Palavras-chave
doença periodontal
RANK
RANKL
OPG
RANK
RANKL
OPG
Como Citar
Reabsorção óssea na doença periodontal: o papel de rank, rankl e opg. Uma revisão da literatura. (2022). Odontoestomatología, 24(40), 1-13. https://doi.org/10.22592/ode2022n40e316
Resumo
A periodontite é uma das doenças bucais mais prevalentes, o estudo de sua patogênese avançou muito nos últimos anos, porém, os detalhes dos mecanismos envolvidos na reabsorção óssea ainda não estão esclarecidos.
RANK, RANKL e OPG são proteínas que possuem papel conhecido em outras doenças do tecido ósseo, neste trabalho foram revisadas as evidências de sua possível participação na patogênese da doença periodontal. Mais evidências são necessárias para entender a relação entre RANK, RANKL, OPG e reabsorção óssea associada à periodontite.
Referências
1. Kinane D, Peterson M, Stathopoulou P. Environmental and other modifying factors of the periodontal diseases. Periodontol 2000 2006; 40(1):107-119.
2. Page RC., Schroeder HE. Pathogenesis of inflammatory periodontal disease. A summary of current work. Lab Invest 1976;33:235-249.
3. Graves DT, Cochran D. The contribution of interleukin-1 and tumor necrosis factor to periodontal tissue destruction. J Periodontol 2003;74:391-401.
4. Garlet GP, Cardoso CR, Silva TA, et al. Cytokine pattern determines the progression of experimental periodontal disease induced by Actinobacillus actinomycetemcomitans through the modulation of MMPs, RANKL, and their physiological inhibitors. Oral Microbiol Immunol 2006;21:12-20.
5. Cochran, DL. Inflammation and bone loss in periodontal disease. J Periodontol 2008;79(8):1569- 1576.
6. Simonet, W. S., Lacey, D. L., Dunstan, C. R., Kelley, M., Chang, M. S., Luthy, R., et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997;89: 309–319.
7. Schwartz Z, Goultschin J, Dean D, Boyan B. Mechanisms of alveolar bone destruction in periodontitis. Periodontol 2000 1997;14(1):158-172.
8. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;15:337– 342.
9. Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, Yasuda H, Yano K et al. RANK Is the Essential Signaling Receptor for Osteoclast Differentiation Factor in Osteoclastogenesis. Biochemical and Biophysical Research Communications. 1998;253(2):395-400.
10. Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E, et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci U S A 1999; 96(7): 3540–3545.
11. Shalhoub V, Elliott G, Chiu L, Manoukian R, Kelley M, Hawkins N, Davi E, Shimamoto G, Beck J, Kaufman SA, Van G, Scully S, Qi M, Grisanti M, Dunstan C, Boyle WJ, Lacey DL. Characterization of osteoclast precursors in human blood. Br J Haematology. 2008;111(2):501-512.
12. Anderson D, Maraskovsky E, Billingsley W, Dougall W, Tometsko M, Roux E et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 1997;390(6656):175-179.
13. Bharti A, Aggarwal B. Ranking the role of RANK ligand in apoptosis. Apoptosis. 2004;9(6):677- 690.
14- Giannopoulou C, Martinelli-Klay C, Lombardi T. Immunohistochemical expression of RANKL, RANK and OPG in gingival tissue of patients with periodontitis.Acta Odontol Scand 2012;70(6):629- Odontoestomatología. 2022, 24 9 634.
15- Xiong J, O’Brien C. Osteocyte RANKL: new insights into the control of bone remodeling. J Bone Miner Res 2012;27(3):499-505.
16- Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, Bonewald LF, Kodama T, Wutz A, Wagner EF, Penninger JM, Takayanagi H. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 2011;17:1231–1234.
17- Rodan GA, Martin TJ. Role of osteoblasts in hormonal control of bone resorption—a hypothesis. Calcif Tissue Int 1981;33:349–51.
18- Takahashi N, Akatsu T, Udagawa N, Sasaki T, Yamaguchi A, Moseley JM, Martin TJ, Suda T. Osteoblastic cells are involved in osteoclast formation. Endocrinology 1988;123:2600–2.
19- Udagawa N, Takahashi N, Akatsu T, Sasaki T, Yamaguchi A, Kodama H, Martin TJ, Suda T. The bone marrow-derived stromal cell lines MC3T3-G2/PA6 and ST2 support osteoclast-like cell differentiation in cocultures with mouse spleen cells. Endocrinology 1989;125: 1805–13.
20- Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998;93:165–76.
21- 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 U S A 1998;95:3597–3602.
22- Xiong, J. O´Brien, C. Osteocyte RANKL: New insights into the control of bone remodeling. J Bon Min Res 2012;27(3):499-505.
23- Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O’Brien CA. Matrix-embedded cells control osteoclast formation. Nat Med 2011;17:1235–41.
24- Choi Y, Mi Woo K, Ko S, Jung Lee Y, Park S, Kim H et al. Osteoclastogenesis is enhanced by activated B cells but suppressed by activated CD8+ T cells. Eur J Immunol 2001;31(7):2179-2188.
25- Kawai, T., Matsuyama, T., Hosokawa, Y., Makihira, S., Seki, M., Karimbux, N. Y., et al. 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.
26-Liu D, Xu JK, Figliomeni L, et al. Expression of RANKL and OPG mRNA in periodontal disease: Possible involvement in bone destruction. Int J Mol Med 2003;11:17-21.
27- Kanamaru F, Iwai H, Ikeda T, Nakajima A, Ishikawa I, Azuma M. Expression of membrane-bound and soluble receptor activator of NF-kappaB ligand (RANKL) in human T cells. Immunol Lett 2004: 94:239–246.
28- Teng YT, Nguyen H, Gao X, Kong YY, Gorczynski RM, Singh B, Ellen RP, Penninger JM. Functional human T-cell immunity and osteoprotegerin ligand control alveolar bone destruction in periodontal infection. J Clin Invest 2000: 106: R59–R67.
29- Nagasawa T, Kobayashi H, Kiji M, Aramaki M, Mahanonda R, Kojima T, Murakami Y, Saito M, Morotome Y, Ishikawa I. LPS-stimulated human gingival fibroblasts inhibit the differentiation of monocytes into osteoclasts through the production of osteoprotegerin. Clin Exp Immunol 2002:130: 338–344.
30- Han X, Kawai T, Eastcott JW, Taubman MA. Bacterial-responsive B lymphocytes induce periodontal bone resorption. J Immunol 2006;176:625–631.
31- Kawai T, Matsuyama T, Hosokawa Y, Makihira S, Seki M, Karimbux NY, et al. 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.
32- Vernal R, Dutzan N, Hernández M, Chandía S, Puente J, León R et al. High Expression Levels of Receptor Activator of Nuclear Factor-Kappa B Ligand Associated With Human Chronic Periodontitis Are Mainly Secreted by CD4+T Lymphocytes. J Periodontol 2006;77(10):1772-1780.
33- Belibasakis G, Bostanci N, Hashim A, Johansson A, Aduse-Opoku J, Curtis M et al. Regulation of RANKL and OPG gene expression in human gingival fibroblasts and periodontal ligament cells by Porphyromonas gingivalis: A putative role of the Arg-gingipains. Microb Pathog 2007;43(1):46-53.
34- Kajiya M, Giro G, Taubman M, Han X, Mayer M, Kawai T. Role of periodontal pathogenic bacteria in RANKL-mediated bone destruction in periodontal disease. J Oral Microbiol 2010;2(1):5532.
35- Ernst CW, Lee JE, Nakanishi T, Karimbux NY, Rezende TM, Stashenko P, et al. Diminished forkhead box P3/CD25 doublepositive T regulatory cells are associated with the increased nuclear factor-kappaB ligand (RANKL) T cells in bone resorption lesion of periodontal disease. Clin Exp Immunol 2007;148: 271-280.
36- Belibasakis, GN. Reddi, D. Bostanci, N. Porphyromonas gingivalis induces RANKL in T cells. Inflammation 2011;34(2):133-138.
37- Chen B, Wu W, Sun W, Zhang Q, Yan F, Xiao Y. RANKL Expression in Periodontal Disease: Where Does RANKL Come from?. Biomed Res Int 2014;2014:1-7.
38- Mackler B, Frostad K, Robertson P, Levy B. Immunoglobulin bearing lymphocytes and plasma cells in human periodontal disease. J Periodont Res 1977;12(1):37-45.
39- Seymour G, Greenspan J. The phenotypic characterization of lymphocyte subpopulations in established human periodontal disease. J Periodont Res 1979;14(1):39-46.
40- Ebersole, JL. Taubman, MA. Smith, DJ. Genco, RJ. Frey, DE. Human inmune responses to oral micro-organisms. I. Association of localized juvenile periodontitis (LJP) with serum antibody responses to actinobacillus actinomycetencomitans. Clin exp immunol 1982; 47,43-52.
41- Mouton, C. Hammond, PG. Slots, J. Genco, RJ. Serum antibodies to oral bactericides asaccharolyticus (Bacteroides gingival): relationship to age and periodontal disease. Infect Immun 1981: 182-192
42- Tew J, Marshall D, Moore W, Best A, Palcanis K, Ranney R. Serum antibody reactive with predominant organisms in the subgingival flora of young adults with generalized severe periodontitis. Infect Immun 1985;48(2):303-311.
43- Taubman M, Yoshie H, Ebersole J, Smith D, Olson C. Host Response in Experimental Periodontal Disease. J Dent Res 1984;63(3):455-460.
44- Yoshie H, Taubman M, Ebersole J, Smith D, Olson C. Periodontal bone loss and immune characteristics of congenitally athymic and thymus cell-reconstituted athymic rats. Infect Immun 1985;50(2):403- 408.
45- Harada Y, Han X, Yamashita K, Kawai T, Eastcott JW, Smith DJ, Taubman MA: Effect of adoptive transfer of antigen-specific B cells on periodontal bone resorption. J Periodont Res 2006; 41:101–107.
46- Crotti T, Smith MD, Hirsch R, Soukoulis S, Weedon H, Capone M, Ahern MJ, Haynes D. Receptor activator NF jB ligand (RANKL) and osteoprotegerin (OPG) protein expression in periodontitis. J Periodont Res 2003;38; 380–387.
47- Dereka, XE. Markopoulou, CE. Fanourakis, G. Tseleni-Balafouta, S. Vrotsos, A. RANKL and OPG mRNA level after non-surgical periodontal treatment. Inflammation 2010, 33(3): 200-206.
48- Nagasawa, T. Kiji, M. Yashiro, R. Hromdee, D. He, L. Kunze, M. Suda, T. Koshy, G. Kobayashi, K. Oda, S. Nitta, H. Ishikawa, I. Roles of receptor activator nuclear factor-kb ligando (RANKL) and osteoprotegerin in periodontal health and disease. Periodontol 2000 2007;43:65-84.
49- Collin-Osdoby, PC. Rothe, L. Anderson, F. Nelson, M. Maloney, W. Osdoby, P. Receptor activator of NF-kb and osteoprotegerin expression by human microvascular endothelial cells regulations by inflammatory citoquines and role in human osteoclastogenesis. J Biol Chem 2001;276(23): 20659– 20672.
50- Zannettino, ACW. Holding, CA. Diamond, P. Atkins, GJ. Kostakis, P. Farrugia, A. Gamble, J. TO, LB. Findlay, DM. Haynes, DR. Osteoprotegerin (OPG) is localized to the weibel.palade bodies of human vascular endothelial cells and is physically associated with von willebrand factor. J Cell Physiol 2005; 204:714–723.
51- Zhang, J. Fu, M. Myles, D. Zhu, X. Du, J. Cao, X. Che., YE. PDGF induces osteoprotegerin expression in vascular smooth muscle cells by multiple signal pathways. Febs Lett 2002; 521:180-184.
52- Collin-Osdoby, P. Regulation of vascular calcification by osteoclasts regulatory factors RANKL and osteoprotegerin. Circ Res 2004;95:1046-1057.
53- Cohen, BE. Hohensinner, PJ. Kaun, C. Maurer, G. Huber, K. Wojta, J. Stains decrease TNF-alpha-induced osteoprotegerin production by endothelial cells and smooth muscle cells in vitro. Biochem Pharmacol 2007;73(1):77-83.
54- Zauli, G. Corallini, F. Bossi, F. Fischetti, F. Durigutto, P. Celeghini, C. Tedesco, F. Secchiero, P. Osteoprotegerin increases leukocyte adhesion to endothelial cells both in vitro and in vivo. Blood 2007;110(2):536-43.
55- Sakata, M. Shiba, H. Komatsuzawa, H. Fujita, T. Ohta, K. Sugai, M. Suginaka, H. Kurihara, H. Expression of osteoprotegerin (osteoclastogenesis inhibitory factor) in cultures of human dental mesenchymal cells and epithelial cells. J Bone Miner Res 1999;14(9):1486-1492.
56- Lu H-K, Chen Y-L, Chang H-C, Li C-L, Kuo MY-P. Identification of the OPG/ RANKL system in gingival crevicular fluid and tissue of patients with chronic periodontitis. J Periodont Res 2006;41:354–360.
57- Lacey DL, Boyle WJ, Simonet WS, Kostenuik PJ, Dougall WC, Sullivan JK, et al. Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. Nat Rev Drug Discov 2012;11(5):401–419.
58- Nakashima, T. Hayashi, M. Takayanagi, H. New insights into osteoclastogenic signaling mechanisms. Trends Endocrinológicos Metab 2012 Nov;23(11):582-90.
59- Wen, S. Beltran, V. Chaparro, A. Espinoza, F. Reidemann, JP. ¿La periodontitis crónica modifica la morbilidad de la artritis reumatoide?: aspectos clínicos y moleculares. Una revisión sistemática. Rev Med Chile 2019;147:762-775.
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61- Walsh, NC. Crotti, TN. Goldring, SR. Gravallese, EM. Rheumatic diseases: the effects of inflammation on bone. Immunol Rev 2005; 208: 228–251
62- Matsuyama, T. Kawai, T. Izumi, Y. Taubman, MA. Expression of major histocompatibility complex class II and CD80 by gingival epithelial cells induces activation of CD4 T cells in response to bacterial challenge. Infect Immun 2005;73(2):1044-1051.
63- Gibertoni, F. Sommer, MEL. Esquisatto, MAM. Amaral, MECD. Olivera, CA. Andrade, TAM. Mendoca, FAC. Santamria, M Jr. Felonato, M. Evolution of periodontal disease: immune response and RANK/ RANKL/OPG system. Braz Dent J 2017 28(6):679-687.
64- Bostancı N, I_lgenli T, Emingil G, Afacan B, Han B, ToÅNz H, Berdeli A, Atilla G, McKay IJ, Hughes FJ, Belibasakis GN. Differential expression of receptor activator of nuclear factor-jB ligand and osteoprotegerin mRNA in periodontal diseases. J Periodont Res 2007; 42: 287–293.
2. Page RC., Schroeder HE. Pathogenesis of inflammatory periodontal disease. A summary of current work. Lab Invest 1976;33:235-249.
3. Graves DT, Cochran D. The contribution of interleukin-1 and tumor necrosis factor to periodontal tissue destruction. J Periodontol 2003;74:391-401.
4. Garlet GP, Cardoso CR, Silva TA, et al. Cytokine pattern determines the progression of experimental periodontal disease induced by Actinobacillus actinomycetemcomitans through the modulation of MMPs, RANKL, and their physiological inhibitors. Oral Microbiol Immunol 2006;21:12-20.
5. Cochran, DL. Inflammation and bone loss in periodontal disease. J Periodontol 2008;79(8):1569- 1576.
6. Simonet, W. S., Lacey, D. L., Dunstan, C. R., Kelley, M., Chang, M. S., Luthy, R., et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997;89: 309–319.
7. Schwartz Z, Goultschin J, Dean D, Boyan B. Mechanisms of alveolar bone destruction in periodontitis. Periodontol 2000 1997;14(1):158-172.
8. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;15:337– 342.
9. Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, Yasuda H, Yano K et al. RANK Is the Essential Signaling Receptor for Osteoclast Differentiation Factor in Osteoclastogenesis. Biochemical and Biophysical Research Communications. 1998;253(2):395-400.
10. Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E, et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci U S A 1999; 96(7): 3540–3545.
11. Shalhoub V, Elliott G, Chiu L, Manoukian R, Kelley M, Hawkins N, Davi E, Shimamoto G, Beck J, Kaufman SA, Van G, Scully S, Qi M, Grisanti M, Dunstan C, Boyle WJ, Lacey DL. Characterization of osteoclast precursors in human blood. Br J Haematology. 2008;111(2):501-512.
12. Anderson D, Maraskovsky E, Billingsley W, Dougall W, Tometsko M, Roux E et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 1997;390(6656):175-179.
13. Bharti A, Aggarwal B. Ranking the role of RANK ligand in apoptosis. Apoptosis. 2004;9(6):677- 690.
14- Giannopoulou C, Martinelli-Klay C, Lombardi T. Immunohistochemical expression of RANKL, RANK and OPG in gingival tissue of patients with periodontitis.Acta Odontol Scand 2012;70(6):629- Odontoestomatología. 2022, 24 9 634.
15- Xiong J, O’Brien C. Osteocyte RANKL: new insights into the control of bone remodeling. J Bone Miner Res 2012;27(3):499-505.
16- Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, Bonewald LF, Kodama T, Wutz A, Wagner EF, Penninger JM, Takayanagi H. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 2011;17:1231–1234.
17- Rodan GA, Martin TJ. Role of osteoblasts in hormonal control of bone resorption—a hypothesis. Calcif Tissue Int 1981;33:349–51.
18- Takahashi N, Akatsu T, Udagawa N, Sasaki T, Yamaguchi A, Moseley JM, Martin TJ, Suda T. Osteoblastic cells are involved in osteoclast formation. Endocrinology 1988;123:2600–2.
19- Udagawa N, Takahashi N, Akatsu T, Sasaki T, Yamaguchi A, Kodama H, Martin TJ, Suda T. The bone marrow-derived stromal cell lines MC3T3-G2/PA6 and ST2 support osteoclast-like cell differentiation in cocultures with mouse spleen cells. Endocrinology 1989;125: 1805–13.
20- Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998;93:165–76.
21- 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 U S A 1998;95:3597–3602.
22- Xiong, J. O´Brien, C. Osteocyte RANKL: New insights into the control of bone remodeling. J Bon Min Res 2012;27(3):499-505.
23- Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O’Brien CA. Matrix-embedded cells control osteoclast formation. Nat Med 2011;17:1235–41.
24- Choi Y, Mi Woo K, Ko S, Jung Lee Y, Park S, Kim H et al. Osteoclastogenesis is enhanced by activated B cells but suppressed by activated CD8+ T cells. Eur J Immunol 2001;31(7):2179-2188.
25- Kawai, T., Matsuyama, T., Hosokawa, Y., Makihira, S., Seki, M., Karimbux, N. Y., et al. 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.
26-Liu D, Xu JK, Figliomeni L, et al. Expression of RANKL and OPG mRNA in periodontal disease: Possible involvement in bone destruction. Int J Mol Med 2003;11:17-21.
27- Kanamaru F, Iwai H, Ikeda T, Nakajima A, Ishikawa I, Azuma M. Expression of membrane-bound and soluble receptor activator of NF-kappaB ligand (RANKL) in human T cells. Immunol Lett 2004: 94:239–246.
28- Teng YT, Nguyen H, Gao X, Kong YY, Gorczynski RM, Singh B, Ellen RP, Penninger JM. Functional human T-cell immunity and osteoprotegerin ligand control alveolar bone destruction in periodontal infection. J Clin Invest 2000: 106: R59–R67.
29- Nagasawa T, Kobayashi H, Kiji M, Aramaki M, Mahanonda R, Kojima T, Murakami Y, Saito M, Morotome Y, Ishikawa I. LPS-stimulated human gingival fibroblasts inhibit the differentiation of monocytes into osteoclasts through the production of osteoprotegerin. Clin Exp Immunol 2002:130: 338–344.
30- Han X, Kawai T, Eastcott JW, Taubman MA. Bacterial-responsive B lymphocytes induce periodontal bone resorption. J Immunol 2006;176:625–631.
31- Kawai T, Matsuyama T, Hosokawa Y, Makihira S, Seki M, Karimbux NY, et al. 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.
32- Vernal R, Dutzan N, Hernández M, Chandía S, Puente J, León R et al. High Expression Levels of Receptor Activator of Nuclear Factor-Kappa B Ligand Associated With Human Chronic Periodontitis Are Mainly Secreted by CD4+T Lymphocytes. J Periodontol 2006;77(10):1772-1780.
33- Belibasakis G, Bostanci N, Hashim A, Johansson A, Aduse-Opoku J, Curtis M et al. Regulation of RANKL and OPG gene expression in human gingival fibroblasts and periodontal ligament cells by Porphyromonas gingivalis: A putative role of the Arg-gingipains. Microb Pathog 2007;43(1):46-53.
34- Kajiya M, Giro G, Taubman M, Han X, Mayer M, Kawai T. Role of periodontal pathogenic bacteria in RANKL-mediated bone destruction in periodontal disease. J Oral Microbiol 2010;2(1):5532.
35- Ernst CW, Lee JE, Nakanishi T, Karimbux NY, Rezende TM, Stashenko P, et al. Diminished forkhead box P3/CD25 doublepositive T regulatory cells are associated with the increased nuclear factor-kappaB ligand (RANKL) T cells in bone resorption lesion of periodontal disease. Clin Exp Immunol 2007;148: 271-280.
36- Belibasakis, GN. Reddi, D. Bostanci, N. Porphyromonas gingivalis induces RANKL in T cells. Inflammation 2011;34(2):133-138.
37- Chen B, Wu W, Sun W, Zhang Q, Yan F, Xiao Y. RANKL Expression in Periodontal Disease: Where Does RANKL Come from?. Biomed Res Int 2014;2014:1-7.
38- Mackler B, Frostad K, Robertson P, Levy B. Immunoglobulin bearing lymphocytes and plasma cells in human periodontal disease. J Periodont Res 1977;12(1):37-45.
39- Seymour G, Greenspan J. The phenotypic characterization of lymphocyte subpopulations in established human periodontal disease. J Periodont Res 1979;14(1):39-46.
40- Ebersole, JL. Taubman, MA. Smith, DJ. Genco, RJ. Frey, DE. Human inmune responses to oral micro-organisms. I. Association of localized juvenile periodontitis (LJP) with serum antibody responses to actinobacillus actinomycetencomitans. Clin exp immunol 1982; 47,43-52.
41- Mouton, C. Hammond, PG. Slots, J. Genco, RJ. Serum antibodies to oral bactericides asaccharolyticus (Bacteroides gingival): relationship to age and periodontal disease. Infect Immun 1981: 182-192
42- Tew J, Marshall D, Moore W, Best A, Palcanis K, Ranney R. Serum antibody reactive with predominant organisms in the subgingival flora of young adults with generalized severe periodontitis. Infect Immun 1985;48(2):303-311.
43- Taubman M, Yoshie H, Ebersole J, Smith D, Olson C. Host Response in Experimental Periodontal Disease. J Dent Res 1984;63(3):455-460.
44- Yoshie H, Taubman M, Ebersole J, Smith D, Olson C. Periodontal bone loss and immune characteristics of congenitally athymic and thymus cell-reconstituted athymic rats. Infect Immun 1985;50(2):403- 408.
45- Harada Y, Han X, Yamashita K, Kawai T, Eastcott JW, Smith DJ, Taubman MA: Effect of adoptive transfer of antigen-specific B cells on periodontal bone resorption. J Periodont Res 2006; 41:101–107.
46- Crotti T, Smith MD, Hirsch R, Soukoulis S, Weedon H, Capone M, Ahern MJ, Haynes D. Receptor activator NF jB ligand (RANKL) and osteoprotegerin (OPG) protein expression in periodontitis. J Periodont Res 2003;38; 380–387.
47- Dereka, XE. Markopoulou, CE. Fanourakis, G. Tseleni-Balafouta, S. Vrotsos, A. RANKL and OPG mRNA level after non-surgical periodontal treatment. Inflammation 2010, 33(3): 200-206.
48- Nagasawa, T. Kiji, M. Yashiro, R. Hromdee, D. He, L. Kunze, M. Suda, T. Koshy, G. Kobayashi, K. Oda, S. Nitta, H. Ishikawa, I. Roles of receptor activator nuclear factor-kb ligando (RANKL) and osteoprotegerin in periodontal health and disease. Periodontol 2000 2007;43:65-84.
49- Collin-Osdoby, PC. Rothe, L. Anderson, F. Nelson, M. Maloney, W. Osdoby, P. Receptor activator of NF-kb and osteoprotegerin expression by human microvascular endothelial cells regulations by inflammatory citoquines and role in human osteoclastogenesis. J Biol Chem 2001;276(23): 20659– 20672.
50- Zannettino, ACW. Holding, CA. Diamond, P. Atkins, GJ. Kostakis, P. Farrugia, A. Gamble, J. TO, LB. Findlay, DM. Haynes, DR. Osteoprotegerin (OPG) is localized to the weibel.palade bodies of human vascular endothelial cells and is physically associated with von willebrand factor. J Cell Physiol 2005; 204:714–723.
51- Zhang, J. Fu, M. Myles, D. Zhu, X. Du, J. Cao, X. Che., YE. PDGF induces osteoprotegerin expression in vascular smooth muscle cells by multiple signal pathways. Febs Lett 2002; 521:180-184.
52- Collin-Osdoby, P. Regulation of vascular calcification by osteoclasts regulatory factors RANKL and osteoprotegerin. Circ Res 2004;95:1046-1057.
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