ace 9a!lure o$ *olar!5at!on ancytoskeletal or,an!5at!on results !n osteoclast ys$unct!on' an

))




2igure 4. ct!#at!on o$ mult!nuclear !mmature osteoclast "*on Bccu*at!on o$ t&e a#@3 ;yk an c-;rc are recru!te !ne*enently to !tscyto*lasm!c oma!n 7-rc *&os*&orylates an act!#ates yk &!c& !n turn !nuces a 3 ot& occu*ancy o$ M-79 an a#@3 colla/orateto *&os*&orylate a 3 &!c& t&en act!#ates ac lea!n, to cytoskeletal or,an!5at!on N9% /!ns to t&e *romoter o$ aK@3' an !ncreases!ts e*ress!on

!n #ary!n, e,rees o$ osteo*etros!s M!neral!5e matr! reco,-n!t!on !s me!ate /y t&e !nte,r!n #@3' t&e *r!nc!*al osteo-clast !nte,r!n' an t&e + (ar,!n!ne-,lyc!ne-as*art!c ac!)se.uence !n osteo*ont!n an /one s!alo*rote!n "*on occu- *at!on o$ #@3' c-;7 k!nase /!ns !rectly to t&e term!nalt&ree am!no ac!s o$ t&e @3 su/un!t %&e s*leen tyros!nek!nase <=' &!c& !s also essent!al $or cytoskeletal or,an!5a-t!on o$ t&e osteoclasts' /!ns to t&e cyto*lasm!c oma!n o$ @3!ne*enently o$ c-;7 %&ere$ore' ;<=' c-;7' an #@3$orm a ternary com*le !n t&e cellF1 %&e I%M-aa*ter *ro-te!ns' a*12 an 9c?' assoc!ate !t& sur$ace rece*tors *res-ent !n osteoclasts suc& as t&e tr!,,er!n, rece*tor e*resse !n

myelo! cells-2 an -3 (%M2' 3)F2 ct!#at!on o$ t&eaa*ter- assoc!ate rece*tor leas to *&os*&orylat!on o$ t&etyros!nes !t&!n t&e I%M' *ro/a/ly /y 7-$am!ly k!nases'&!c& !n turn recru!t an act!#ate <= k!naseF3 Hoe#er' t&ema!ntenance o$ I%M-!n!t!ate ;<= act!#!ty !s uner t&eae,!s o$ t&e assoc!ate c-7F4 ct!#ate I%M-/oun <='tar,ets t&e a# $am!ly o$ ,uan!ne nucleot!e ec&an,e $actors(+9s)' ma!nly a#3 &!c& *reom!nates !n osteoclasts' lea-!n, to !nuct!on o$ t&e &o +%ase' acFE ot& #@3 !nte,r!ns!,nal!n, an M-7;9 occu*ancy o$ c-9M;' colla/orate to

*&os*&orylate a#3' &!c& !n turn act!#ates ac' lea!n, toor,an!5at!on !n t&e osteoclast cytoskeletonF6 (9!,ure 6)

)


#@3 !nte,r!n' *resents as a *otent!al ant!-resor*t!#e tar-,et $or t&e treatment o$ osteo*oros!s ;mall molecule!n&!/!tors o$ t&e !nte,r!n' /one s*ar!n, !n oo*&orectBm!5erats an !n osteo*orot!c omen are *resently !n cl!n!cal tr!-alsFF Moreo#er' small molecular e!,&t com*ouns t&atm!m!c t&e tr!*e*t!e + se.uence' reco,n!5e /y t&e !nte-,r!n' ere s&on to &a#e s!m!lar e$$ectsF8 re#!ous &umanan mouse stu!es &a#e clearly emonstrate t&e role o$%M2 12 s!,nal!n, !n c&emota!s o$ /ot& enr!t!ccells an osteoclasts' as ell as !n normal /one resor*t!on /ymature osteoclasts ur!n, in vitro con!t!onsF2 ecent e#!-ence contens t&at %M2 may /e an attract!#e tar,et $ort&e *&armacolo,!c moulat!on o$ /one remoel!n, !n *at&o-lo,!c con!t!ons s!nce %M2 /lockae &as /een re*orteto *re#ent t&e $unct!onal resor*t!on an re,ulate m!,rat!ono$ osteoclastsFG %&e *&enoty*e o$ c-7 knock-out m!ce !scons!stent !t& osteo*etros!s' &!c& su,,ests t&at !n&!/!torsa,a!nst t&!s en5yme may also /e t&era*eut!c $or osteo*oro-s!s80 9!nally' <=' as a neus o$ a no#el s!,nal!n, *at&ayre,ulat!n, osteoclast $unct!on' !s !tsel$ a can!ate ant!-resor*t!#e t&era*eut!c tar,etF1




Conclusion

Intense researc& e$$ort ur!n, t&e last 10 years &as *ro#et&at osteoclasto,enes!s !s a mult!com*le *rocess !n#ol#!n,many !$$erent sta,es !t& mult!*le !nteract!ons amon, t&emnt!-resor*t!#e ru,s suc& as estro,en' ralo!$ene an /!*&os-

*&onates' t&e ma!nstay o$ ant!-osteoclast!c t&era*y unt!lrecently' are knon to !ncrease t&e a*o*tos!s o$ osteoclasts an!n&!/!t t&e!r /one resor*t!#e act!#!ty Hoe#er' ue to t&e $actt&at /one $ormat!on !s t!,&tly cou*le to /one resor*t!on' t&ea/ro,at!on o$ osteoclasts resulte !n reuce /one $ormat!onas ell %&e eta!le knole,e o$ t&e molecular mec&an!smsan t&e onstream s!,nal!n, *at&ays !n#ol#e !n osteoclas-to,enes!s as ell as t&e screen!n, $or t&e osteoclast s*ec!$!c,enes !nuce /y t&ese *at&ays' *ro#!e a no#el $!el $or t&e,enerat!on o$ t&era*eut!c a,ents t&at can man!*ulate osteo-clast act!#!ty !t&out !nter$er!n, !t& /one $ormat!on %&!s *os-s!/!l!ty !s !llustrate /y recent stu!es us!n, !n&!/!tors o$ c-7't&e #-%ase or c&lor!e c&annel 7>7-F !n osteoclasts' &ere

/one resor*t!on as ecrease /ut /one $ormat!on as ma!n-ta!ne81 Hoe#er' &et&er t&ese !m*ortant $!n!n,s !n an!-mals !ll translate !nto !m*ro#e $racture e$$!cacy !n cl!n!cal tr!-als rema!ns to /e seen #en so' t&e *ros*ect o$ us!n, *&arma-ceut!cal !nter#ent!on to !n&!/!t /one resor*t!on !t&out !n&!/!t-!n, /one $ormat!on !s no a !st!nct *oss!/!l!ty82 Moreo#ert&ere !s also #ery l!ttle knon a/out t&e role o$ canon!cal Lnts!,nal!n, !n osteoclasts Lnt3a re,ulates osteoclast !$$erent!a-t!on #!a an !n!rect mec&an!sm !n#ol#!n,' t&rou,& un2' t&eon-re,ulat!on o$ N=> e*ress!on an !nuct!on83 %&eserec!*rocal c&an,es !n N=> an + e*ress!on me!atet&e e$$ects o$ Lnt s!,nal!n, on osteoclast !$$erent!at!on in

vivo es*!te t&e maCor role o$ Lnt s!,nal!n, !n osteo/lasto,e-nes!s84' !t !s st!ll lar,ely unknon &et&er an to &at etent !t!rectly a$$ects osteoclasts8E 9!nally' alt&ou,& t&e currentknole,e &ols t&at N=>N= !nteract!on an su/se-.uent s!,nal!n, #!a %9-6 are /ot& essent!al an ae.uate$or t&e ,enerat!on o$ $unct!onal osteoclasts' recent ata &a#esu,,este t&at alternat!#e *at&ays !ne*enent o$ N=>s!,nal!n, may e!st t!mulat!on o$ %N9' t&e om!nantcytok!ne etant !n !n$lammatory osteolys!s' !n t&e *resence o$co-$actors suc& as %+9-/' &as *ro#e to *ro#!e ae.uatelyosteoclasts $rom &emato*o!et!c *recursors $rom %N7-'N=-' or %96-null m!ce86

ase on current knole,e' $uture !nter#ent!ons t&at !ll

select!#ely alter a s*ec!$!c sta,e o$ t&e osteoclasto,enes!s or!ent!$!cat!on o$ !st!nct !$$erent!at!on *at&ays may /ea/le to s&!$t /ack or e#en re#erse /one loss !n *at&olo,!calcon!t!ons' suc& as t&e *ostmeno*ausal osteo*oros!s orc&ron!c !n$lammatory /one !seases

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)3




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clasts an ,!ant cells J * Me 200E;202:34E-E1 6GHum*&rey M' ,asaara =' <ao L' ;*usta ;7'

as M' >ane N' >an!er >>' Nakamura M7 %&es!,nal!n, aa*ter *rote!n 12 re,ulates mult!nucle-at!on ur!n, osteoclast e#elo*ment one M!ner es2004;1G:224-34

F0 u J' 7&en, %' 9en, H%' a#los NJ' U&en, MH;tructure an $unct!on o$ -%ases !n osteoclasts: *otent!al t&era*eut!c tar,ets $or t&e treatment o$ oste-olys!s H!stol H!sto*at&ol 200F;22:443-E4

F1 Uou L' =!taura H' ee#e J' >on, 9' %y/ule!c5 >'&att!l J' +!ns/er, MH' oss 9' %e!tel/aum > yk'c-;rc' t&e #@3 !nte,r!n' an I%M !mmunorece*tors'!n concert' re,ulate osteoclast!c /one resor*t!on J 7ell!ol 200F;1F6:8FF-88

F2 Hum*&rey M' ,asaara =' <ao L' ;*usta ;7'as M' >ane N' >an!er >>' Nakamura M7 %&es!,nal!n, aa*ter *rote!n 12 re,ulates mult!nucle-at!on ur!n, osteoclast e#elo*ment J one M!ner es2004;1G:224-34

F3 M$!csa! ' Hum*&rey M' an U!$$le J' Hu <'ur,&art ' ;*usta ;7' MaCumar ;' >an!er >>'>oell 7' Nakamura M7 %&e !mmunomoulatoryaa*ter *rote!ns 12 an 9c rece*tor ,amma-c&a!n(9c,amma) re,ulate e#elo*ment o$ $unct!onalosteoclasts t&rou,& t&e ;yk tyros!ne k!nase roc Natlca c! " 2004;101:61E8-63

F4 M!ya5ak! %' ;anCay ' Ne$$ >' %anaka ;' Horne L7'

aron ;rc k!nase act!#!ty !s essent!al $or osteoclast$unct!on J !ol 7&em 2004;2FG:1F660-6

FE 9acc!o ' %e!tel/aum ;>' 9uC!kaa =' 7&a**el J7'Uallone ' %y/ule!c5 >' oss 9' ;at L a#3re,ulates osteoclast $unct!on an /one mass Nat Me200E;11:284-G0

F6 %e!tel/aum ;> steoclasts an !nte,r!ns nn N <ca c! 2006;1068:GE-G

FF Mur*&y M+' 7erc&!o =' ;toc& ;' +ottes!ener ='

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Lu M' ecker ' an t&e >-00084EF04 ;tuy +rou*$$ect o$ >-00084EF04' an #@3 !nte,r!n anta,on!st' onmarkers o$ /one turno#er an /one m!neral ens!ty !n *ostmeno*ausal osteo*orot!c omen J 7l!nnocr!nol Meta/ 200E;G0:2022-8

F8 7oleman J' ras&ear =M' ske 7' Hutc&!nson JH'

Mcean 7' uon, le %' 9euston ' 9ernane5-Met5ler 7' +ent!le M' Hartman +' =!mmel '>eu 7%' >!*$ert >' Merkle =' enny*acker 'rueksar!tanont %' oan +' Lesolosk! +' oan' u,,an M Non*e*t!e al*&a#/eta3 anta,on!stsart 11: !sco#ery an *recl!n!cal e#aluat!on o$ *otental*&a#/eta3 anta,on!sts $or t&e *re#ent!on an treat-ment o$ osteo*oros!s J Me 7&em 2004;4F:482G-3F

FG Hum*&rey M' as M' ;*usta ;7' N!em! 7'%orc&!a J' >an!er >>' ;eaman L' Nakamura M7%M2' a 12-assoc!ate rece*tor' re,ulatesosteoclast !$$erent!at!on an $unct!on J one M!ner es 2006;21:23F-4E

80 oyce 9' !n, >' <ao U' &akes*eare L7' Lan, <'Metcal$ 7 III' unaramoort&! ' al,arno 7' Iul!ucc!J' ayer %= 9uture ant!-cata/ol!c t&era*eut!c tar,ets !n

/one !sease nn N < ca c! 2006;1068:44F-EF81 =arsal M' Henr!ksen = steoclasts control

osteo/last act!#!ty one=y- steo#!s!on 200F;4:1G-24 82Mart!n %J' N, =L Ne a,ents $or t&e treatment o$

osteo*oros!s one=y-steo#!s!on 200F;4:28F-G8 83*encer +J' "tt!n, J7' t&er!,e >' rnett %' +ene#er

+ Lnt s!,nal!n, !n osteo/lasts re,ulates e*ress!on o$ t&erece*tor act!#ator o$ N9O l!,an an !n&!/!ts osteo-clasto,enes!s in vitro J 7ell c! 200E;11G:1283-G6

84 <a#ro*oulou M' <o#os J+ %&e role o$ t&e Lnt s!,-

nal!n, *at&ay !n osteo/last comm!tment an !$$eren-t!at!on Hormones (t&ens) 200F;6:2FG-G4

8E >!u 9' =o&lme!er ' Lan, 7< Lnt s!,nal!n, an skele-tal e#elo*ment 7ell !,nal 2008;20:GGG-100G 86 =!m N'

=aono <' %akam! M' >ee J' >ee H' kaa 9'=!m JH' =o/ayas&! %' ,ren ' Nakano H' <e&L7' >ee =' >oren5o J' 7&o! < steoclast !$$eren-t!at!on !ne*enent o$ t&e %N7-N=-%96a!s J * Me 200E;202:E8G-GE

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