Fiziologia patologica a miscarii dentare

FIZIOLOGIA PATOLOGICA A MISCARII DENTARE

Miscarea dentara ortodontica este un proces care combina raspunsurile fiziologice si patologice la aplicarea fortelor externe. Miscarea dentara ortodontica (King si colab., 1991a) este insotita de o leziune reversibila minora a tesuturilor de sustinere ale dintelui, existand o adaptare fiziologica a osului alveolar si ligamentului parodontal la solicitarea mecanica. Prin urmare, mecanismele relevante inflamatorii trebuie sa fie luate in considerare impreuna cu mecanotransductia scheletala pentru o intelegere deplina a miscarii dentare ortodontice.

Tabloul clinic al miscarii dentare ortodontice releva desfasurarea a trei faze: o deplasare dentara initiala, aproape instantanee; o intarziere, in care nu are loc nici o miscare vizibila si o perioada de miscare dentara liniara. Fortele aplicate creaza tensiuni in tesuturile de sustinere ale dintelui care se manifesta aproape imediat si care pot fi clasificate ca fiind compresiune si tractiune. In absenta posibilitatii transformarii acestei solicitari in date care sa permita masurarea ei directa, au fost create diferite modele de elemente finite pentru a le descrie. Analiza elementelor finite de transfer al sarcinii de la dinte prin intermediul ligamentului parodontal la nivelul osului alveolar trebuie sa tina cont de proprietatile fizice si morfologia parodontiului. Ligamentul parodontal este cunoscut a fi un material non-linear vasco-elastic, dar modele elementelor finite folosite in ortodontie asociaza proprietatile ligamentului parodontal unui corp omogen, liniar elastic, izotrop si continuu. De asemenea, nu sunt facute ajustari pentru diferentele din micromorfologia acestuia. Rezultatele studiilor elementelor finite care incearca sa tina seama de acest raport dintre incarcare (solicitare) - efect asupra parodontiului nu pot fi explicate in termenii simpli de compresie si de tensiune aparute de-a lungul directiei de incarcare. De asemenea, tensiunea pare a fi mult mai frecventa decat compresia (Cattaneo si colab, 2005.). Cu toate acestea, deoarece terminologia presiune-tensiune este atat de raspandita in literatura de specialitate si, in general, poate servi ca un mijloc convenabil pentru a distinge intre diferitele procese ce insotesc deplasarea dentara ortodontica, va fi utilizata aici.

Evenimentul initial inflamator, din site-urile de compresie este cauzat de constrictia vaselor mici din ligamentul parodontal, care este urmata de necroze focale, cunoscute datorita aspectului lor histologic ca hialinizare si de hiperemie compensatorie in ligamentul parodontal adiacent (Murrell si colab., 1996) si vasele pulpare (Kvinnsland si colab, 1989.). Aceste zone necrotice elibereaza diversi chemo-receptori (Lindskog si Lilja, 1983) care atrag acid-fosfataza-pozitiva tartrat-rezistenta din celulele gigantice, fagocitare, multi-nucleate, de la periferia ligamentului parodontal necrotic (Brudvik si Rygh, 1994a, b). Aceste celule resorb ligamentul parodontal necrotic, precum si osul alveolar subiacent si cementul. Osteoclastele sunt recrutate din spatiile medulare adiacente (Rody si colab, 2001.). Pana cand aceste celule pot fi recrutate si zonele necrotice indepartate, miscarea dentara este impiedicata, rezultatul clinic fiind acela al unei perioade de intarziere. Aceasta este urmata de depunerea de cement nou (Brudvik si Rygh, 1995;. Casa si colab, 2006), dentina secundara (Nixon si colab , 1993.), si os de neoformatie (King si colab, 1991b). in vecinatatea zonelor de resorbtie.

Exista numeroase dovezi care sugereaza ca mecanismele neurovasculare joaca un rol important in miscarea dentara, prin dezvoltarea unei reactii inflamatorii. Cresterea neurotransmitatorilor in ligamentul parodontal, a CGRP (Kvinnsland si Kvinnsland, 1990) si substanta P (Nicolay si colab, 1990.), poate persista perioade indelungate, dupa deplasarea dentara ortodontica (Norevall si colab, 1995, 1998.). Mai mult decat atat, aceste componente au capacitatea de a produce vasodilatatie si permeabilitate vasculara crescuta, insotita de proliferarea celulelor endoteliale si a fibroblastilor (Hall si colab., 2001), precum si extravazarea de leucocite (Toms si colab, 2000.). Distributia si intensitatea colorarii imunoreactive pentru alti factori bioactivi asociati fibrelor nervoase din ligamentul parodontal (Saito si colab, 1993;. Deguchi si colab, 2003.) si endoteliului (Lew si colab, 1989;. Lew, 1989; Sims, 1999; Drevensek si colab., 2006), , se coreleaza de asemenea fie cu remodelarea de raspuns a tesuturilor, indusa mecanic, fie cu miscarea dentara ortodontica. De asemenea, diferiti alti factori asociati fibrelor nervoase alveolare inferiore amana cresterea fluxului sanguin in ligamentul parodontal dupa aplicarea fortei (Vandevska-Radunovic si colab, 1998.).

Eliberarea de citokine pro-inflamatorii si enzime lizozomale care promoveaza resorbtia tesuturilor din zonele de compresie este bine documentata. Prostaglandinele, IL-1, IL-6, TNFα si RANKL (receptor activator of nuclear factor kappa B ligand) au toate un nivel crescut in ligamentul parodontal in timpul deplasarii dentare (Yamaguchi si Kasai, 2005). Cresteri ale enzimelor lizozomale, fosfatazei acide, fosfatazei acide tartrat-rezistente (Lilja si colab, 1983, 1984;.. Keeling si colab, 1993) si a catepsinei B ( Yamaguchi si colab, 2004) au fost, de asemenea, localizate in zonele de compresie, sugerandu-se ca acestea pot juca un rol decisiv in timpul deplasarii dentare ortodontice in procesul de degradare a tesuturilor moi si dure, prin cresterea numarului de macrofage si dendritelor de legatura celulare (Vandevska-Radunovic si colab, 1997.).

Zonele de tensiune generate ortodontic, in general, au fost caracterizate ca fiind in primul rand osteogene, fara o componenta semnificativa inflamatorie. Cu toate acestea, exista dovezi ca raspunsurile inflamatorii la tensiuni pot fi dependente de solicitare (intindere) , deoarece tractiunile de magnitudine mica sunt antiinflamatorii si induc semnale anabolice dependente de magnitudine in celulele osteoblastice, legate de ligamentul parodontal, culminand cu reglarea transcriptiei genei inflamatorii (Long si colab, 2001). In schimb, tractiunile mari actioneaza ca stimuli proinflamatorii si cresc eliberarea citokinelor inflamatorii (Long si colab, 2002.). Aceasta constatare a fost confirmata recent printr-un model de miscare dentara in care s-a presupus ca tractiunea usoara este insotita de absenta marcanta a IL-1α si COX-2, in timp ce compresia sau intinderile (tractiunile) mari de o crestere a reglarii IL -1α si COX-2 (prezentat de Madhavan si colab, 2008). Dovezile morfologice de dezagregare celulara din zonele de tensiune ale ligamentului parodontal aparute in cursul deplasarilor dentare au fost descrise, de asemenea, dupa numai 5 minute de solicitare, sugerandu-se implicarea in continuare a unui mecanism inflamatoriu (Orellana si colab, 2002; Orellana-Lezcano si colab, 2005). In ciuda acestui fapt, mecanismul de osteogeneza din zonele de tensiune din miscarea dentara nu este bine inteles, concluzii rezonabile putand fi insa trase folosind modele diferite de mecanotransductie.

O problema care pare paradoxala, la inceput, este observatia ca zonele de compresie din miscarea dentare ortodontice sunt in primul rand resorbtive, in timp ce zonele de tractiune sunt osteogene. Aceast lucru pare contrar datelor din literatura cu privire la solicitarile mecanice osoase, care descriu site-uri de solicitare (incarcare) ca fiind site-uri osteogene, iar pe cele de descarcare ca fiind resorbtive (Frost, 2004). Exista doua explicatii posibile pentru aceste diferente. In primul rand, zonele de compresie au in mod clar o componenta de injurie tisulara, suprapusa peste transductia fiziologica, cu creerea de produse inflamatorii care au in primul rand un rol resorbtiv, stimuland celulele sa elimine tesutul lezat. In al doilea rand, resorbtia din zonele de comprimare din miscarea dentara ar putea fi perceputa ca rezultat al scaderii solicitarii (intinderii) normale din ligamentul parodontal functional, in timp ce osteogeneza din zonele de tensiune ar putea fi o reflectare a incarcarii fibrelor principale ale ligamentului parodontal (Melsen, 2001 ). Aceasta din urma ar putea fi, de asemenea, insotita de intinderi (solicitari) ale procesului alveolar transmise prin fibrele principal ale ligamentului parodontal sau datorate actiunii (presiunii) directe a radacinii dentare asupra osului alveolar.

Exista o mare variabilitate in raspunsul tesuturilor ligamentui parodontal la deplasarea dentara. Acest lucru se poate datora nu numai diferentelor in semnalele biomecanice, dar si diferentelor specifice care tin de organismul gazda, cum ar fi ritmurile diurne, ocluzia (Miyoshi si colab, 2001.) (Esashika si colab., 2003), metabolismul sistemic (Verna si Melsen, 2003 ), varsta (King si colab, 1995; Kyomen si Tanne, 1997; Ren si colab, 2003), sau variatia normala in desenul trabecular osos.

CERINTELE DEPLASARII DENTARE ORTODONTICE:

Rolul ligamentului parodontal in deplasarile dentare:

Anchiloza dentara si implantele pot  servi pentru a demonstra rolul esential al ligamentului parodontal in miscarea dentara. Dintii cu anchiloza prezinta leziuni focale caracterizate prin prezenta de punti osoase care elimina ligamentul parodontal in aceste zone. In mod similar, in cazul implantelor cu sau fara osteointegrare lipseste ligamentul parodontal. In ambele cazuri, dintii nu raspund la miscarea dentara ortodontica. O consecinta a acestor constatari o constituie acceptarea actuala pe scara larga de catre ortodonti a miniimplantelor ca dispozitive temporare de ancoraj. De asemenea, explica de ce dintii temporari cu anchiloza par sa se scufunde in timp ce dintii adiacenti continua sa se adapteze la cresterea faciala verticala.

Rolul specific al ligamentului parodontal in miscarea dentara nu este bine inteles, dar prin natura lui unica biomecanica, celulara si moleculara este fara indoiala important. Dintr-o perspectiva biomateriala, ligamentul parodontal este o substanta complexa, armata cu fibre care raspunde la forta intr-o maniera vascoelastica si non-lineara (Jonsdottir si colab, 2006.). Acest raspuns este caracterizat printr-o deplasare instantanee, urmata de o deplasare mai treptata care atinge un maximum dupa 5 ore (van Driel si colab, 2000.), sugerand ca compartimentele lichide din ligamentul parodontal pot juca un rol important in transmiterea si amortizare fortelor care actioneaza asupra dintilor. Solicitarea (intinderea) care i-a nastere in ligamentul parodontal prin aplicarea fortei are in mod clar consecinte biologice pentru tesut in sine si, eventual, pentru alte tesuturi dentare de sprijin (de exemplu, osul alveolar si cement).

Celulele ligamentului parodontal raspund la cresterea fortei prin proliferarea si apoptozei celulare. Aceste doua procese concurente par sa controleze populatii diferite de celule din ligamentul parodontal si reflecta o biomecanica specifica (Mabuchi si colab, 2002.).

Componentele majoritare fibroase ale matricei extracelulare a ligamentului parodontal (colagen, tropoelastina si fibronectina) sunt consecinta adaptarii la aplicarea fortei (Howard si colab, 1998;. Redlich si colab, 2004a.). Metaloproteinazele matricei (MMPs) si inhibitorii lor specifici, TIMPs (tissue inhibitors of metalloproteinases), par sa actioneze intr-un mod coordonat pentru a regla remodelarea colagenului. Nivelurile de exprimare in ligamentul parodontal de MMP-2, 8, 9, 13 si TIMPs 1-3 cresc tranzitoriu in timpul miscarii dentare ortodontice. Cu toate acestea, aceste gene au modele diferite de exprimare in zonele de compresie si de tensiune, sugerand ca remodelarea colagenului este reglata diferentiat functie de mecanica (Howard si colab, 1998;. Takahashi si colab, 2003, 2006.). Aceasta concluzie este sprijinita de observatiile care arata ca tensiunea previne degradarea matricei prin inhibarea MMP-1 (Arnoczky si colab, 2004), in timp ce reducerea tensiunii imbunatateste resorbtia matricei extracelulare (Von den Hoff, 2003). Expresia consolidarii MMP-1 in fibroblastele ligamentului parodontal poate fi, de asemenea, rezultatul efectului direct al fortei asupra genelor (Redlich si colab, 2004b.).

Proteoglicanii matricei sunt, de asemenea, alterati in ligamentul parodontal in timpul miscarii dentare ortodontice. Condroitin sulfatul (CS) ligamentului parodontal si sulfatul de heparina (SA) cresc in timpul miscarii dentare si scad in hipofunctie. Modelele complexe ale modificarilor CS si HS in timpul miscarii dentare fac dificila interpretarea rolurilor lor (Esashika si colab, 2003.). Acidul hialuronic (HA), prezent in ligamentul parodontal, se poate lega in cantitati crescute de versican si leaga proteine localizate in zonele de compresie, pentru a crea mari agregate hidratate. Acestea pot actiona fie prin limita deteriorarii tesutului prin disiparea fortelor compresive excesive, fie prin oferirea unui spatiu care faciliteaza migrarea celulelor resorbtive in aceste zone (Sato si colab, 2002.).

Remodelarea osoasa:

Remodelarea osoasa este un proces ciclic si reprezinta un raspuns la necesitatea repararii si reinnoirii continue a scheletului pe tot parcursul vietii. Frost a descris o unitate de baza multicelulara care efectueaza o serie coordonata de evenimente cuprinse in ciclul de remodelare. Un ciclu de remodelare are patru faze: activarea, resorbtia, inversarea si formarea. Desi aceasta succesiune de evenimente a fost confirmata in numeroase contexte si este larg acceptat modul in care decurg reparatiile scheletului in sine, mecanismele precise de control ale unitatilor de baza multicelulare nu sunt bine intelese. Calendarul evenimentelor histologice care se desfasoara in zonele de compresie din miscarea dentara ortodontica este in concordanta cu un ciclu de remodelare (King si colab, 1991b). Acestia, citeaza impreuna cu o multitudine de dovezi ale aparitiei de leziuni tisulare, ideea ca remodelarea este un proces predominant al turnoverului osos din zonele de compresie ortodontice.

Un aspect important este reprezentat de modul in care sunt initiate ciclurile de remodelare. Mai multe dovezi experimentale au legat remodelarea osoasa de microleziuni si de cresterea ulterioara a activitatii celulare  Microfisurile osoase cauzate de oboseala sau traume pot juca un rol important in initierea ciclurilor de remodelare (Galleyv si colab., 2006), deoarece deplasarile fisurale sunt capabile sa rupa procesele celulare osteocitice, determinand secretia directa de molecule bioactive in matricea extracelulara, declansand un raspuns (Hazenberg si colab, 2006.). Prevalenta crescuta a microfisurilor in zonele de comprimare din miscarea dentara ortodontica sugereaza, ca ele sunt importante in initierea remodelarii osoase ortodontice (Verna si colab, 2004.).

Un alt concept important pentru remodelarea osoasa este cel de cuplare intre resorbtie si formare. Mecanismele de cuplare au fost postulate ca fiind un mijloc prin care nu se pierde si nici nu se castiga os in timpul repararii. Mecanismul exact prin care este obtinuta cuplarea nu este bine inteles, dar se considera ca este controlat prin eliberarea moleculelor paracrine de catre celulele unitatii de baza multicelulare. In primele stadii de reparatie din timpul deplasarii dentare, aparitia mai multor factori paracrini (de exemplu, IGF-II, IGFBP-5 sau -6) in interiorul lacunelor si in cementoblaste sugereaza ca acestea pot fi implicate in controlul aceastei secvente a remodelarii (Hazenberg si colab, 2006.).

Un alt aspect legat de cuplare implica ratele relative ale resorbtiei comparativ cu ale formarii. Formarea este destul de rapida, dupa care devine semnificativ mai lenta. Acest lucru are consecinte importante pentru oasele in curs de remodelare extensiva - de exemplu, in perioada de premenopauza (Recker si colab, 2004.). In aceste cazuri, formarea osoasa nu poate tine pasul cu cantitatea mare de resorbtie, rezultatul final fiind pierderea neta de masa osoasa. Imposibilitatea proceselor formative de a tine pasul cu resorbtie in cursul proceselor extinse de remodelare din zonele de compresie din timpul tratamentului ortodontic, ar putea explica manifestari clinice ca mobilitatea dentara si largirea spatiului ligamentului parodontal.

REGLAREA MOLECULARA A OSTEOCLASTOGENEZEI:

Biologiea osteoclastelor a suferit o revolutie la sfarsitul anilor 1990, nu numai prin descoperirea unui set critic de molecule care regleaza osteoclastogeneza dar si prin elucidarea modului in care acestea interactioneaza.. In special, un membru al familiei liganzilor TNF, RANKL, s-a dovedit initial a fi o legatura membranara pentru proteinele prezente in osteoblaste si celulele stromale, precum si pentru alte tipuri de celule (Anderson si colab, 1997; Wong si colab, 1997; Yasuda si colab, 1998a). Celula-celula de semnal dintre celulele cu RANKL pe suprafata lor si precursorii osteoclastilor transporta RANK receptorul inducand atat formarea cat si activarea osteoclastelor (Yasuda si colab, 1999). Dintre cele trei izoforme ale RANKL, care au fost identificate, doua sunt proteine transmembranare, in timp ce a treia-RANKL3-este o forma solubila (Ikeda si colab, 2001).

Receptorul pentru RANKL al precursorilor osteoclastelor este activator al receptorilor de NF-κB (RANK), identificat pentru prima data de catre Anderson si colab. (1997). La randul sau, CSF-1 este necesar pentru a creste reglarea expresiei genelor RANK in precursorii osteoclastelor (Arai si colab, 1999), si acesta este unul dintre motivele pentru care CSF-1 este necesar osteoclastogenezei. Cresterea si diferentierea preosteoclastelor mononucleare sunt de asemenea dependente de CSF-1 (Stanley si colab, 1983;. Tanaka si colab, 1993.). Mai mult decat atat, CSF-1 pare sa aiba proprietati chemotactice pentru recrutare celulelor progenitoare ale osteoclastelor (Wang si colab, 1988;. Bober si colab, 1995;. Que si Wise, 1997).

Cuplarea de tip celula-celula de semnalizare implica legarea RANKL la RANK ceea ce are ca rezultat recrutarea unor diferiti membri ai receptorilor TNF asociati factorilor (TRAFs) in cadrul precursorilor osteoclastelor, dintre care TRAF6 pare a juca un rol cheie (Darnay si colab, 1999 ; Wong si colab, 1999). De exemplu, TRAF6 activeaza caile de semnalizare pentru NFκB si c-Fos (Boyle si colab, 2003.). Soarecii care nu prezinta gena c-Fos nu au osteoclaste, dar au precursori ai osteoclastelor (Grigoriadis si colab, 1994.) si acelasi lucru este valabil si pentru soarecii lipsiti de genele NFκB (Franzoso si colab, 1997;.Iotsova si colab, 1997). Mai mult decat atatla acesti soareci, dintii nu erup. Un interes deosebit in ceea ce priveste c-Fos este acela ca RANKL de semnalizare prin intermediul c-Fos induce gena interferonului-β (IFN-β) in celulele progenitoare ale osteoclastilor si un feed-back negativ al sintezei IFN-β in celule pentru a inhiba expresia c-FOS (Takayanagi si colab, 2002.).

TRAF6 se leaga, de asemenea, la Src tirozin kinaza, care este probabil molecula efectoare in activarea osteoclastelor, deoarece este necesara rearanjarii proteinelor citoskeletale pentru a forma o granita neregulata (ruffled border) (Boyce si colab, 1992.). Src pare, de asemenea, sa determine supravietuirea osteoclastelor prin prevenirea apoptozei (Wong si colab, 1999; Xing si colab, 2001).

Este evident necesar si un mijloc pentru reglarea si inhibarea stimularii osteoclastogenezei. Molecula care face acest lucru este osteoprotegerinul, o glicoproteina secretata care este un receptor capcana pentru RANKL (Simonet si colab, 1997;. Tsuda si colab, 1997;. Yasuda si colab, 1998b.). Legarea osteoprotegerinului la RANKL inhiba cuplajul de tip celula-celula de semnalizare care are loc intre RANKL de pe membrana lor celulara si precursorii osteoclastelor, ceea ce are ca rezultat inhibarea osteoclastogenezei (Yasuda si colab, 1998b, 1999.). Rezultatele obtinute in vivo, arata o supraproductie (supraexprimare) de osteoprotegerin la soareci transgenici in osteopetroza si prezenta a mai putine osteoclaste, desi celulele mononucleare TRAP-pozitive (preosteoclastele) sunt prezente (Simonet si colab., 1997). Injectarea de osteoprotegerin recombinant la soareci conduce la aceleasi rezultate (Simonet si colab, 1997).

Fuziunea precursorilor osteoclastelor, pentru a forma osteoclastele par sa impuna existenta unei molecule receptor transmembranare, DC-STAMP (dendritic cell-specific transmembrane protein) (Kukita si colab, 2004;. Yagi si colab, 2005.). Expresia genica a DC-STAMP este indusa in precursorii osteoclastelor de catre RANKL si inhibarea acestei expresii de catre mici interferente RNAs care inhiba formarea osteoclastelor (Kukita si colab, 2004.). Soarecii care nu au DC-STAMP de asemenea, nu au osteoclaste multinucleate si nu au celule mononucleare care sa fie tartratrezistente la fosfataza acida - TRAP-pozitive (Yagi si colab, 2005.).

Molecule implicate in osteoclastogeneza pot fi gasite in tabelul 1

Tabel cu importanta relativa a factorilor de reglare a deplasarii dentare:

Scala de apreciere este: (+) efect slab; (++) efect moderat; (+++) efect puternic.

In deplasarea dentara:

Osteoclastogeneza in miscarea dentara ortodontica este initiata de catre doua modificari legate de aplicarea fortei: leziuni tisulare, cu aparitia ulterioara a proceselor inflamatorii in ligamentul parodontal si deformarea procesului alveolar. Osteoclastele si celulele progenitoare ale osteoclastelor, sunt identificate prin sinteza de ATP-aza tartratrezistenta si H (+)-ATP-aza immunohistochimica, care apar in zonele de compresie in termen de cateva zile de la aplicarea fortelor. Inductia osteoclastelor, reprezentata de preosteoclastele mononucleare, are loc prima in spatiile vasculare si medulare ale crestei alveolare, urmate de cresterea lor in spatiul ligamentului parodontal (Yokoya si colab, 1997;.Rody si colab, 2001). Numarul lor in ligamentul parodontal si osul alveolar, in corelatie cu predictia asupra intinderii (solicitarii) prin metoda elementelor finite (FEM), este mai mare in zonele de compresie comparativ cu cele de tensiune (Kawarizadeh si colab, 2004.). Cresteri ale citokinelor proinflamatorii (IL-1, 6, 8, si TNFα) se coreleaza, de asemenea, cu aceasta distributie (Alhashimi si colab, 2001; Bletsa si colab, 2006; Lee si colab, 2007), sugerand ca citokinele sunt initiatori importanti ai osteoclastogenezei in miscarea dentara. Experimentele au demonstrat de asemenea ca aceste citokine interactioneaza sinergic cu bradikinina si trombina in biosinteza de prostaglandine, mediind astfel resorbtia osoasa inflamatorie (Marklund si colab, 1994;. Ransjo si colab, 1998.). De asemenea, exista dovezi ca administrarea locala de rhVEGF imbunatateste semnificativ numarul de osteoclaste din zonele de presiune in timpul deplasarii dentare ortodontice la soarecii cu osteopetroza (Kaku si colab, 2001.) si ca tratamentul cu anticorpi anti-VEGF reduce numarul osteoclastelor si rata de deplasare dentara (Kohno si colab, 2005.). Analiza acestor date sugereaza ca mecanismul VEGF-CSF-1, descris anterior in osteoclastogeneza asociata eruptiei dentare, poate fi, de asemenea, important in miscarea dentara ortodontica (vezi daca este cazul portiunea din articol netradusa).

Modificarile in RANK, RANKL si osteoprotegerin in tesuturile dentare-de sprijin in timpul miscarii dentare ortodontice au fost demonstrate de Oshiro si colab. (2002), respectiv de (Kanzaki si colab, 2001.). prin stimularea RANKL si inhibarea osteoclastogenezeide catre osteoprotegerin. Fortele de compresie cresc reglarea RANKL pe calea PGE2, sprijinind osteoclastogeneza (Kanzaki si colab, 2002.), in timp ce transferul local de gene de la osteoprotegerin la tesuturile de sustinere ale dintelui inhiba osteoclastogeneza mediata RANKL si miscarea dentara (Kanzaki si colab., 2004). Cresteri ale RANKL si scaderi ale osteoprotegerinului au fost demonstrate, de asemenea, in cazurile severe de resorbtiei radiculara de cauza ortodontica, sugerandu-se ca acest mecanism poate fi important pentru aceste sechele ale tratamentului ortodontic (Yamaguchi si colab, 2006.).

Clearance-ul osteoclastelor in zonele de compresie, in experimente pe sobolani, are loc (apare) dupa 5-7 zile de la activarea aparatul (King si colab, 1991b.). Acest lucru este initiat in parte prin apoptoza osteoclastelor, urmata de necroza secundara (Noxon si colab, 2001.). Fortele fizice actioneaza prin intermediul receptorilor specifici pentru legarea moleculelor, cum ar fi integrinele, prin adeziuni focale ale proteinelor si a citoscheletului - pentru a activa anumite cai ale proteinkinazei (p.38 MAPK si JNK / SAPK vezi articol- parte netradusa), care la randul sau, amplifica semnalul si activeaza caspases (cysteine-aspartic proteases sau cysteine-dependent aspartate-directed proteases), determinand apoptoza osteoclastelor. Fenotipul celular si caracterul stimulilor fizici determina caile care sunt activate si, in consecinta, variabilitatea raspunsurilor la un stimul specific in diferitele tipuri de celule (Hsieh si Nguyen, 2005). In plus fata de osteoclaste, osteocitele s-au dovedit a fi supuse apoptozei in zonele de compresie ortodontica (Hamaya si colab., 2002), dar detaliile modului in care aceste doua mecanisme difera raman neclare. Aceasta din urma este legat de lipsa de utilizare (Bakker si colab, 2004.), sugerand ca descarcarea fibrelor principale ale ligamentului parodontal in aceste zone poate fi importanta.

REGLAREA MOLECULARA A OSTEOGENEZEI

Tractiunea determina activitatea osteogenica si natura sarcinilor aplicate determina recrutarea osteoblastilor. Sarcinile statice nu par sa joace un rol important in osteogeneza scheletala. In schimb, osteogeneza este influentata de episoadele de incarcare (solicitare) care depasesc un anumit prag si cele mai importante caracteristici ale acestor sarcini sunt ritmul solicitarii, amplitudinea si durata (Forwood si Turner, 1995). La priima vedere, osteogeneza in raport cu deplasarea dentara pare neobisnuita, deoarece multe aparate ortodontice sunt concepute pentru a fi statice, sau pentru a disipa incet sarcinile. Cu toate acestea, este important sa realizam ca dentitia este expusa mai multor schimbari de incarcare in timpul masticatiei, deglutitiei si vorbirii, sugerand ca sarcinile aplicate dentitiei sunt rareori statice.

Osteogeneza asociata solicitarilor ortodontice este mediata de diferite molecule osteoinductive. In general, cele mai multe dintre aceste molecule sunt reglate de catre tractiune si actioneaza prin stimularea proliferarii celulelor precursoare ale osteoblastilor in ligamentul parodontal, formarea ulterioara de os si inhibarea resorbtiei osoase. Moleculele care au fost legate de deplasarile dentare ortodontice sunt TGFβ (Brady si colab, 1998), diverse BMPs (Mitsui si colab, 2006.), sialoproteine osoase (BSP) (Domon si colab, 2001), si factorul de crestere epidermal (FEG) (Guajardo si colab, 2000;. Gao si colab, 2002.). Desi mecanismele exacte in cadrul osteogenezei declansate de solicitarile ortodontice nu au fost examinate pe larg, pot fi trase concluzii rezonabile din literatura de specialitate pe tema mecanotransductiei osoase.

Daca e cazul exista mecanismele transductiei netraduse

STUDII VIITOARE

O mai buna cunoastere a evenimentelor moleculare din timpul miscarii dentare va oferi clinicienilor noi instrumente importante pentru monitorizarea raspunsurilor biologice la tratament. Aceasta ar trebui sa conduca la un tratament mai eficient cu un risc mai mic de aparitie a unor sechele

Diagnostic:

Astazi, nu exista modalitati convenabile de monitorizare a biomecanicii ortodontice din punct de vedere clinic. Modificarile in caracteristicile solicitarii altereaza semnificativ raspunsurile celulare. Prin urmare, pare rezonabil ca sunt necesare metode imbunatatite pentru monitorizarea fortelor ortodontice in timp real precum si imbunatatirea modelelor elementelor finite de studiere a solicitarilor care iau nastere in tesuturi.

Monitorizarea unor biomarkeri selectati din lichidul gingival in timpul tratamentului ortodontic prezinta un potential diagnostic considerabil. Cu toate acestea, aceasta abordare ridica unele probleme semnificative de exemplu, obtinerea de esantioane care sa fie necontaminate de componente bacteriene sau produse inflamatorii gingivale si micro-teste suficient de sigure si precise pentru esantioane de volum de ordinul μL, variatie in prelevarea de probe in functie de locatie si de secventa de esantioane, dezvoltarea de instrumente pentru a citi probele intr-un cadru clinic. Biomarkerii care sa urmeze calea autocrina / paracrina si efectori ai activitatii celulare au fost determinati cu succes in lichidul gingival in timpul miscarii dentare. Au fost raportate cresteri in citokinele resorbtive osoase, IL 2, 6, si 8 (Basaran si colab, 2006.), si TNFα (Lowney si colab, 1995). Recent, raporturile dintre IL-1β si receptorul antagonist al IL-1 in lichidul gingival au putut prezice viteza de deplasare dentara ortodontica intr-un cadru clinic (Iwasaki si colab, 2001.). In plus, nivelurile in fluidul gingival crevicular de RANKL si osteoprotegerin par sa reflecte o crestere a activitatii osteoclastice in ligamentul parodontal, cu niveluri mai ridicate pentru formare si mai mici pentru acesta din urma, la 24 de ore dupa activarea aparatului (Nishijima si colab, 2006.).

Enzimele care intervin in remodelarea osoasa au fost, de asemenea determinate in lichidul gingival si pot reflecta diferentele temporale si spatiale din cadrul acestei activitati in timpul deplasarii dentare ortodontice. Modificarile in  nivelurile fosfatazei acide si alcaline par sa sugereze la inceput o activitate resorbtiva osoasa, urmata de o activitate formativa, amintind de un ciclu de remodelare osoasa (Insoft si colab, 1996.). Cresteri in MMP 1, 2 (Ingman si colab, 2005;Cantarella si colab, 2006), 8 (Apajalahti si colab, 2003), si catepsinei B (Sugiyama si colab, 2003) au fost de asemenea raportate, sugerand ca ele pot fi utile pentru evaluarea clinica a degradarii matricei extracelulare. Prezenta in lichidul gingival crevicular al proteoglicanului, sulfatheparanului, indica faptul ca proteoglicanii pot fi, de asemenea, biomarkeri utili pentru procesele resorbtive din osul alveolar (Waddington si colab, 1994.).

Terapeutice:

Exista numeroase rapoarte cu privire la efectele administrarii diferitelor medicamente, hormoni si alte substante biologic active asupra deplasarii dentare ortodontice. Acestea pot fi clasificate in doua categorii generale: substante care imbunatatesc circulatia dentara si care o impiedica. Primul grup ar putea fi folositor alaturi de semnalele conventionale ortodontice biomecanice pentru a imbunatati timpul de tratament si eficienta acestuia, in timp grupul din urma ar fi util pentru ancoraj si stabilitatea rezultatelor posttratament.

Abordarile farmacologice de succes pentru reglarea miscarii dentare ortodontice au atacat in principal problema controlului osteoclastelor. Deoarece chiar si modificarile de numar ale osteoclastelor si a activitatii lor se coreleaza cu deplasarea dentara si resorbtia radiculara, s-au cautat substante care sa actioneze asupra osteoclastelor. Aceste substante au insa ,de obicei, efecte similare asupra odontoclastelor. Ca o consecinta, atunci cand acestea inhiba resorbtia radiculare, ele inhiba, de asemenea, miscarea dentara si invers.

Desi citokinele proinflamatorii nu au fost inca utilizate pentru a ameliora deplasarea dentara, administrarea de receptori solubili pentru IL-1 si TNFα s-a dovedit ca reduce numarul osteoclastelor si deplasarea dentara la sobolani (Jager si colab, 2005.). Metabolitii vitaminei D au capacitatea de a creste activitatea osteoclastica si administrarea lor locala poate creste deplasarea dentara ortodontica, la sobolani, pe aceasta cale (Collins si Sinclair, 1988). Mai multe medicamente care inhiba caile prostaglandinelor sunt eficiente in reducerea activitatii osteoclastice in tesuturile paradentale, reducand deplasarea dentara, sau limitand resorbtiile radiculare. Acestea includ aspirina, acetaminofenul, ibuprofenul, indometacinul si clodronatul (Kehoe si colab, 1996;. Liu si colab, 2006.).

Directionarea receptorului v 3 integrinei poate reduce capacitatea odontoclastelor de a se atasa pe suprafata dintilor si astfel poate constitui un mijloc eficient de reducere a resorbtiei radiculare in timpul deplasarii dentare (Talic si colab, 2006.). De asemenea, osteoprotegerinul poate reduce activitatea osteoclastica, deplasarea dentara si resorbtia radiculara (Penolazzi si colab, 2006.). Tetraciclinele modificate chimic au capacitatea de a inhiba MMPs fara nici un efect antibacterian. Acestea inhiba numarul osteoclastelor din zonele de compresie, eventual prin cresterea apoptozei sau reducerea migratiei. S-a dovedit ca ele reduc miscarea dentara ortodontice (Bildt si colab., 2006) si resorbtia radiculara (Mavragani si colab, 2005.). Bisfosfonatii actioneaza asupra osteoclastelor inhiband activitatea lor resorbtiva. Acestia inhiba, de asemenea, deplasarile dentare ortodontice (Igarashi si colab, 1994;. Liu si colab, 2002.), dar prezinta un riscul de a produce osteonecroza maxilarelor. Relaxinul uman  actioneaza prin cresterea turnoverului tesutului conjunctiv fibroas.

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