Osteoclastogenesis in Periodontitis: Signaling Pathway, Synthetic and Natural Inhibitors
Abstract
Osteoclast activities are responsible for the resorption of bone cells found in several bone diseases, one of which is periodontitis and arthritis. The downregulating signals of Receptor Activator of Nuclear Factor kB (RANK)-RANK Ligand and Tumor Necrosis Factor (TNF)-a are the major cause of the bone destruction. Studies and experiments have been performed to overcome this matter. Various medications are now available to treat bone-related diseases, targeting the specific aspect of the signaling. Synthetic drugs such as denosumab and bisphosphonates have complex pharmacological action and have been the leading choice in treatment. Evidence in studies proved that natural resources including herbal products have potential application to therapy for bone loss, with caffeic acid and Caffeic Acid Phenethyl Ester (CAPE) showing significant inhibitory results and Chinese herbs such as Herba epimedii (Yín Yáng Huò) and Fructus psoraleae(Bǔ Gǔ Zhī) proved to contain components that give similar effects to estrogen. The purpose of this review is to discuss the therapy value of available synthetic and natural therapeutic agents. Understanding the mechanisms of both agents will not only clarify their function as therapeutic agents, but can also be the key to the treatment of diseases caused by bone resorption by targeting specific aspects of osteoclastogenesis.
Keywords: osteoclastogenesis, TNF, RANKL, bone resorption, natural resource, signaling, treatment
Full Text:
PDFReferences
Patil CS, Kirkwood KL. MAPK P38 MAPK Signaling in Oral-Related Diseases. J Dent Res. 2007; 86(9): 812-25. CrossRef
Thouverey C, Caverzasio J. Focus on The P38 MAPK Signaling Pathway in Bone Development and Maintenance. Bonekey Rep. 2015; 4: 711. doi: 10.1038/Bonekey.2015.80. CrossRef
Putnam SE, Scutt AM, Bicknell K, Priestley CM, Williamson EM. Natural Products as Alternative Treatments for Metabolic Bone Disorders and for Maintenance of Bone Health. Phytother Res. 2007; 21(2): 99-112. CrossRef
Sandra F, Kukita T, Tang QY, Iijima T. Cafeic Acid Inhibits NFkappab Activation of Osteoclastogenesis Signaling Pathway. Indones Biomed J. 2011; 3(3): 216-22. CrossRef
Park CK, Kim HJ, Kwak HB, Lee TH, Bang MH, Kim CM, et al. Inhibitory Effects of Stewartia koreana on Osteoclast Differentiation and Bone Resorption. Int Immunopharmacol. 2007; 7(12): 1507-16. CrossRef
Fadanelli ME, Bone HG. Combining Bisphosphonates with Hormone Therapy for Postmenopausal Osteoporosis. Treat Endocrinol. 2004; 3(6): 361-9. CrossRef
Miyazaki T, Tokimura F, Tanaka S. A Review of Denosumab for The Treatment of Osteoporosis. Patient Prefer Adherence. 2014; 8: 463-71. CrossRef
Revu S, Neregård P, Klint E, Korotkova M, Catrina AI. Synovial Membrane Immunohistology in Early-Untreated Rheumatoid Arthritis Reveals High Expression of Catabolic Bone Markers That is Modulated by Methotrexate. Arthritis Res Ther. 2013; 15(6): 1-10. CrossRef
Kwak HB, Kim JY, Kim KJ, Choi MK, Kim JJ, Kim KM, et al. Risedronate Directly Inhibits Osteoclast Differentiation and Inflammatory Bone Loss. Biol Pharm Bull. 2009; 32(7): 1193-8. CrossRef
Barbato L, Francioni E, Bianchi M, Mascitelli E, Brancato L, Duvina M, et al. Periodontitis and Bone Metabolism. Clin Cases Miner Bone Metab. 2015; 12(2): 174-7. CrossRef
Gruber R. Cell Biology of Osteoimmunology. Wien Med Wochenschr. 2010; 160(17-18): 438-45. CrossRef
Sandra F, Hendarmin L, Nakamura S. Osteoprotegerin (OPG) Binds with Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL): Suppression of TRAIL-Induced Apoptosis in Ameloblastomas. Oral Oncol. 2006; 42(2): 415-20. CrossRef
Kukita A, Ichigi Y, Takigawa I, Watanabe T, Kukita T, Miyamoto H. Infection of RANKL-Primed RAW-D Macrophages with Porphyromonas Gingivalis Promotes Osteoclastogenesis in A TNFa-Independent Manner. Plos One. 2012; 7(6): 1-12. doi:10.1371/Journal.Pone.0038500. CrossRef
Kim JH, Kim N. Signaling Pathways in Osteoclast Differentiation. Chonnam Med J. 2016; 52(1): 12-7. CrossRef
Soysa NS, Alles N, Aoki K, Ohya K. Osteoclast Formation and Differentiation: An Overview. J Med Dent Sci. 2012; 59(3): 65-74. Link
Chambers TJ. Regulation of The Differentiation and Function of Osteoclasts. J Pathol. 2000; 192(1): 4-13. CrossRef
Boyce BF, Xing L. Functions Of RANKL/RANK/OPG in Bone Modeling and Remodeling. Arch Biochem Biophys. 2008; 473(2): 139–46. CrossRef
Bell NH. RANK Ligand and The Regulation of Skeletal Remodeling. J Clin Invest. 2003; 111(8): 1120-2. CrossRef
Boyle WJ, Simonet WS, Lacey DL. Osteoclast Differentiation and Activation. Nature. 2003; 423(6937): 337-42. CrossRef
Kim N, Kadono Y, Takami M, Lee J, Lee SH, Okada F, et al. Osteoclast Differentiation Independent of The TRANCE-RANK-TRAF6 Axis. J Exp Med. 2005; 202(5): 589-95. CrossRef
Kobayashi N, Kadono Y, Naito A, Matsumoto K, Yamamoto T, Tanaka S, et al. Segregation of TRAF6-Mediated Signaling Pathways Clarifies Its Role in Osteoclastogenesis. EMBO J. 2001; 20(6): 1271-80. CrossRef
Kawamura N, Kugimiya F, Oshima Y, Ohba S, Ikeda T, Saito T, et al. Akt1 in Osteoblasts and Osteoclasts Controls Bone Remodeling. Plos One. 2007; 2(10): 1-11. CrossRef
Maruotti N, Grano M, Colucci S. Osteoclastogenesis and Arthritis. Clin Exp Med. 2011; 11(3): 137-45. CrossRef
Wada T, Nakashima T, Hiroshi N, Penninger JM. RANKL-RANK Signaling in Osteoclastogenesis and Bone Disease. Trends Mol Med. 2006; 12(1): 17-25. CrossRef
Aliprantis AO, Ueki Y, Sulyanto R, Park A, Sigrist KS, Sharma SM, et al. NFATc1 in Mice Represses Osteoprotegerin During Osteoclastogenesis and Dissociates Systemic Osteopenia From Inflammation in Cherubism. J Clin Invest. 2008; 118(11): 3775-89. CrossRef
Walsh MC, Choi Y. Biology of The RANKL-RANK-OPG System In Immunity, Bone, And Beyond. Front Immunol. 2014; 5: 1-11. doi: 10.3389/fimmu.2014.00511. CrossRef
Ding X, Boney-Montoya J, Owen BM, Bookout AL, Coate C, Mangelsdorf DJ, et al. Βklotho is Required for Fibroblast Growth Factor 21 Effects on Growth and Metabolism. Cell Metab. 2012; 16(3): 387-93. CrossRef
Weitzmann MN, Pacifici R. The Role of T Lymphocytes in Bone Metabolism. Immunol Rev. 2005; 208: 154-68. CrossRef
Wu L, Guo Q, Yang J, Ni B. Tumor Necrosis Factor Alpha Promotes Osteoclast Formation via PI3K/Akt Pathway-Mediated Blimp1 Expression Upregulation. J Cell Biochem. 2016; 118(6): 1308-15. CrossRef
Koga T, Kodama T, Ochi S, Shinohara M, Sato K, Takai T, et al. Pathological Role of Osteoclast Costimulation in Arthritis-Induced Bone Loss. PNAS. 2007; 104(27): 11394-9. CrossRef
Faccio R, Takeshita S, Zallone A, Ross F, Teitelbaum S. C-Fms and The Αvβ3 Integrin Collaborate During Osteoclast Differentiation. J Clin Invest. 2003; 111(5): 749-58. CrossRef
Catrina AI, Trollmo C, Klint E, Engstrom M, Lampa J, Hermansson Y, et al. Evidence That Anti-tumor Necrosis Factor Therapy with Both Etanercept and Infliximab Induces Apoptosis in Macrophages, but Not Lymphocytes, in Rheumatoid Arthritis Joints Extended Report. Arthritis Rheum. 2005; 52(1): 61-72. CrossRef
Pers J, Saraux A, Pierre R, Youinou P. Anti-TNF-a Immunotherapy is Inflammation without Clinical Attachment Loss in Subjects with Rheumatoid Arthritis. J Periodontol. 2008; 79(9): 1645-51. CrossRef
Yamashita T, Takahashi N, Udagawa N. New Roles of Osteoblasts Involved in Osteoclast Differentiation. 2012; 3(11): 175-81. CrossRef
Ross F. M-CSF, C-Fms, and Signaling in Osteoclasts and Their Precursors. Ann NY Acad Sci. 2006; 1068(1): 110-6. 81. CrossRef
Newton A. Protein Kinase C: Structural and Spatial Regulation by Phosphorylation, Cofactors, and Macromolecular Interactions. Chem Rev. 2001; 101(8): 2353-64. CrossRef
Russell RGG. Pharmacological Diversity A-mong Drugs That Inhibit Bone Resorption. Curr Opin Pharmacol. 2015; 22: 115-30. CrossRef
Drake MT, Clarke BL, Khosla S. Bisphosphonates: Mechanism of Action and Role in Clinical Practice. Mayo Clin Proc. 2008; 83(9): 1032-45. CrossRef
Kim YH, Kim G, Baek JH. Inhibitory Action of Bisphosphonates on Bone Resorption Does Not Involve The Regulation Of RANKL and OPG Expression. Exp Mol Med. 2002; 34(2): 145-51. CrossRef
Watts NB, Diab DL. Long-Term Use of Bisphosphonates in Osteoporosis. J Clin Endocrinol Metab. 2010; 95(4): 1555-65. CrossRef
Kim H, Ha H, Lee J, Jung K, Yang D, Woo KM, et al. Trichostatin A Inhibits Osteoclastogenesis and Bone Resorption by Suppressing The Induction of C-Fos By RANKL. Eur J Pharmacol. 2009; 623(1-3): 22-9. CrossRef
Yi T, Baek J. Trichostatin A-Mediated Upregulation of P21 Osteoclast Apoptosis. Exp Mol Med. 2007; 39(2): 213-21. CrossRef
Vigushin DM, Ali S, Pace PE, Mirsaidi N, Ito K, Adcock I, et al. Trichostatin A is A Histone Deacetylase Inhibitor with Potent Antitumor Activity Against Breast Cancer in vivo. Clin Cancer Res. 2001; 7(4): 971-6. Link
Lopez-Olivo MA, Siddhanamatha HR, Shea B, Tugwell P, Wells GA, Suarez-Almazor ME. Methotrexate for Treating Rheumatoid Arthritis. Cochrane Database Syst Rev. 2014; (6): CD000957. doi: 10.1002/14651858.CD000957.pub2. CrossRef
Deeming GMJ, Collingwood J, Pemberton MN. Methotrexate and Oral Ulceration. Br Dent J. 2005; 198(2): 83-5. CrossRef
Lewiecki EM, Miller PD, Mcclung MR, Cohen SB, Bolognese MA, Liu Y, et al. Two-Year Treatment with Denosumab (AMG 162) in A Randomized Phase 2 Study of Postmenopausal Women with Low BMD. Journals Bone Miner Res. 2007; 22(12): 1832-41. CrossRef
Quan YT, Kukita T, Ushijima Y, Kukita A, Nagata K, Sandra F, et al. Regulation of Osteoclastogenesis by Simon Extracts Composed of Caffeic Acid and Related Compounds: Successful Suppression of Bone Destruction Accompanied with Adjuvant-Induced Arthritis in Rats. Histochem Cell Biol. 2006; 125(3): 215-25. CrossRef
Ha J, Choi H, Lee Y, Lee ZH, Kim H. International Immunopharmacology Caffeic Acid Phenethyl Ester Inhibits Osteoclastogenesis by Suppressing NFκB and Downregulating NFATc1 And C-Fos. Int Immunopharmacol; 2009; 9(6): 774-80. CrossRef
Mirabeau TY, Samson ES. Effect of Allium Cepa and Allium Sativum on Some Immunological Cells in Rats. Afr J Tradit Complement Altern Med. 2012; 9(3): 374-9. CrossRef
Tang C, Huang T, Chang C, Fu W. Water Solution of Onion Crude Powder Inhibits RANKL-Induced Osteoclastogenesis Through ERK, P38 and NFκB Pathways. Osteoporos Int. 2009; 20(1): 93-103. CrossRef
Silva T, Oliveira C, Borges F. Caffeic Acid Derivatives, Analogs and Applications: A Patent Review. Expert Opin Ther Patents. 2014; 24(11): 1257-70. CrossRef
Sandra F, Kukita T, Muta T, Iijima T. Caffeic Acid Inhibited Receptor Activator of Nuclear Factor Κb Ligand (RANKL)-Tumor Necrosis Factor (TNF)a-TNF Receptor Associated Factor (TRAF)6-induced Osteoclastogenesis Pathway. Indones Biomed J. 2013; 5(3): 173-8. CrossRef
Sandra F, Sidharta MA. Caffeic Acid Induced Apoptosis in MG63 Osteosarcoma Cells Through Activation of Caspases. Mol Cell Biomed Sci. 2017; 1(1): 28-33. CrossRef
Kuo Y, Jim W, Su L, Chung C, Lin C. Caffeic Acid Phenethyl Ester is A Potential Therapeutic Agent For Oral Cancer. Int J Mol Sci. 2015; 16(5): 10748-66. CrossRef
Ang ESM, Pavlos NJ, Chai LY, Qi M, Cheng TS, Steer JH, et al. Caffeic Acid Phenethyl Ester, An Active Component of Honeybee Propolis Attenuates Osteoclastogenesis and Bone Resorption via The Suppression of RANKL-Induced NFkB and NFAT Activity. J Cell Physiol. 2009; 221(3): 642-9. CrossRef
Hung MW, Shiao MS, Tsai LC, Chang GG, Chang TC. Apoptotic Effect of Caffeic Acid Phenethyl Ester and Its Ester and Amide Analogues in Human Cervical Cancer ME180 Cells. Anticancer Res. 2003; 23(6C): 4773-80. Link
Weaver CM, Alekel L, Ward WE, Ronis MJ. Flavonoid Intake and Bone Health Connie. J Nutr Gerontol Geriatr. 2012; 31(3): 239-53. CrossRef
Taku K, Melby MK, Nishi N, Omori T, Kurzer MS. Soy Isoflavones for Osteoporosis: An Evidence-Based Approach. Maturitas. 2011; 70(4): 333-8. CrossRef
Kostelac D, Rechkemmer G, Briviba K. Phytoestrogens Modulate Binding Response of Estrogen Receptors Alpha and Beta to The Estrogen Response Element. J Agric Food Chem. 2003; 51(26): 7632-5. CrossRef
Karieb S, Fox SW. Phytoestrogens Directly Inhibit TNF-Α-Induced Bone Resorption in RAW264.7 Cells by Suppressing C-Fos-Induced NFATc1 Expression. J Cell Biochem. 2011; 112(2): 476-87. CrossRef
Bharti AC, Takada Y, Aggarwal BB. Curcumin (Diferuloylmethane) Inhibits Receptor Activator of NF-kB Ligand-Induced NFkB Activation in Osteoclast Precursors and Suppresses Osteoclastogenesis. J Immunol. 2004; 172(10): 5940-7. CrossRef
Leung P, Siu W. Herbal Treatment for Osteoporosis: A Current Review. J Tradit Complement Med. 2013; 3(2): 82-7. CrossRef
Shim K, Lee C, Yim N, Ha H, Ma JY. A Water Extract of Malva Verticillata Seeds Suppresses Osteoclastogenesis and Bone Resorption Stimulated by RANK Ligand. BMC Complement Altern Med. 2016; 16(1): 332. doi: 10.1186/S12906-016-1295-6. CrossRef
DOI: https://doi.org/10.21705/mcbs.v2i1.16
Copyright (c) 2018 Cell and BioPharmaceutical Institute
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Indexed by:
Cell and BioPharmaceutical Institute
