Das RANKL-, RANK- und OPG-System in der Regulation der Osteoklastogenese bei der kieferorthopädischen Zahnbewegung

Zusammenfassung

Molekulare und zelluläre Grundlagen der kieferorthopädischen Zahnbewegung bilden die Basis einer erfolgreichen Therapie. Der Osteoklast, als exklusive, zur Knochenresorption befähigte Zelle spielt dabei eine zentrale Rolle. Ziel dieses Übersichtsartikels ist es, die Bedeutung der Schlüsselmoleküle Receptor activator of nuclear factor-kappa-B ligand (RANKL), dessen Antagonisten Osteoprotegerin und dem Rezeptor RANK, bei der Genese und Aktivierung von Osteoklasten darzustellen. Die molekularen Regulationsmechanismen werden mit den histologischen Beobachtungen und klinischen Erfahrungen aus der Kieferorthopädie verknüpft. Ein Ausblick auf das therapeutische Potenzial der Schlüsselmoleküle in der kieferorthopädischen Zahnbewegung schließt den Beitrag ab.

Abstract

Orthodontic therapy should follow the fundamental principles of molecular and cellular biology. The osteoclast is the exclusive bone resorbing cell and therefore central to orthodontic tooth movement. The article describes the role of molecules which are the key to osteoclastogenesis and activation: receptor activator of nuclear factor-kappa-B ligand (RANKL), the decoy receptor osteoprotegerin and RANK, the latter being the receptor for RANKL. Data from histological observations and clinical experience in orthodontics will be viewed in the light of these fundamental molecular and cellular mechanisms. The therapeutic potential of these key molecules in orthodontic tooth movement will also be discussed.

Schlüsselwörter

RANKL - OPG - Zahnbewegung - Resorption - Osteoklast - Kieferorthopädie

Key words

RANKL - OPG - tooth movement - resorption - osteoclast - orthodontics

Literatur

• 1 Göz G. Zahnbewegung. in Kieferorthopädie II - Therapie. In: Diedrich P (Hrsg). 4. Auflage. Urban und Fisher, München, Jena 2000 2007; 28-42
• 2 Krishnan V, Davidovitch Z. Cellular, molecular, and tissue-level reactions to orthodontic force.  Am J Orthod Dentofacial Orthop. 2006;  129 469 ,  e 461-e 432
• 3 Weiland F. Kontinuierliche versus nicht-kontinuierliche Kräfte in der Kieferorthopädie. Habilitationsschrift 2001; 9-10
• 4 Parfitt A M. Osteonal and hemi-osteonal remodeling: the spatial and temporal framework for signal traffic in adult human bone.  J Cell Biochem. 1994;  55 273-286
• 5 Ott S M. Sclerostin and Wnt signaling - the pathway to bone strength.  J Clin Endocrinol Metab. 2005;  90 6741-6743
• 6 Martin T J, Sims N A. Osteoclast-derived activity in the coupling of bone formation to resorption.  Trends Mol Med. 2005;  11 76-81
• 7 Riggs B L, Parfitt A M. Drugs used to treat osteoporosis: the critical need for a uniform nomenclature based on their action on bone remodeling.  J Bone Miner Res. 2005;  20 177-184
• 8 Seeman E, Delmas P D. Bone quality - the material and structural basis of bone strength and fragility.  N Engl J Med. 2006;  354 2250-2261
• 9 Rosen C J. Clinical practice. Postmenopausal osteoporosis.  N Engl J Med. 2005;  353 595-603
• 10 Chavassieux P M, Arlot M E, Reda C, Wei L, Yates A J, Meunier P J. Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis.  J Clin Invest. 1997;  100 1475-1480
• 11 Boyle W J, Simonet W S, Lacey D L. Osteoclast differentiation and activation.  Nature. 2003;  423 337-342
• 12 Teitelbaum S L, Ross F P. Genetic regulation of osteoclast development and function.  Nat Rev Genet. 2003;  4 638-649
• 13 Parfitt A M. Osteoclast precursors as leukocytes: importance of the area code.  Bone. 1998;  23 491-494
• 14 Alhashimi N, Frithiof L, Brudvik P, Bakhiet M. Chemokines are upregulated during orthodontic tooth movement.  J Interferon Cytokine Res. 1999;  19 1047-1052
• 15 Stenbeck G, Horton M A. Endocytic trafficking in actively resorbing osteoclasts.  J Cell Sci. 2004;  117 827-836
• 16 Chambers T J. Regulation of the differentiation and function of osteoclasts.  J Pathol. 2000;  192 4-13
• 17 Simonet W S, Lacey D L, Dunstan C R, Kelley M, Chang M S, Luthy R, Nguyen H Q, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan H L, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes T M, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle W J. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density.  Cell. 1997;  89 309-319
• 18 Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL.  Proc Natl Acad Sci USA. 1998;  95 3597-3602
• 19 Suda T, Takahashi N, Martin T J. Modulation of osteoclast differentiation.  Endocr Rev. 1992;  13 66-80
• 20 Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie M T, Martin T J. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families.  Endocr Rev. 1999;  20 345-357
• 21 Li J, Sarosi I, Yan X Q, Morony S, Capparelli C, Tan H L, McCabe S, Elliott R, Scully S, Van G, Kaufman S, Juan S C, Sun Y, Tarpley J, Martin L, Christensen K, McCabe J, Kostenuik P, Hsu H, Fletcher F, Dunstan C R, Lacey D L, Boyle W J. RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism.  Proc Natl Acad Sci U S A. 2000;  97 1566-1571
• 22 Kong Y Y, Yoshida H, Sarosi I, Tan H L, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos A J, Van G, Itie A, Khoo W, Wakeham A, Dunstan C R, Lacey D L, Mak T W, Boyle W J, Penninger J M. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis.  Nature. 1999;  397 315-323
• 23 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 1260-1268
• 24 Daroszewska A, Ralston S H. Mechanisms of disease: genetics of Paget's disease of bone and related disorders.  Nat Clin Pract Rheumatol. 2006;  2 270-277
• 25 Fata J E, Kong Y Y, Li J, Sasaki T, Irie-Sasaki J, Moorehead R A, Elliott R, Scully S, Voura E B, Lacey D L, Boyle W J, Khokha R, Penninger J M. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development.  Cell. 2000;  103 41-50
• 26 Koga T, Inui M, Inoue K, Kim S, Suematsu A, Kobayashi E, Iwata T, Ohnishi H, Matozaki T, Kodama T, Taniguchi T, Takayanagi H, Takai T. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis.  Nature. 2004;  428 758-763
• 27 Mocsai A, Humphrey M B, Van Ziffle J A, Hu Y, Burghardt A, Spusta S C, Majumdar S, Lanier L L, Lowell C A, Nakamura M C. The immunomodulatory adapter proteins DAP 12 and Fc receptor gamma-chain (FcRgamma) regulate development of functional osteoclasts through the Syk tyrosine kinase.  Proc Natl Acad Sci USA. 2004;  101 6158-6163
• 28 Kawai T, Matsuyama T, Hosokawa Y, Makihira S, Seki M, Karimbux N Y, Goncalves R B, Valverde P, Dibart S, Li Y P, Miranda L A, Ernst C W, Izumi Y, Taubman M A. B and T lymphocytes are the primary sources of RANKL in the bone resorptive lesion of periodontal disease.  Am J Pathol. 2006;  169 987-998
• 29 Teng Y T, Nguyen H, Gao X, Kong Y Y, Gorczynski R M, Singh B, Ellen R P, Penninger J M. Functional human T-cell immunity and osteoprotegerin ligand control alveolar bone destruction in periodontal infection.  J Clin Invest. 2000;  106 R59-67
• 30 Valverde P, Kawai T, Taubman M A. Potassium channel-blockers as therapeutic agents to interfere with bone resorption of periodontal disease.  J Dent Res. 2005;  84 488-499
• 31 Nukaga J, Kobayashi M, Shinki T, Song H, Takada T, Takiguchi T, Kamijo R, Hasegawa K. Regulatory effects of interleukin-1 beta and prostaglandin E 2 on expression of receptor activator of nuclear factor-kappaB ligand in human periodontal ligament cells.  J Periodontol. 2004;  75 249-259
• 32 Wada N, Maeda H, Yoshimine Y, Akamine A. Lipopolysaccharide stimulates expression of osteoprotegerin and receptor activator of NF-kappa B ligand in periodontal ligament fibroblasts through the induction of interleukin-1 beta and tumor necrosis factor-alpha.  Bone. 2004;  35 629-635
• 33 Lam J, Takeshita S, Barker J E, Kanagawa O, Ross F P, Teitelbaum S L. TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand.  J Clin Invest. 2000;  106 1481-1488
• 34 Wei S, Kitaura H, Zhou P, Ross F P, Teitelbaum S L. IL-1 mediates TNF-induced osteoclastogenesis.  J Clin Invest. 2005;  115 282-290
• 35 Hikita A, Yana I, Wakeyama H, Nakamura M, Kadono Y, Oshima Y, Nakamura K, Seiki M, Tanaka S. Negative regulation of osteoclastogenesis by ectodomain shedding of receptor activator of NF-kappaB ligand.  J Biol Chem. 2006;  281 36846-36855
• 36 Mogi M, Otogoto J, Ota N, Togari A. Differential expression of RANKL and osteoprotegerin in gingival crevicular fluid of patients with periodontitis.  J Dent Res. 2004;  83 166-169
• 37 Oshiro T, Shiotani A, Shibasaki Y, Sasaki T. Osteoclast induction in periodontal tissue during experimental movement of incisors in osteoprotegerin-deficient mice.  Anat Rec. 2002;  266 218-225
• 38 Kanzaki H, Chiba M, Arai K, Takahashi I, Haruyama N, Nishimura M, Mitani H. Local RANKL gene transfer to the periodontal tissue accelerates orthodontic tooth movement.  Gene Ther. 2006;  13 678-685
• 39 Kanzaki H, Chiba M, Takahashi I, Haruyama N, Nishimura M, Mitani H. Local OPG gene transfer to periodontal tissue inhibits orthodontic tooth movement.  J Dent Res. 2004;  83 920-925
• 40 Low E, Zoellner H, Kharbanda O P, Darendeliler M A. Expression of mRNA for osteoprotegerin and receptor activator of nuclear factor kappa beta ligand (RANKL) during root resorption induced by the application of heavy orthodontic forces on rat molars.  Am J Orthod Dentofacial Orthop. 2005;  128 497-503
• 41 Lossdorfer S, Gotz W, Jager A. Immunohistochemical localization of receptor activator of nuclear factor kappaB (RANK) and its ligand (RANKL) in human deciduous teeth.  Calcif Tissue Int. 2002;  71 45-52
• 42 Fukushima H, Kajiya H, Takada K, Okamoto F, Okabe K. Expression and role of RANKL in periodontal ligament cells during physiological root-resorption in human deciduous teeth.  Eur J Oral Sci. 2003;  111 346-352
• 43 Yamaguchi M, Aihara N, Kojima T, Kasai K. RANKL increase in compressed periodontal ligament cells from root resorption.  J Dent Res. 2006;  85 751-756
• 44 Nishijima Y, Yamaguchi M, Kojima T, Aihara N, Nakajima R, Kasai K. Levels of RANKL and OPG in gingival crevicular fluid during orthodontic tooth movement and effect of compression force on releases from periodontal ligament cells in vitro.  Orthod Craniofac Res. 2006;  9 63-70
• 45 Kawasaki K, Takahashi T, Yamaguchi M, Kasai K. Effects of aging on RANKL and OPG levels in gingival crevicular fluid during orthodontic tooth movement.  Orthod Craniofac Res. 2006;  9 137-142
• 46 Uematsu S, Mogi M, Deguchi T. Interleukin (IL)-1 beta, IL-6, tumor necrosis factor-alpha, epidermal growth factor, and beta 2-microglobulin levels are elevated in gingival crevicular fluid during human orthodontic tooth movement.  J Dent Res. 1996;  75 562-567
• 47 Basaran G, Ozer T, Kaya F A, Kaplan A, Hamamci O. Interleukine-1 beta and tumor necrosis factor-alpha levels in the human gingival sulcus during orthodontic treatment.  Angle Orthod. 2006;  76 830-836
• 48 Basaran G, Ozer T, Kaya F A, Hamamci O. Interleukins 2, 6, and 8 levels in human gingival sulcus during orthodontic treatment.  Am J Orthod Dentofacial Orthop. 2006;  130 7 ,  e 1-e 6
• 49 Hamaya M, Mizoguchi I, Sakakura Y, Yajima T, Abiko Y. Cell death of osteocytes occurs in rat alveolar bone during experimental tooth movement.  Calcif Tissue Int. 2002;  70 117-126
• 50 Verna C, Dalstra M, Lee T C, Melsen B. Microdamage in porcine alveolar bone due to functional and orthodontic loading.  Eur J Morphol. 2005;  42 3-11
• 51 McClung M R, Lewiecki E M, Cohen S B, Bolognese M A, Woodson G C, Moffett A H, Peacock M, Miller P D, Lederman S N, Chesnut C H, Lain D, Kivitz A J, Holloway D L, Zhang C, Peterson M C, Bekker P J. Denosumab in postmenopausal women with low bone mineral density.  N Engl J Med. 2006;  354 821-831
• 52 Body J J, Facon T, Coleman R E, Lipton A, Geurs F, Fan M, Holloway D, Peterson M C, Bekker P J. A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer.  Clin Cancer Res. 2006;  12 1221-1228
• 53 Schett G, Hayer S, Zwerina J, Redlich K, Smolen J S. Mechanisms of disease: the link between RANKL and arthritic bone disease.  Nat Clin Pract Rheumatol. 2005;  1 47-54
• 54 Adachi H, Igarashi K, Mitani H, Shinoda H. Effects of topical administration of a bisphosphonate (risedronate) on orthodontic tooth movements in rats.  J Dent Res. 1994;  73 1478-1486
• 55 Stark T M, Sinclair P M. Effect of pulsed electromagnetic fields on orthodontic tooth movement.  Am J Orthod Dentofacial Orthop. 1987;  91 91-104
• 56 Kale S, Kocadereli I, Atilla P, Asan E. Comparison of the effects of 1,25 dihydroxycholecalciferol and prostaglandin E 2 on orthodontic tooth movement.  Am J Orthod Dentofacial Orthop. 2004;  125 607-614