rocïnõâk18 ORTODONCIE Molekula rnõâ souhra morfogeneze zubuê a cï elistnõâch kostõâ a souvisejõâcõâ poruchy. CÏ aâ st 2: Remodelace a defekty Molecular symphony of tooth-bone morphogenesis and related disorders. Part 2: Remodelling and defects * MUDr. PrÏemysl KrejcÏ õâ, Ph.D. **,**** doc. RNDr. Eva MatalovaÂ, Ph.D., **,*** RNDr. Jana FleischmannovaÂ, Ph.D. **,**** prof. MVDr. Ivan MõÂsÏ ek, CSc. * Klinika zubnõâho leâ karïstvõâ, Le karïskaâ fakulta, Univerzita Palacke ho, Olomouc * Clinic of Dental Medicine, Medical Faculty, Palacky University Olomouc ** LaboratorÏ embryologie zïivocï ichuê,uâ stav zïivocïisïneâ fyziologie a genetiky, AV CÏ R v.v.i., Brno ** Laboratory of Animal Embryology, Institute of Animal Physiology and Genetics, v.v.i., AS CR Brno *** Katedra fyziologie zï ivocï ichuê, JihocÏ eskaâ univerzita, CÏ eskeâ BudeÏ jovice *** Department of Animal Physiology, Faculty of Biological Science, University of South Bohemia, CÏ eskeâ BudeÏ jovice **** Veterina rnõâ a farmaceutickaâ univerzita Brno **** University of Veterinary and Pharmaceutical Sciences Brno Souhrn Zubnõ leâ karïi se ve sveâ praxi cï asto setkaâ vajõâ s probleâ my spojenyâ mi s poruchami komplexu zubuê acï elistnõâ kosti, ktereâ jsou naâ sledkem jak vyâ vojovyâ ch defektuê, tak onemocneï nõâ nebo uâ razuê. Tato prïehlednaâ praâ ce navazuje na prvnõâ cïaâ st publikovanou v minuleâmcï õâsle kteraâ shrnovala vyâ vojoveâ aspekty souhry zubuê a kostõâ. Druha cï aâ st si klade za cõâl diskutovat homeostaâ zu komplexu zubuê a kostõâ, zejmeâ na remodelaci kostõâ beï hem formovaâ nõâ zubnõâ korunky a korïenuê a beï hem erupce zubu. Selha nõâ molekulaâ rnõâ komunikace na straneï zubu nebo kosti, muêzïe mõât pro druhou tkaânï fataâ lnõâ naâ sledky, protozïe zuby a kosti se vzaâ jemneï ovlivnï ujõâ. V teâtocïaâ sti prïehledu jsou zmõâneï neâ neï ktereâ poruchy vyâ voje zubuê, ktereâ zpuê sobujõâ defekty kostõâ a naopak (Ortodoncie 2009, 18, cï. 5, s. 14-21). Abstract Dentists in their praxis often face problems connected with the teeth-jawbone disorders resulting from developmental defects as well as disease and trauma. This review is a follow-up of the first part published in the previous issue of this journal which summarised the developmental aspects of tooth-bone interplay. Second part aims to discuss homeostasis of the tooth-bone complex, particularly remodelling of bone during tooth crown and root formation, and during tooth eruption. Tooth and bone reciprocally influence each other, therefore failure in molecular communication of tooth or bone may have fatal consequences on development of the other one. Several disorders of tooth development causing bone defects and vice versa are mentioned in this review (Ortodoncie 2009, 18, No. 5, p. 14-21). KlõÂcÏ ovaâ slova: odontogeneze, osteogeneze, zubnõâ abnormality Key words: odontogenesis, osteogenesis, dental disorders 14 www.orthodont-cz.cz e-mail: redakce@orthodont-cz.cz
ORTODONCIE rocïnõâk18 REMODELACE KOSTI V INTERAKCI SE ZUBY Kosti prïedstavujõâ prïi plneï nõâ svyâ ch fyzikaâ lnõâch a fyziologickyâ ch funkcõâ velmi dynamickeâ struktury, remodelace prorïezanyâch zubuê je naopak teâmeïrï nulovaâ. ProtozÏ e jsou vyvõâjejõâcõâ se zuby obklopeny plneï mineralizovanou kostnõâ tkaâ nõâ tvorïenou osteoblasty/osteocyty (Obr. 1), musõâ dojõât beï hemerupce do dutiny uâ stnõâ k jejõâ resorpci. BunÏ ky zubnõâho vaku proto rekrutujõâ osteoklasty, aby provedly resorpci kosti a uvolnily cestu pro erupci zubu. Osteoklasty se tvorïõâ z hematopoetickyâ ch progenitoruê linie monocytuê a makrofaâguê migrujõâcõâch z krve. Diferenciace zahrnuje utvaârïenõâ mnohojadernyâch buneï k a jejich polarizaci umozïnï ujõâcõâ spraâvneâ nasednutõâ na extracelulaâ rnõâ matrix kosti a tõâm naâ slednou resorpci kosti. Diferenciace osteoklastuê (Obr. 2) je z velkeâ cï aâ sti zprotrïedkovaâ na kolonie stimulujõâcõâmi faktory, zejmeâ na M-csf spolecïneï s interakcemi Rank/Rankl/Opg a transkripcïnõâmi faktory jako jsou NFkappaB, C-fos a C-src [1]. Obr. 1: Interakce Rank, Rankl a Opg prïi maturaci osteoklastuê a remodelaci kostõâ. Fig. 1: Rank, Rankl and Opg interactions in osteoclast maturation and bone remodelling. BONE REMODELLING IN INTERACTION WITH TEETH To fulfil their physical and physiological functions, bones are very dynamic structures, whereas, remodelling of erupted teeth is none or very limited. As teeth develop encased in fully mineralized alveolar bone, formed by osteoblasts/osteocytes (Fig. 1), this must be resorbed during eruption of teeth into the oral cavity. Dental follicle cells therefore recruit osteoclasts that resorb bone to formthe way out for the erupting tooth. Osteoclasts differentiate from the monocyte-macrophage haematopoietic progenitors migrating from the blood. The differentiation involves formation of multinuclear cells and their polarization enabling correct attachment to the extracellular bone matrix and following bone resorption. Differentiation of osteoclasts (Fig. 2) is largely mediated by colony-stimulating factors, particularly M-csf together with Rank/Rankl/ Opg signalling and transcription factors, such as NFkappaB, C-fos, and C-src [1]. Stimulation of Rank expressed on the surface of osteoclast progenitors by its ligand Rankl induces differentiation of osteoclasts and bone resorption. Opg (osteoprotegerin), a decoy receptor of Rank, silences bone resorption via competition with Rankl (Fig. 3). Alveolar osteoclast differentiation involves periodontal ligament fibroblasts as a source of Rankl. Osteoclasts attached to the bone, with fully developed ruffled borders, dissolute hydroxyapatite crystals and subsequently degrade remaining extracellular proteins. Demineralization is mediated by acidification of the resorption lacuna mediated by a vacuolar type of H + -ATPase. Demineralised bone in the resorption lacunae is degraded by proteolytic enzymes, particularly cysteine proteinases, and matrix metalloproteinases. Tooth eruption is a physiologic process that strongly influences the normal development of the craniofacial Obr. 2: Signa lnõâ draâ hy rïõâdõâcõâ diferenciaci a maturaci osteocytuê z pluripotentnõâho mesenchymaâ lnõâho progenitoru. Fig. 2: Signalling pathways governing osteocyte differentiation and maturation from pluripotent mesenchymal progenitor. Obr. 3: Schematicke znaâ zorneï nõâ diferenciace osteoklastuê a asociovanyâch poruch. Fig. 3: Schematic display of osteoclast differentiation from hematopoietic stemcell and related disorders. www.orthodont-cz.cz e-mail: redakce@orthodont-cz.cz 15
rocïnõâk18 ORTODONCIE Stimulace Rank na membraâ naâ ch osteoklastovyâch progenitoruê vazbou jeho ligandu Rankl indukuje diferenciaci osteoklastuê a tõâmresorpci kosti. Opg (osteoprotegerin), kteryâ je decoy (falesï nyâ m) receptorem pro Rank, tlumõâ resorpci kosti kompeticõâ s Rankl (Obr. 3). Diferenciace alveolaâ rnõâch osteoklastuê zahrnuje fibroblasty z periodontaâ lnõâch vlaâ ken jako zdroj Rankl. Osteoklasty nasedajõâcõâ na kost s plneï vyvinutyâ mlemem (ruffled border) rozpousï teï jõâ hydroxyapatitoveâ krystaly a naâ sledneï degradujõâ zbytky extracelulaâ rnõâch proteinuê. Demineralizace je zprostrïedkovaâ na okyselenõâm resorpcï nõâch lakun umozïneïnyâmvakuolovyâmi H + -AT- Pa zami. V resorpcï nõâch lakunaâ ch je demineralizovanaâ kost degradovaâ na proteolytickyâ mi enzymy, zejmeâ na cysteinovyâ mi proteaâ zami a matrixovyâ mi metaloproteinaâ zami. Erupce zubu prïedstavuje fyziologickyâ proces, kteryâ vyâ razneï ovlivnï uje normaâ lnõâ vyâ voj kraniofaciaâ lnõâho komplexu. OpozÏ deï naâ erupce muê zï e u ortodontickyâch pacientuê prïõâmo ovlivnit spraâ vnou diagnoâ zu, celkovyâ plaâ n leâ cï ebneâ ho postupu a jeho cï asovaâ nõâ [2]. SELHA NI KOSTI VE VZTAHU K ZUBU Erupce zubuê je regulovaâna rïadou cytokinuê, vcï etneï epidermaâ lnõâho ruê stoveâ ho faktoru, transformujõâcõâho faktoru b, interleukinu-1, kolonie stimulujõâcõâho faktoru 1 a PTHRP [3].Po erupci zubu je produkce kosti iniciovaâ na v bazaâ lnõâ cïaâ sti zubnõâho luêzï ka, a to z duê vodu pevneâ fixace prorïezaneâ ho zubu v cï elisti. Tyto procesy jsou stimulovaâ ny ruê stovyâ mi faktory exprimovanyâ mi bunïkami zubnõâho vaku. MysÏ i deficientnõâ v Mt1-mmp vykazujõâ obecneï vysï sï õâ resorpci kosti a opozïdeï nou erupci zubu, cozï m uê zï e byâ t zpuê sobeno praâ veï nedostatecï nyâ m ruê stemalveolaâ rnõâ kosti [4]. Kostnõ tkaâ nï se neustaâ le reorganizuje, cozï umozïnï uje reparaci a samoobnovu, naprïõâklad po frakturaâ ch a stejneï tak adaptaci k mechanickeâ mu zatõâzï enõâ, ktereâ mu kost musõâ odolaâ vat. U dospeï leâ ho jedince se proto kombinuje uâ rovenï reorganizace kostõâ, kolagenoveâ matrix, geometrie a denzita praâ veï na zaâ kladeï mechanickeâ schopnosti. Defekty v teï chto parametrech mohou vyuâ stit v neï kteraâ onemocneï nõâ, naprï. osteoporoâ zu, osteopetroâ zu, osteogenesis imperfecta nebo Pagetovu nemoc [5]. Osteoporo za prïedstavuje defekty vztahujõâcõâ se k mikroarchitekturïe kostõâ, pozmeï neï neâ mu slozï enõâ nekolagennõâch proteinuê a snõâzï eneâ hustoteï mineraâ lnõâ hmoty zpuê sobujõâcõâ zvyâsï eneâ riziko fraktur. Na molekulaâ rnõâ uâ rovni je zaâ vazïnaâ osteoporoâ za zpuê sobena deficiencõâ Opg a G-csf [6,7]. Opg deficientnõâ mysï i vykazujõâ rychlejsï õâ reorganizaci kostnõâ tkaâneï,meâneï stabilnõâ kostnõâ strukturu, nespraâ vneâ propojenõâ staryâ ch a noveï vytvaâ rïenyâ ch osteoblastuê a cï astyâ vyâ skyt kostnõâch fraktur. Ovariektomie vyvolaâvaâ u mysï õâ zvyâsï enou osteoklastogenezi spolecï neï se snõâzï enou osteoblastogenezõâ, tedy obdobnyâ projev jako u menopauzaâ lnõâch zïen [8]. complex. A delay in eruption can directly affect the accurate diagnosis, overall treatment planning, and timing of treatment for the orthodontic patient [2]. BONE FAILURES RELATED TO TOOTH Tooth eruption is regulated by various cytokines, including epidermal growth factor, transforming growth factor-b, interleukin-1, colony stimulating factor-1 and PTHRP [3]. After eruption of the tooth, the bone production is initiated in the basal part of the dental socket to provide proper fixation of the erupted tooth in the jaw. These processes are underscored by growth factors expressed by the dental follicle cells. Mt1-mmp-deficient mice show generalised increase in bone resorption and delayed tooth eruption which may be caused by inefficient growth of the alveolar bone [4]. Bone tissue is constantly 'turning over', allowing bone to repair itself, for instance after a fracture, and to adapt to the mechanical loads that are placed on it. In the adult skeleton, the rate of bone turnover, collagen matrix, structure, geometry, and density all combined to determine the bone's overall mechanical competence. Defects in these parameters can result in diseases such as osteoporosis, osteopetrosis, osteogenesis imperfecta, and Paget's disease [5]. Osteoporosis is a disease related to disrupted bone microarchitecture, altered non-collagenous protein composition, and decreased bone mineral density causing a higher risk of fractures. At molecular level, severe osteoporosis results fromopg deficiency and G-csf [6,7]. Opg deficient mice have faster bone turnover, less stable bone structure, incorrect attachment between old and newly formed osteoblasts and a high incidence of bone fractures. Ovariectomy in mice results in increased osteoclastogenesis as well as decreased osteoblastogenesis, a phenotype observed in the postmenopausal women [8]. Rankl, the key mediator of bone resorption in normal and pathological states, stimulates the formation and activity of osteoclasts, by binding to Rank receptor present on osteoclasts and their progenitors. These processes are disrupted by binding of Rankl to Opg, a soluble decoy receptor binding Rankl and blocking its interaction with Rank. Whilst no mutations in the Rankl gene have yet been identified in human disease, mutations that result in enhanced Rank signalling through inactivation of Opg or activation of Rank are associated with juvenile Paget's disease and familial expansile osteolysis (FEO) [9]. FEO is an autosomal dominant disorder featuring constitutive activation of Rank due to an 18-bp tandem duplication (TNFRSF11A). A similar, 27-bp duplication causes what has been called a familial form of early- 16 www.orthodont-cz.cz e-mail: redakce@orthodont-cz.cz
ORTODONCIE rocïnõâk18 Rankl, kteryâ je klõâcï ovyâ mmediaâ toremresorpce kostõâ za normaâ lnõâch i patologickyâ ch stavuê, podporuje formovaâ nõâ a aktivitu osteoklastuê vazbou na Rank receptor, kteryâ se nachaâ zõâ na osteoklastech a jejich progenitorech. Tyto procesy jsou porusï eny prïi vyvaâ zaâ nõâ Rankl na solubilnõâ decoy (falesï nyâ) receptor Opg, kteryâ vyvazuje Rankl a blokuje jeho interakci s Rank. ZatõÂmco mutace v genu Rankl dosud nebyly identifikovaâ ny v souvislosti s zïaâ dnou lidskou nemocõâ, mutace, ktereâ vedou ke zvyâsï eneâ Rank signalizaci cestou inaktivace Opg nebo aktivacõâ Rank, jsou asociovaâ ny s juvenilnõâ Pagetovou nemocõâ a familiaâ rnõâ expanzivnõâ osteolyâ zou (FEO) [9]. FEO je dominantnõâ autozomaâ lnõâ onemocneï nõâ vykazujõâcõâ konstitutivnõâ aktivaci Rank z duê vodu tandemoveâ duplikace 18-bp (TNFRSF11A). Obdobna duplikace, 27-bp, zpuê sobuje tzv. familiaâ rnõâ formu cï asneâ Pagetovy nemoci kostõâ (PDB2). Expanzivnõ skeletaâ lnõâ hyperfosfataâ zie (ESH) zahrnuje tandemovou duplikaci 15 paâ ruê bazõâ v TNFRSF11A. DeaktivujõÂcõ mutace genu koâ dujõâcõâho Opg (TNFRSF11B) zpuê sobuje veï tsï inu prïõâpaduê juvenilnõâ Pagetovy nemoci [10]. Pagetova nemoc (PDB1) je cï astyâ monemocneï nõâmcharakterizovanyâ mohniskovyâ mi lozï isky zvyâsï eneâ reorganizace kostõâ v jedneâ nebo võâce kostech skeletu. Geneticke faktory, ktereâ bymohly hraâtvyâznamnou roli v tomto onemocneï nõâ, jsou mutace identifikovaneâ ve cï tyrïech genech. NejduÊ lezï iteï jsï õâm z nich je SQSTM1 (Sequestosome 1), kteryâ je steï zï ejnõâm proteinemv signaâ lnõâ draâ ze nukleaâ rnõâho faktoru kappab (NFkappaB). Vzhledemk urcï iteâ mu vlivu faktoruê zï ivotnõâho prostrïedõâ se vyâ zkumzameï rïuje naprïõâklad na infekce zpuê sobeneâ paramyxoviry, aktuaâ lnõâ poznatky vsï ak dosud nejsou jednoznacïneâ [11]. Dysfunkce nebo absence osteoklastuê zpuê sobujõâ osteopetroâ zu, kampatrïõâ skupina vzaâ cnyâ ch, ale zaâ vazïnyâ ch onemocneï nõâ charakterizovanyâ ch naâ ruê stem kostnõâ hmoty, malformacemi kostry a selhaâ nõâmkostnõâ drïeneï, cozï muêzïe byât fataâ lnõâ [12]. Osteopetro za u lidõâ je zpuê sobena mutacemi v rïadeï genuê, mezi ktereâ patrïõâ TCIRG1 koâ dujõâcõâ a3 podjednotku H+ATPa zy a souvisejõâcõâ s võâce nezï 50%prÏõÂpaduÊ,da le geny ClCN7 a OSTM1, ktereâ spolu uâ zce funkcïneï souvisejõâ a zahrnujõâ asi 10 % prïõâpaduê vyznacï ujõâcõâch se takeâ neurodegeneracõâ. DalsÏõ geny jsou zahrnuty ve vzaâ cnyâ ch formaâ ch osteopetroâ zy sruê zneï zaâ vazïnyâmi projevy a byly asociovaâ ny takeâ s dalsï õâmi syndromy, aktuaâ lneï byl nalezen mutovanyâ gen Rankl takeâ u neï kteryâ ch pacientuê postraâ dajõâcõâch osteoklasty. Autozoma lneï recesivnõâ osteopetroâ za se strïedneï zaâ vazï nyâ mi projevy muê zï e v neï kteryâ ch prïõâpadech souviset s mutacõâ podmõâneï nou ztraâ tou funkce genuê CAII a PLEKHM1. DominantneÏ negativnõâ mutace genu ClCN7 zpuê sobuje Albers-SchoÈ nbergovu chorobu, kteraâ prïedstavuje nejfrekventovaneï jsï õâ, heterogennõâ formu osteopetroâ zy, s rozsahemod asymptomatickyâ ch, prïes strïednõâ azï po velmi zaâ vazï neâ projevy, onset Paget's disease of bone (PDB2). Expansile skeletal hyperphosphatasia (ESH) involves a 15-bp tandemduplication in TNFRSF11A. Deactivating mutations of the gene encoding Opg (TNFRSF11B) causes most cases of juvenile Paget disease [10]. Paget's disease (PDB1) is a common disease characterised by focal areas of increased bone turnover, affecting one or several bones throughout the skeleton. Genetic factors have an important role in this disease, and mutations have been identified in four genes. The most important of these is SQSTM1 (Sequestosome 1), which makes a scaffold protein in the nuclear factor kappab (NFkappaB) signalling pathway. As environmental factors also contribute, the research has focused e. g. on paramyxovirus infection as a possible trigger, but evidence for this notion is conflicting [11]. Dysfunction in or lack of osteoclasts result in osteopetrosis, a group of rare but often severe, genetic disorders characterized by an increase in bone mass, skeletal malformations and bone marrow failure that may be fatal [12]. Human osteopetrosis relies on loss-of-function mutations of various genes, including the TCIRG1 gene, encoding for the a3 subunit of the H+ATPase and accounting for more than 50 % of cases, the ClCN7 and the OSTM1 genes, which have closely related function and account for approximately 10 % of cases, also presenting with neurodegeneration. Further genes are implicated in rare forms of osteopetrosis with various severities and association with other syndromes and, recently, the Rankl gene has been found to be mutated in a subset of patients lacking osteoclasts. Autosomal recessive osteopetrosis may also have intermediate severity, with a small number of cases due to loss-of-function mutations of the CAII or the PLEKHM1 genes. Dominant negative mutations of the ClCN7 gene cause the Albers-SchoÈ nberg disease, which represents the most frequent, heterogeneous formof osteopetrosis, ranging fromasymptomatic to intermediate/severe, thus suggesting additional genetic/environmental determinants affecting penetrance [13]. Tooth osteopetrotic phenotype includes delayed, defective or even none tooth eruption causing missing or malformed teeth. Hypomineralization of enamel and dentin, tooth decay and defects of the periodontium are more common compared to healthy individuals [14, 15]. Animal models of osteopetrosis are either spontaneous or with targeted genetic manipulations. Osteopetrosis with tooth eruption defects was observed in mice deficient in genes engaged in osteoclast differentiation and function, e. g. Rankl, Csf1, Pthrp, c-fos, bhlh-zip, Mitf/Tfe3, C-src, Atp6i [16, 17]. Other genes, such as Rankl, Atp6V0A3, Clc7 have been reported so far in association with human osteopetrosis. www.orthodont-cz.cz e-mail: redakce@orthodont-cz.cz 17
rocïnõâk18 ORTODONCIE cozï naznacï uje mozï nou soucï innost s dalsï õâmi genetickyâmi a environmentaâ lnõâmi faktory [13]. Zubnõ fenotyp u osteopetroâ zy zahrnuje opozïdeï nou, defektnõâ, prïõâpadneï chybeï jõâcõâ erupci zubuê, cozï zpuê sobuje malformovaneâ nebo chybeï jõâcõâ zuby. Hypomineralizace skloviny a zuboviny, zubnõâ kazy a defekty periodoncia jsou mnohem beïzïneïjsï õâ ve srovnaâ nõâ se zdravyâmi jedinci [14, 15]. ZvõÂrÏecõ modely osteopetroâ zy jsou bud' spontaâ nnõâ nebo vyvolaneâ cõâlenou genetickou manipulacõâ. Osteopetro za zahrnujõâcõâ defektnõâ erupci zubu byla pozorovaâ na u mysï õâ deficientnõâch v genech zapojenyâch v diferenciaci a funkci osteoklastuê, naprï. Rankl, Csf1, Pthrp, c-fos, bhlh-zip, Mitf/Tfe3, C-src, Atp6i [16, 17]. DalsÏ õâ geny jako Rankl, Atp6V0A3 a Clc7 byly dosud asociovaâ ny s osteopetroâ zou u lidõâ. PrÏedcÏ asnaâ ztraâ ta zubuê m uê zï e byâ t cï asto jedinyâ mprojevemhypofosfateâ mie kostõâ, cozï je onemocneï nõâ zpuê sobeneâ mutacemi v genu koâ dujõâcõâmtkaânï oveï nespecifickou alkalickou fosfataâ zu. Nedocha zõâ k difuâ znõâ distribuci Ca2+ do kostõâ, cozï vede k nõâzkeâ hustoteï kostnõâ hmoty a hyperkalceâ mii, daâ le ke zvracenõâ, neschopnosti prïibrat na teï lesneâ hmotnosti a zveï tsï enõâ epifyâz. SELHA NI ZUBU VE VZTAHU KE KOSTI VyÂvoj a homeostaâ ze alveolaâ rnõâ kosti muêzïe byât na druhou stranu ovlivneï na hypodonciõâ, chirurgickyâmi zaâsahy, traumatem nebo neleâ cï enyâ mi onemocneï nõâm i zubuê.v duê sledku ztraâ ty mechanickeâ ho zatõâzï enõâ je chybeï nõâ nebo ztraâ ta zubu zhoubnaâ i pro alveolaâ rnõâ kost. Proto jsou ageneze zubuê v neï kteryâch prïõâpadech doprovaâ zeny ztraâ tou nebo vyâ raznou redukcõâ alveolaâ rnõâ kosti, cozï je zdrojemobtõâzïõâ prïi spraâ vneâ fixaci zubnõâch implantaâ tuê. Extrakce zubu je naâ sledovaâ na pokracï ujõâcõâ resorpcõâ zbyleâ alveoaâ rnõâ kosti. K resorbci v bezzubeâ cï e- listi dochaâ zõâ jak v prïõâpadeï pouzïõâvaâ nõâ zubnõâ proteâ zy, tak i bez nõâ a prïicï õâtaâ se rïadeï souvisejõâcõâch faktoruê u konkreâtnõâho pacienta. Parodontitis jako bakteriaâ lnõâ zaâneï tliveâ onemocneï nõâ je doprovaâ zena tvorbou parodontaâ lnõâho chobotu a resorpcõâ alveolaâ rnõâ kosti naâ sledovanou ztraâ tou zubuê. NadmeÏ rnaâ resorpce kosti prïi chronickeâmzaâneï tu je zrïejmeï naâ sledkeâ mupregulace Rank-Rankl signalizace. InfiltrujõÂcõ leukocyty mohou zvyâsï it resorpci kosti bud' produkcõâ samotneâ ho Rankl nebo cestou zaâ neï tlivyâ ch mediaâ toruê (interleukin-1, prostaglandin E2). Mutace v genu pro lysozomaâ lnõâ proteaâ zu katepsin C zpuê sobujõâ agresivnõâ prepubertaâ lnõâ parodontitidu. Syndromy Papillon-Lefevre (PLS) a Haim-Munk (HMS) jsou hyperkeratoâ zy v oblasti dlanõâ a plosek, keratoderma palmoplantaris (PPK) spojeneâ s prïedcï asnou destrukcõâ periodoncia uâ stõâcõâ v prïedcï asnou ztraâ tu zubuê [18]. AcÏ koliv PLS i HMS vykazujõâ obdobneâ zaâ kladnõâ rysy PPK a zaâ vazïneâ parodontitidy, je u HMS evidovaâna rïada dalsï õâch znakuê vcï etneï arachnodaktilie, akroosteolyâ zy, atrofickyâ ch zm eï n nehtuê a radio- Premature tooth loss may be often the only feature of milder cases of bone hypophosphatasia, a disorder caused by mutations in a gene coding tissue nonspecific alkaline phosphatase. Ca2+ is not diffusely deposited in bones leading to low bone density and hypercalcemia, further to vomiting, inability to gain weight and enlargement of the epiphyses. TOOTH FAILURES RELATED TO BONE On the other hand, alveolar bone development and homeostasis may be affected by hypodontia, surgical interventions, trauma or untreated tooth-related diseases. Due to loss of mechanical load, absence or loss of a tooth is deleterious to alveolar bone. Therefore, tooth agenesis is in some cases accompanied by loss or great reduction of alveolar bone creating problems with proper fixation of tooth implants. Tooth extraction is followed by continuous resorption of the remaining alveolar bone. Resorption in the edentulous jaw occurs whether or not dentures are worn and is attributed to a number of interrelated factors particular to the individual patient. Periodontitis, as a bacterial inflammatory disease, is accompanied by periodontal pocket formation and alveolar bone resorption, followed by tooth loss. The excessive bone resorption in chronic inflammation seems to be most likely resulting from upregulation of Rank/Rankl signalling. Infiltrating leukocytes may enhance bone resorption either via production of Rankl itself or via inflammatory mediators (interleukin-1, prostaglandin E2). Mutations in the the lysosomal protease cathepsine C gene cause agressive prepubertal periodontitis. Papillon-Lefevre syndrome (PLS) and Haim-Munk syndrome (HMS) are palmoplantar keratoderma (PPK) conditions associated with premature periodontal destruction resulting in premature tooth loss [18]. Although both PLS and HMS share the cardinal features of PPK and severe periodontitis, a number of additional findings are reported in HMS including arachnodactyly, acro-osteolysis, atrophic changes of the nails, and a radiographic deformity of the fingers. While PLS cases have been identified throughout the world, HMS has only been described among descendants of a religious isolate originally fromcochin, India [19]. Lysosomal trafficking regulator CHS1/LYST gene deficiency results in human into an immunodeficiency associated with generalised periodontitis, Chediak- Higashi syndrome (CHS). CHS is a rare autosomal recessive disorder, patients show hypopigmentation, recurrent infections, mild coagulation defects and varying neurologic problems [20, 21]. Cathepsin C mice have normal structured periodontium and no periodontal infections [22]. 18 www.orthodont-cz.cz e-mail: redakce@orthodont-cz.cz
ORTODONCIE rocïnõâk18 grafickeâ deformity prstuê. ZatõÂmco prïõâpady PLS byly identifikovaâ ny po celeâ msveïteï, HMS byl popsaâ n pouze mezi potomky naâ bozï enskeâ separace z Cochin v Indii [19]. Deficience v genu pro lysozomaâ lnõâ regulaâ tor CHS1/LYST vede u lidõâ k imunodeficienci asociovaneâ s generalizovanou paradontoâ zou, syndromem Chediak-Higashi (CHS). CHS je vzaâ cnyâ mautozomaâ lneï recesivnõâmonemocneï nõâm,prïi ktereâ mpacienti vykazujõâ hypopigmentaci, rekurentnõâ infekce, mõârneâ defekty koagulace a ruê zneâ neurologickeâ probleâ my [20, 21]. MysÏ i bez katepsinu C majõâ normaâ lnõâ strukturu periodoncia a nevykazujõâ zïaâ dneâ parodontaâ lnõâ infekce [22]. Jak zuby, tak kosti jsou zasazï eny prïi kleidokraniaâ lnõâ dysplazii (CCD), vrozeneâ m onemocneï nõâ zpuê sobeneâ mmutacõâ v Runx2 [23]. CCD je charakterizovaâ na trvale otevrïenyâ mi nebo opozï deï neï uzavrïenyâmi suturami, hypoplastickyâmi azï aplastickyâmi klõâcïnõâmi kostmi, malyâ mvzruê stem, nadpocï etnyâ mi zuby zejmeâ na ve staâleâ dentici a mnoha dalsï õâmi skeletaâ lnõâmi anomaâ liemi. Fenotypove spektrumje vsï ak velmi variabilnõâ ivraâ mci rodin a zahrnuje jak mõârneï postizï eneâ jedince zejmeâ na se zubnõâmi abnormalitami tak i zaâ vazïneâ stavy s generalizovanou osteoporoâ zou [24]. MysÏ i s chybeï jõâcõâmlokusemrunx2 zcela postraâ dajõâ osifikaci, heterozygotnõâ mysï i vykazujõâ podobnyâ fenotyp jako CCD [25]. MOZÏ NOSTI REPARACE KOMPLEXU ZUB-KOST Tka nï oveâ inzï enyâ rstvõâ zalozï eneâ na vyuzï itõâ kmenovyâ ch buneï k je novou vyâzvou pro mozïnosti reparace a naâ hrady zubuê a okolnõâch struktur. FunkcÏ nõâ souhra prïirozenyâch zubuê a alveolaâ rnõâ kosti, stejneï jako naâ sledneâ zaâ konitosti resorpce kosti prïi udrzï ovaâ nõâ homeostaâ ze musõâ byâ t kliniky braânavuâ vahu zejmeânaprïi vyârobeï umeïleâ ho chrupu a takeâ prïi provaâ deï nõâ uâ speï sï nyâ ch implantologickyâ ch zaâ krokuê. Pokroky ve vytvaâ rïenõâ zubnõâ korunky s vyuzï itõâmkmenovyâ ch buneï k v poslednõâmdesetiletõâ byly shrnuty v tomto cï asopisu [32]. RÏ õâzenaâ tkaânï ovaâ regenerace umozï nï uje hojenõâ periodoncia aplikacõâ umeï lyâ ch barieâ r, ktereâ zabranï ujõâ repopulaci posï kozeneâ ho periodoncia bunï kami epitelu a pojivoveâ tkaâneïdaâ sneï. To umozïnï uje bunï kaâ mpdl, cementoblastuê ma osteoblastuê mselektivnõâ migraci, proliferaci a diferenciaci v mõâstech posï kozenõâ. Artificielnõ vyâztuhy a barieâ ry lze pouzï õât pro dodaânõâ bioaktivnõâch molekul a osõâdlenõâ bunï kami, ktereâ nahradõâ nemocnou nebo posï kozenou tkaânï. Vhodne je umõâsteï nõâ takovyâ ch vyâ ztuh do zubnõâho luê zï ka po extrakci, prezervace alveolaâ rnõâho vyâbeï zï ku ihned po extrakci zabranï uje ze 40-60 % atrofii kosti [26]. Deriva ty skloviny poskytujõâcõâ ruê stoveâ faktory Bmp-2 a BMP-7 jsou komercï neï dostupneâ pro regeneraci periodoncia [27, 28], Pdgf a Bmp-7 klonovaneâ do adenovirovyâ ch vektoruê byly uâ speï sï neï pouzï ity u zvõârïecõâch modeluê prïi hojenõâ posï kozeneâ ho periodoncia a bylo ukaâzaâ no, zïe aplikace purifikovanyâ ch rekombinantnõâch ruê stovyâ ch faktoruê Pdfg, Bmp-2, Bmp-7 a zejmeâ na Fgf-2 podporuje regeneraci Both bone and teeth are affected in cleidocranial dysplasia (CCD), a congenital disorder caused by Runx2 mutation [23]. CCD is characterized by persistently open or delayed closure of sutures, hypoplastic or aplastic clavicles, short stature, supernumerary teeth specific to permanent dentition often accompanied by delayed or disturbed eruption of regular permanent teeth, and many other skeletal anomalies. However, the phenotypic spectrumis extremely variable even within families, ranging from mildly affected individuals merely with dental abnormalities to severely affected patients with generalized osteoporosis [24]. Mice deficient in Runx2 locus completely lack ossification, heterozygous mice show a similar phenotype to CCD [25]. POSSIBLE REPARATIONS OF TOOTH-BONE COMPLEX Stem-cell based tissue engineering is a new challenging way how to repair or replace teeth and surrounding structures. The functional interplay of the natural teeth and the alveolar bone, and subsequent bone resorption patterns in homeostasis, must be understood by the clinicians to fabricate dentures as well as to performsuccessful implant dentistry. Progress in in vitro tooth crown formation using mesenchymal stem cells has been done in the last decade were reviewed [32]. Guided tissue regeneration provides periodontal wound healing by application of artificial barriers that exclude the re-population of periodontal defects by epithelial and gingival connective cells. This allows the PDL cells, cementoblasts, and osteoblasts to selectively migrate, proliferate and differentiate within the periodontal defects. Artificial scaffolds and barriers may be used to deliver bioactive molecules and populated by cells to replace the diseased or injured tissue. Setting of such scaffolds in the extraction socket immediately after surgery is beneficial, immediate preservation of the alveolar ridge after extraction prevents 40-60 % of the bone atrophy [26]. Enamel derivatives supplying Bmp-2 and Bmp-7 growth factors are commercially available for periodontal regeneration [27, 28], Pdgf and Bmp-7 cloned in adenoviral vectors were successfully used in periodontal defect healing in animal models. Application of purified recombinant growth factors Pdgf, Bmp-2, Bmp-7, and partially also Fgf-2 have been shown to promote alveolar bone regeneration [29]. The rhbmp- 12 treatment induces periodontal ligament, bone and cementum formation [30]. Recently, a comparative study of periodontal defects found that rhbmp-2 in association with collagen sponges promoted superior bone regeneration more than rhbmp-12. Moreover, Bmp-2 and Bmp-7 delivered in absorbable collagen www.orthodont-cz.cz e-mail: redakce@orthodont-cz.cz 19
rocïnõâk18 ORTODONCIE alveolaâ rnõâ kosti [29]. OsÏ etrïenõâ rhbmp-12 indukuje formovaâ nõâ periodontaâ lnõâch ligament, kosti a cementu [30]. Srovna vacõâ studie aktuaâ lneï ukaâ zaly, zï e rhbmp-2 v kolagenoveâ mnosicï i podporuje povrchovou regeneraci kostõâ jesïteï võâce nezï rhbmp-12. Bmp-2 a Bmp-7 aplikovaneâ na absorbujõâcõâmkoagenoveâ mnosicï i navõâc aktuaâ lneï obdrzïely v USA schvaâ lenõâ U rïadu pro kontrolu potravin a leâkuê (the US Food and Drug Administration) pro specifickeâ klinickeâ prïõâpady [31]. Regenerace funkcï nõâho zubu vcï etneï korïenuê touto cestou a jeho spraâ vnaâ fixace v cï elisti staâle zuê staâ vajõâ pro tyto biomedicõânskeâ prïõâstupy velkou vyâzvou. PodeÏ kovaâ nõâ Grantova podpora aktuaâ lnõâho vyâ zkumu: GA CÏ R 524/ 08/J032 (buneï cï neâ a molekulaâ rnõâ interakce beï hem vyâvoje zubuê a kostõâ), GA AV KJB500450802 (molekulaâ rnõâ odontogeneze), GA AV IAA600450904 (molekulaâ rnõâ embryogeneze), vyâ zkumnyâ zaâ meï r U ZÏ FG AV CÏ R, v.v.i (AVOZ 50450515). Mezina rodnõâ spolupraâ ce: Freie UniversitaÈ t Berlin (RJ Radlanski), King's College London (AS Tucker, PT Sharpe). Literatura/references 1. Lerner, U. H.: New molecules in the tumor necrosis factor ligand and receptor subfamilies with importance for physiological and pathological bone resorption. Crit. Rev. Oral Biol. Med. 2004, 15, s. 64-81. 2. Suri, L.; Gagari, E.; Vastardis H.: Delayed tooth eruption: pathogenesis, diagnosis and treatment. A literature review. Amer. J. Orthodont. dentofacial Orthoped. 2004, 126, s. 432-445. 3. Shroff, B.; Kashner, J. E.; Keyser, J. D.; Hebert, C.; Norris, K.: Epidermal growth factor and epidermal growth factor-receptor expression in the mouse dental follicle during tooth eruption. Arch. Oral Biol. 1996, 41, s. 613-617. 4. Bartlett, J. D.; Zhou, Z.; Skobe, Z; Dobeck, J. M.; Tryggvason, K.: Delayed tooth eruption in membrane type-1 matrix metalloproteinase deficient mice. Connect. Tissue Res. 2003, 44, s. 300-304. 5. Datta, H. K.; Ng, W. F.; Walker, J. A.; Tuck, S. P.; Varanasi, S. S.: The cell biology of bone metabolism. J. clin. Pathol. 2008, 61, s. 577-587. 6. Takahashi, T.; Wada, T.; Mori, M.; Kokai, Y.; Ishii, S.: Overexpression of the granulocyte colony-stimulating factor gene leads to osteoporosis in mice. Lab. Invest. 1996, 74, s. 827-834. 7. Bucay, N.; Sarosi, I.; Dunstan, C. R.; Morony, S.; Tarpley, J.; Capparelli, C.; Scully, S.; Tan, H. L.; Xu, W.; Lacey, D. L.; Boyle, W. J.; Simonet, W. S.: Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes. Dev. 1998, 12, s. 1260-1268. 8. Lazner, F.; Gowen, M.; Pavasovic, D.; Kola, I.: Osteopetrosis and osteoporosis: two sides of the same coin. Hum. Mol. Genet. 1999, 8, s. 1839-1846. sponges have recently received approval by the US Food and Drug Administration for specific clinical cases [31].However, regeneration of a functional tooth including root formation and its fixation in the jaw still remains a great challenge for such biomedical approaches. Acknowledgement Grant support of recent research: GA CR 524/08/ J032 (cellular and molecular interactions during tooth-jawbone development), GA AV KJB500450802 (molecular odontogenesis), GA AV IAA600450904 (molecular embryogenesis), IAPG CAS, v.v.i. (AVOZ 50450515). International cooperation: Freie UniversitaÈ t Berlin (RJ Radlanski), King's College London (AS Tucker, PT Sharpe). 9. Blair, J. M.; Zheng, Y.; Dunstan, C. R.: RANK ligand. Int. J. Biochem. Cell Biol. 2007, 39, s. 1077-1081. 10. Whyte, M. P.: Paget's disease of bone and genetic disorders of RANKL/OPG/RANK/NF-kappaB signaling. Ann. N. Y. Acad. Sci. 2006, 1068, s. 143-164. 11. Ralston, S. H.; Langston, A. L.; Reid, I. R.: Pathogenesis and management of Paget's disease of bone. Lancet 2008; 372 (9633), s. 155-163. 12. Askmyr, M.; Flores, C.; Fasth, A.; Richter, J.: Prospects for gene therapy of osteopetrosis. Curr. Gene Ther. 2009, 9, s. 150-159. 13. Del Fattore, A.; Cappariello, A.; Teti, A.: Genetics, pathogenesis and complications of osteopetrosis. Bone 2008, 42, s. 19-29. 14. Gomes, M. F.; Rangel, D. C.; Starling, C. C.; Goulart, M. G.: Familial malignant osteopetrosis in children: a case report. Spec. Care Dentist. 2006, 26, s. 106-110. 15. Luzzi, V.; Consoli, G.; Daryanani, V.; Santoro, G.; Sfasciotti, G. L.; Polimeni, A.: Malignant infantile osteopetrosis: dental effects in paediatric patients. Case reports. Eur. J. Paediatr. Dent. 2006, 7, s. 39-44. 16. Li, Y. P.; Chen, W.; Liang, Y.; Li, E.; Stashenko, P.: Atp6ideficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification. Nat. Genet. 1999, 23, s. 447-451. 17. Kornak, U.; Kasper, D.; BoÈ sl, M. R.; Kaiser, E.; Schweizer, M.; Schulz, A.; Friedrich, W.; Delling, G.; Jentsch, T. J.: Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell. 2001, 104, s. 205-215. 20 www.orthodont-cz.cz e-mail: redakce@orthodont-cz.cz
ORTODONCIE rocïnõâk18 18. Toomes, C.; James, J.; Wood, A. J.; Wu, C. L.; McCormick, D.; Lench, N.; Hewitt, C.; Moynihan, L.; Roberts, E.; Woods, C. G.; Markham, A.; Wong, M.; Widmer, R.; Ghaffar, K. A.; Pemberton, M.; Hussein, I.R.; Temtamy, S. A.; Davies, R.; Read, A. P.; Sloan, P.; Dixon, M. J.; Thakker, N. S.: Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat. Genet. 1999, 23, s. 421-424. 19. Hart, T. C.; Hart, P. S.; Michalec, M. D.; Zhang, Y.; Firatli, E.; Van Dyke, T. E.; Stabholz, A.; Zlotogorski, A.; Shapira, L.; Soskolne, W. A.: Haim-Munk syndrome and Papillon- Lefevre syndrome are allelic mutations in cathepsin. C. J. Med. Genet. 2000, 37, s. 88-94. 20. Kaplan, J.; De Domenico, I.; Ward, D. M.: Chediak-Higashi syndrome. Curr. Opin. Hematol. 2008, 15, s. 22-29. 21. Bailleul-Forestier, I.; Monod-Broca, J.; Benkerrou, M.; Mora, F.; Picard, B.: Generalized periodontitis associated with Che diak-higashi syndrome. J. Periodontol. 2008, 79, s. 1263-1270. 22. de Haar, S. F.; Hiemstra, P. S.; van Steenbergen, M. T.; Everts, V.; Beertsen, W.: Structure of the periodontium in cathepsin C-deficient mice. Infect. Immun. 2006, 74, s. 5284-5291. 23. Mundlos, S.; Otto, F.; Mundlos, C.; Mulliken, J. B.; Aylsworth, A. S.; Albright, S.; Lindhout, D.; Cole, W. G.; Henn, W.; Knoll, J. H.; Owen, M. J.; Mertelsmann, R.; Zabel, B. U.; Olsen, B. R.: Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell. 1997, 89, s. 773-779. 24. Yoshida, T.; Kanegane, H.; Osato, M.; Yanagida, M.; Miyawaki, T.; Ito, Y.; Shigesada, K.: Functional analysis of RUNX2 mutations in cleidocranial dysplasia: novel insights into genotype-phenotype correlations. Blood Cells Mol. Dis. 2003, 30, s. 184-193. 25. Yoda, S.; Suda, N.; Kitahara, Y.; Komori, T.; Ohyama, K.: Delayed tooth eruption and suppressed osteoclast number in the eruption pathway of heterozygous Runx2/Cbfa1 knockout mice. Arch. Oral Biol. 2004, 49, s. 435-442. 26. Marei, M. K.; Nouh, S. R.; Fata, M. M.; Faramawy, A. M.: Fabrication of polymer root form scaffolds to be utilized for alveolar bone regeneration. Tissue Eng. 2003, 9, s. 713-731. 27. Kemoun, P.; Laurencin-Dalicieux, S.; Rue, J.; Vaysse F, Romeas, A.; Arzate, H.; Conte-Auriol, F.; Farges, J. C.; Salles, J. P.; Brunel, G.: Localization of STRO-1, BMP- 2/-3/-7, BMP receptors and phosphorylated Smad-1 during the formation of mouse periodontium. Tissue Cell. 2007, 39, s. 257-266. 28. Sculean, A.; Windisch, P.; DoÈ ri, F.; Keglevich, T.; MolnaÂr, B.; Gera, I.: Emdogain in regenerative periodontal therapy. A review of the literature. Fogorv. Sz. 2007, 100, s. 220-232. 29. Jin, Q. M.; Zhao, M.; Economides, A. N.; Somerman, M. J.; Giannobile, W. V.: Noggin gene delivery inhibits cementoblast-induced mineralization. Connect. Tissue Res. 2004, 45, s. 50-59. 30. WikesjoÈ, U. M.; Qahash, M.; Thomson, R. C.; Cook, A. D.; Rohrer, M. D.; Wozney, J. M.; Hardwick, W. R.: rhbmp-2 significantly enhances guided bone regeneration. Clin. Oral Implants Res. 2004, 15, s. 194-204. 31. Bessa, P. C.; Casal, M.; Reis, R. L.: Bone morphogenetic proteins in tissue engineering: the road fromlaboratory to clinic, part II (BMP delivery). J. Tissue Eng. Regen. Med. 2008, 2, s. 81-96. 32. MatalovaÂ, E.; FleischmannovaÂ, J.; KrejcÏ õâ, P.; MõÂsÏ ek I.: VyuzÏitõ kmenovyâch buneï k a tkaânï oveâ ho inzïenyârstvõâ pro naâhradu zubuê. Ortodoncie 2008, 17, cï. 3, s. 34-39. MUDr. PrÏemysl KrejcÏ õâ, Ph.D. Klinika zubnõâho leâ karïstvõâ LF FN Palacke ho 12, 772 00 Olomouc CÏ lenskyâ poplatek pro rok 2010 cï inõâ 1500,- KcÏ nebo 45,- EUR. CÏ lenoveâ v zameï stnaneckeâ m vztahu 800,- KcÏ nebo 25,- EUR. Postgraduanti, duê chodci a zïeny na materïskeâ dovoleneâ 300,- KcÏ nebo 10,- EUR. RegistracÏ nõâ polatek cï inõâ 500,- KcÏ. PrÏedplatne cï asopisu Ortodoncie pro necï leny CÏ OSje 1000,- KcÏ za rok nebo 35,- EUR. U hrada poplatku do 28. 2. 2010, cï.uâ.: 32932-021/0100, konst. symbol: 0558, variab. symbol: rodneâ cï õâslo. PrÏi nezaplacenõâ prïõâspeï vkuê po dvou põâsemnyâch urgencõâch bude ukoncï eno cï lenstvõâ v CÏ OS. www.orthodont-cz.cz e-mail: redakce@orthodont-cz.cz 21