title: Porphyromonas gingivalis-derived lysine gingipain enhances osteoclast differentiation induced by tumor necrosis factor-α and interleukin-1β but suppresses that by interleukin-17A: importance of proteolytic degradation of osteoprotegerin by lysine gingipain.
abstract: Periodontitis is a chronic inflammatory disease accompanied by alveolar bone resorption by osteoclasts. Porphyromonas gingivalis, an etiological agent for periodontitis, produces cysteine proteases called gingipains, which are classified based on their cleavage site specificity (i.e. arginine (Rgps) and lysine (Kgps) gingipains). We previously reported that Kgp degraded osteoprotegerin (OPG), an osteoclastogenesis inhibitory factor secreted by osteoblasts, and enhanced osteoclastogenesis induced by various Toll-like receptor (TLR) ligands (Yasuhara, R., Miyamoto, Y., Takami, M., Imamura, T., Potempa, J., Yoshimura, K., and Kamijo, R. (2009) Lysine-specific gingipain promotes lipopolysaccharide- and active-vitamin D3-induced osteoclast differentiation by degrading osteoprotegerin. Biochem. J. 419, 159-166). Osteoclastogenesis is induced not only by TLR ligands but also by proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-17A, in inflammatory conditions, such as periodontitis. Although Kgp augmented osteoclastogenesis induced by TNF-α and IL-1β in co-cultures of mouse osteoblasts and bone marrow cells, it suppressed that induced by IL-17A. In a comparison of proteolytic degradation of these cytokines by Kgp in a cell-free system with that of OPG, TNF-α and IL-1β were less susceptible, whereas IL-17A and OPG were equally susceptible to degradation by Kgp. These results indicate that the enhancing effect of Kgp on cytokine-induced osteoclastogenesis is dependent on the difference in degradation efficiency between each cytokine and OPG. In addition, elucidation of the N-terminal amino acid sequences of OPG fragments revealed that Kgp primarily cleaved OPG in its death domain homologous region, which might prevent dimer formation of OPG required for inhibition of receptor activator of nuclear factor κB ligand. Collectively, our results suggest that degradation of OPG by Kgp is a crucial event in the development of osteoclastogenesis and bone loss in periodontitis.
authors.affiliation: From the Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan, the Department of Prosthodontics, School of Dentistry, Showa University, Tokyo 142-8555, Japan.
authors.forename: Tomohito
authors.initials: T
authors.lastname: Akiyama
authors.affiliation: From the Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan, yoichim@dent.showa-u.ac.jp.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: From the Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yoshimura
authors.affiliation: From the Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamada
authors.affiliation: From the Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Takami
authors.affiliation: From the Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Suzawa
authors.affiliation: From the Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan, the Department of Prosthodontics, School of Dentistry, Showa University, Tokyo 142-8555, Japan.
authors.forename: Marie
authors.initials: M
authors.lastname: Hoshino
authors.affiliation: the Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Tokyo 142-8555, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Imamura
authors.affiliation: the Department of Molecular Pathology, Faculty of life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Akiyama
authors.affiliation: the Department of Molecular Pathology, Faculty of life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Yasuhara
authors.affiliation: the Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Tokyo 142-8555, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Mishima
authors.affiliation: From the Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan, the Department of Prosthodontics, School of Dentistry, Showa University, Tokyo 142-8555, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Maruyama
authors.affiliation: the Department of Microbiology, School of Medicine, Showa University, Tokyo 142-8555, Japan.
authors.forename: Chikara
authors.initials: C
authors.lastname: Kohda
authors.affiliation: the Department of Microbiology, School of Medicine, Showa University, Tokyo 142-8555, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: the Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, 30-387 Krakow, Poland, the Oral Health and Systemic Diseases Group, University of Louisville School of Dentistry, Louisville, Kentucky 40202, and.
authors.forename: Jan
authors.initials: J
authors.lastname: Potempa
authors.affiliation: the Bioindustry Division, Oriental Yeast Company Ltd., Tokyo 174-8505, Japan.
authors.forename: Hisataka
authors.initials: H
authors.lastname: Yasuda
authors.affiliation: the Department of Prosthodontics, School of Dentistry, Showa University, Tokyo 142-8555, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Baba
authors.affiliation: From the Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Kamijo
mesh_terms: D018829:Adhesins, Bacterial / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D021461:Animals, Outbred Strains; D016866:Bacteroidaceae Infections / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D000080867:Gingipain Cysteine Endopeptidases; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D053244:Osteoprotegerin / Q000378:metabolism*; D010518:Periodontitis / Q000378:metabolism*; D016966:Porphyromonas gingivalis / Q000201:enzymology*; D053245:RANK Ligand / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018829:Adhesins, Bacterial; D000080867:Gingipain Cysteine Endopeptidases; D020381:Interleukin-17; D053583:Interleukin-1beta; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; D014409:Tumor Necrosis Factor-alpha; D003546:Cysteine Endopeptidases
keywords: Cell Differentiation; Cytokine; Gingipain; Inflammation; Osteoclast; Osteoprotegerin; Proteolytic Enzyme
references.citation: Periodontol 2000. 2010 Oct;54(1):15-44
references.pmid: 20712631
references.citation: J Periodontal Res. 1997 Jan;32(1 Pt 1):61-8
references.pmid: 9085244
references.citation: J Biol Chem. 1998 Mar 20;273(12):6611-4
references.pmid: 9506956
references.citation: Infect Immun. 1999 Jun;67(6):2804-9
references.pmid: 10338484
references.citation: Cell. 1998 Apr 17;93(2):165-76
references.pmid: 9568710
references.citation: Immunol Rev. 2005 Dec;208:181-93
references.pmid: 16313349
references.citation: J Periodontol. 2003 Mar;74(3):391-401
references.pmid: 12710761
references.citation: J Biol Chem. 2005 Dec 16;280(50):41155-64
references.pmid: 16215261
references.citation: J Biol Chem. 1994 Jan 7;269(1):406-11
references.pmid: 8276827
references.citation: J Periodontal Res. 2009 Aug;44(4):565-7
references.pmid: 18717779
references.citation: Ann N Y Acad Sci. 2006 Apr;1068:225-33
references.pmid: 16831922
references.citation: Biochemistry. 1967 Aug;6(8):2378-88
references.pmid: 6049463
references.citation: Cell. 1997 Apr 18;89(2):309-19
references.pmid: 9108485
references.citation: Infect Immun. 2004 Mar;72(3):1706-14
references.pmid: 14977979
references.citation: Infect Immun. 2002 May;70(5):2480-6
references.pmid: 11953385
references.citation: J Cell Biochem. 2003 Feb 1;88(2):259-66
references.pmid: 12520524
references.citation: J Dent Res. 2011 Sep;90(9):1052-61
references.pmid: 21248364
references.citation: Gene. 1991 Dec 15;108(2):193-9
references.pmid: 1660837
references.citation: Biochem J. 2009 Apr 1;419(1):159-66
references.pmid: 19102726
references.citation: Exp Cell Res. 1999 Feb 25;247(1):84-93
references.pmid: 10047450
references.citation: J Periodontol. 2003 Jan;74(1):111-8
references.pmid: 12593605
references.citation: Oral Microbiol Immunol. 2009 Feb;24(1):11-7
references.pmid: 19121064
references.citation: Nat Immunol. 2012 Mar 25;13(5):465-73
references.pmid: 22447028
references.citation: J Clin Invest. 1999 May;103(9):1345-52
references.pmid: 10225978
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3597-602
references.pmid: 9520411
references.citation: J Dent Res. 2001 Oct;80(10):1875-9
references.pmid: 11706944
references.citation: J Periodontol. 2008 Aug;79(8 Suppl):1569-76
references.pmid: 18673012
references.citation: Calcif Tissue Int. 2013 Feb;92(2):77-98
references.pmid: 22782502
references.citation: Arthritis Rheum. 2004 Jan;50(1):277-90
references.pmid: 14730626
references.citation: Biochem Biophys Res Commun. 1999 Aug 11;261(3):598-602
references.pmid: 10441472
references.citation: Endocrinology. 1998 Mar;139(3):1329-37
references.pmid: 9492069
references.citation: Methods Enzymol. 1997;282:223-35
references.pmid: 9330291
references.citation: J Dent Res. 2011 Oct;90(10):1164-70
references.pmid: 21471325
references.citation: Biol Chem. 1997 Mar-Apr;378(3-4):223-30
references.pmid: 9165075
references.citation: J Immunol. 2004 Feb 15;172(4):2504-10
references.pmid: 14764723
references.citation: J Oral Sci. 2011 Sep;53(3):263-71
references.pmid: 21959652
references.citation: J Dent Res. 2007 May;86(5):446-50
references.pmid: 17452566
references.citation: J Clin Invest. 2005 Feb;115(2):282-90
references.pmid: 15668736
references.citation: J Oral Microbiol. 2011 Jan 17;3:
references.pmid: 21547019
references.citation: Endocr Rev. 1999 Jun;20(3):345-57
references.pmid: 10368775
references.citation: Mol Microbiol. 1997 Jun;24(6):1179-87
references.pmid: 9218767
references.citation: Infect Immun. 2007 Mar;75(3):1436-42
references.pmid: 17220315
references.citation: J Biol Chem. 1998 Feb 27;273(9):5117-23
references.pmid: 9478964