SOCS2 regulates alveolar bone loss in Aggregatibacter actinomycetemcomitans-induced periodontal disease.

Publisher: Birkhäuser Country of Publication: Switzerland NLM ID: 9508160 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1420-908X (Electronic) Linking ISSN: 10233830 NLM ISO Abbreviation: Inflamm Res Subsets: MEDLINE

Original Publication: Basel, Switzerland : Birkhäuser, c1995-

Alveolar Bone Loss*/genetics ; Periodontal Diseases*/metabolism; Mice ; Animals ; Aggregatibacter actinomycetemcomitans/metabolism ; Mice, Inbred C57BL ; Osteoclasts/metabolism ; Cytokines/metabolism ; Suppressor of Cytokine Signaling Proteins/genetics ; Suppressor of Cytokine Signaling Proteins/metabolism

Introduction: The role of suppressor of cytokine signaling 2 (SOCS2) in Aggregatibacter actinomycetemcomitans (Aa)-induced alveolar bone loss is unknown; thus, it was investigated in this study.
Methods: Alveolar bone loss was induced by infecting C57BL/6 wild-type (WT) and Socs2-knockout (Socs2 ^-/- ) mice with Aa. Bone parameters, bone loss, bone cell counts, the expression of bone remodeling markers, and cytokine profile were evaluated by microtomography, histology, qPCR, and/or ELISA. Bone marrow cells (BMC) from WT and Socs2 ^-/- mice were differentiated in osteoblasts or osteoclasts for analysis of the expression of specific markers.
Results: Socs2 ^-/- mice intrinsically exhibited irregular phenotypes in the maxillary bone and an increased number of osteoclasts. Upon Aa infection, SOCS2 deficiency resulted in the increased alveolar bone loss, despite decreased proinflammatory cytokine production, in comparison to the WT mice. In vitro, SOCS2 deficiency resulted in the increased osteoclasts formation, decreased expression of bone remodeling markers, and proinflammatory cytokines after Aa-LPS stimulus.
Conclusions: Collectively, data suggest that SOCS2 is a regulator of Aa-induced alveolar bone loss by controlling the differentiation and activity of bone cells, and proinflammatory cytokines availability in the periodontal microenvironment and an important target for new therapeutic strategies. Thus, it can be helpful in preventing alveolar bone loss in periodontal inflammatory conditions.
(© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Åberg CH, Kelk P, Johansson A. Aggregatibacter actinomycetemcomitans: virulence of its leukotoxin and association with aggressive periodontitis. Virulence. 2015;6(3):188–95. (PMID: 2549496310.4161/21505594.2014.982428)
Mark Bartold P, Van Dyke TE. Host modulation: controlling the inflammation to control the infection. Periodontol 2000. 2017;75(1):317–29. (PMID: 2875829910.1111/prd.12169)
Haubek D, Johansson A. Pathogenicity of the highly leukotoxic JP2 clone of Aggregatibacter actinomycetemcomitans and its geographic dissemination and role in aggressive periodontitis. J Oral Microbiol. 2014;14:6.
Monasterio G, Castillo F, Ibarra JP, Guevara J, Rojas L, Alvarez C, et al. Alveolar bone resorption and TH1/TH17-associated immune response triggered during Aggregatibacter actinomycetemcomitans-induced experimental periodontitis are serotype-dependent. J Periodontol. 2018;89(10):1249–61. (PMID: 3003084510.1002/JPER.17-0563)
De Souza JAC, Nogueira AVB, De Souza PPC, Cirelli JA, Garlet GP, Rossa C. Expression of suppressor of cytokine signaling 1 and 3 in ligature-induced periodontitis in rats. Arch Oral Biol. 2011;56(10):1120–8. (PMID: 2151124910.1016/j.archoralbio.2011.03.022)
Inagaki-Ohara K, Yoshimura A. SOCS, inflammation and metabolism. JAKSTAT. 2013;2(3): e24053. (PMID: 240695503772102)
Rakesh K, Agrawal DK. Controlling cytokine signaling by constitutive inhibitors. Biochem Pharmacol. 2005;70(5):649–57. (PMID: 1593672810.1016/j.bcp.2005.04.042)
Fox SW, Haque SJ, Lovibond AC, Chambers TJ. The possible role of TGF-β-induced suppressors of cytokine signaling expression in osteoclast/macrophage lineage commitment In Vitro. J Immunol. 2003;170(7):3679–87. (PMID: 1264663310.4049/jimmunol.170.7.3679)
Santos MRG, Queiroz-Junior CM, Madeira MFM, Machado FS. Suppressors of cytokine signaling (SOCS) proteins in inflammatory bone disorders. Bone. 2020;140: 115538. (PMID: 3273092610.1016/j.bone.2020.115538)
Letellier E, Haan S. SOCS2: physiological and pathological functions. Front Biosci - Elit. 2016;8(1):189–204. (PMID: 10.2741/e760)
Machado FS, Johndrow JE, Esper L, Dias A, Bafica A, Serhan CN, et al. Anti-inflammatory actions of lipoxin A4 and aspirin-triggered lipoxin are SOCS-2 dependent. Nat Med. 2006;12(3):330–4. (PMID: 1641587710.1038/nm1355)
Esper L, Roman-Campos D, Lara A, Brant F, Castro LL, Barroso A, et al. Role of SOCS2 in modulating heart damage and function in a murine model of acute Chagas disease. Am J Pathol. 2012;181(1):130–40. (PMID: 22658486338816610.1016/j.ajpath.2012.03.042)
Brant F, Miranda AS, Esper L, Gualdrón-López M, Cisalpino D, de Souza DDG, et al. Suppressor of cytokine signaling 2 modulates the immune response profile and development of experimental cerebral malaria. Brain Behav Immun. 2016;54:73–85. (PMID: 2676599710.1016/j.bbi.2016.01.002)
Cramer A, Galvão I, de Sá NV, Gaio P, de Melo Oliveira NF, Rates Gonzaga Santos M, et al. Role of Suppressor of cytokine signaling 2 during the development and resolution of an experimental arthritis. Cell Immunol. 2022;372:104476. (PMID: 3503375210.1016/j.cellimm.2021.104476)
Gaio P, Gualdrón-López M, Cramer A, Esper L, de Menezes Filho JER, Cruz JS, et al. SOCS2 expression in hematopoietic and non-hematopoietic cells during Trypanosoma cruzi infection: correlation with immune response and cardiac dysfunction. Clin Immunol. 2022;234: 108913. (PMID: 3495434710.1016/j.clim.2021.108913)
Monti-Rocha R, Cramer A, Leite PG, Antunes MM, Pereira RVS, Barroso A, et al. SOCS2 is critical for the balancing of immune response and oxidate stress protecting against acetaminophen-induced acute liver injury. Front Immunol. 2019;9:3134. (PMID: 30723477634969410.3389/fimmu.2018.03134)
Cramer A, De Lima Oliveira BC, Leite PG, Rodrigues DH, Brant F, Esper L, et al. Role of SOCS2 in the regulation of immune response and development of the experimental autoimmune encephalomyelitis. Mediators Inflamm. 2019;2019:1872593. (PMID: 31949423694291310.1155/2019/1872593)
Zadjali F, Santana-Farre R, Vesterlund M, Carow B, Mirecki-Garrido M, Hernandez-Hernandez I, et al. SOCS2 deletion protects against hepatic steatosis but worsens insulin resistance in high-fat-diet-fed mice. FASEB J. 2012;26(8):3282–91. (PMID: 2256283310.1096/fj.12-205583)
Val CH, de Oliveira MC, Lacerda DR, Barroso A, Batista NV, Menezes-Garcia Z, et al. SOCS2 modulates adipose tissue inflammation and expansion in mice. J Nutr Biochem. 2020;76: 108304. (PMID: 3181656110.1016/j.jnutbio.2019.108304)
Garlet GP, Cardoso CR, Campanelli AP, Martins W, Silva JS. Expression of suppressors of cytokine signaling in diseased periodontal tissues: a stop signal for disease progression? J Periodontal Res. 2006;41(6):580–4. (PMID: 1707678510.1111/j.1600-0765.2006.00908.x)
Madeira MFM, Queiroz-Junior CM, Costa GM, Werneck SMC, Cisalpino D, Garlet GP, et al. Platelet-activating factor receptor blockade ameliorates Aggregatibacter actinomycetemcomitans-induced periodontal disease in mice. Infect Immun. 2013;81(11):4244–51. (PMID: 24002061381184510.1128/IAI.01046-13)
Queiroz-Junior CM, Madeira MFM, Coelho FM, Costa VV, Bessoni RLC, da Cunha Sousa LF, et al. Experimental arthritis triggers periodontal disease in mice: Involvement of TNF-α and the oral microbiota. J Immunol. 2011;187(7):3821–30. (PMID: 2189065610.4049/jimmunol.1101195)
Arirachakaran P, Apinhasmit W, Paungmalit P, Jeramethakul P, Rerkyen P, Mahanonda R. Infection of human gingival fibroblasts with Aggregatibacter actinomycetemcomitans: an in vitro study. Arch Oral Biol. 2012;57(7):964–72. (PMID: 2234859210.1016/j.archoralbio.2012.01.014)
He D et al. Mechanical load-induced H 2 S production by periodontal ligament stem cells activates M1 macrophages to promote bone remodeling and tooth movement via STAT1. Stem Cell Res Ther 2020;11:112. https://doi.org/10.1186/s13287-020-01607-9. (PMID: 10.1186/s13287-020-01607-9321691047071778)
Yamashita T, Yao Z, Li F, Zhang Q, Badell IR, Schwarz EM, et al. NF-κB p50 and p52 regulate receptor activator of NF-κB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1. J Biol Chem. 2007;282(25):18245–53. (PMID: 1748546410.1074/jbc.M610701200)
Walsh MC, Lee J, Choi Y. Tumor necrosis factor receptor- associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system. Immunol Rev. 2015;266(1):72–92. (PMID: 26085208479983510.1111/imr.12302)
Zhou A, Yu H, Liu J, Zheng J, Jia Y, Wu B, et al. Role of hippo-YAP signaling in osseointegration by regulating osteogenesis, angiogenesis, and osteoimmunology. Front Cell Dev Biol. 2020;8:780. (PMID: 32974339746666510.3389/fcell.2020.00780)
Alvarez C, Monasterio G, Cavalla F, Córdova LA, Hernández M, Heymann D, et al. Osteoimmunology of oral and maxillofacial diseases: translational applications based on biological mechanisms. Front Immunol. 2019;10:1664. (PMID: 31379856665767110.3389/fimmu.2019.01664)
Metcalf D, Greenhalgh CJ, Viney E, Wilison TA, Starr R, Nicola NA, et al. Gigantism in mice lacking suppressor of cytokine signalling-2. Nature. 2000;405(6790):1069–73. (PMID: 1089045010.1038/35016611)
Lorentzon M, Greenhalgh CJ, Mohan S, Alexander WS, Ohlsson C. Reduced bone mineral density in SOCS-2-deficient mice. Pediatr Res. 2005;57(2):223–6. (PMID: 1558568210.1203/01.PDR.0000148735.21084.D3)
Chaves De Souza JA, Nogueira AVB, Chaves De Souza PP, Kim YJ, Silva Lobo C, Lopes De Oliveira GJP, et al. SOCS3 expression correlates with severity of inflammation, expression of proinflammatory cytokines, and activation of STAT3 and p38 MAPK in LPS-induced inflammation in vivo. Mediators Inflamm. 2013. https://doi.org/10.1155/2013/650812 . (PMID: 10.1155/2013/650812240787763775441)
Ali M, Kucko N, Jansen JA, Yang F, Walboomers XF. The effect of lipoxin A4 on E. coli LPS-induced osteoclastogenesis. Clin Oral Investig. 2020;25(3):957–69. (PMID: 32506323787823910.1007/s00784-020-03385-3)
Cui K, Tang Z, Li CC, Wang T, Rao K, Wang SG, et al. Lipoxin A4 improves erectile dysfunction in rats with type i diabetes by inhibiting oxidative stress and corporal fibrosis. Asian J Androl. 2018;20(2):166–72. (PMID: 2911154110.4103/aja.aja_49_17)
Ponzetti M, Rucci N. Updates on osteoimmunology: what’s new on the cross-talk between bone and immune system. Front Endocrinol (Lausanne). 2019;18(10):236. (PMID: 10.3389/fendo.2019.00236)
Kodama J, Kaito T. Osteoclast multinucleation: review of current literature. Int J Mol Sci. 2020;21(16):5685. (PMID: 32784443746104010.3390/ijms21165685)
Chakravarti A, Raquil MA, Tessier P, Poubelle PE. Surface RANKL of Toll-like receptor 4-stimulated human neutrophils activates osteoclastic bone resorption. Blood. 2009;114(8):1633–44. (PMID: 1954647910.1182/blood-2008-09-178301)
Hajishengallis G. New developments in neutrophil biology and periodontitis. Periodontol. 2000;82(1):78–92. (PMID: 10.1111/prd.12313)
Hayashi T, Kaneda T, Toyama Y, Kumegawa M, Hakeda Y. Regulation of receptor activator of NF-κB ligand-induced osteoclastogenesis by endogenous interferon-β (INF-β) and suppressors of cytokine signaling (SOCS). The possible counteracting role of SOCSs in IFN-β-inhibited osteoclast formation. J Biol Chem. 2002;277(31):27880–6. (PMID: 1202397110.1074/jbc.M203836200)
Piessevaux J, Lavens D, Montoye T, Wauman J, Catteeuw D, Vandekerckhove J, et al. Functional cross-modulation between SOCS proteins can stimulate cytokine signaling. J Biol Chem. 2006;281(44):32953–66. (PMID: 1695689010.1074/jbc.M600776200)
Tannahill GM, Elliott J, Barry AC, Hibbert L, Cacalano NA, Johnston JA. SOCS2 can enhance interleukin-2 (IL-2) and IL-3 signaling by accelerating SOCS3 degradation. Mol Cell Biol. 2005;25(20):9115–26. (PMID: 16199887126577210.1128/MCB.25.20.9115-9126.2005)
Dif F, Saunier E, Demeneix B, Kelly PA, Edery M. Cytokine-inducible SH2-containing protein suppresses PRL signaling by binding the PRL receptor. Endocrinology. 2001;142(12):5286–93. (PMID: 1171322810.1210/endo.142.12.8549)
Lomaga MA, Yeh WC, Sarosi I, Duncan GS, Furlonger C, Ho A, et al. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev. 1999;13(8):1015–24. (PMID: 1021562831663610.1101/gad.13.8.1015)
McBerry C, Gonzalez RMS, Shryock N, Dias A, Aliberti J. SOCS2-induced proteasome-dependent TRAF6 degradation: a common anti-inflammatory pathway for control of innate immune responses. PLoS ONE. 2012;7(6): e38384. (PMID: 22693634336791410.1371/journal.pone.0038384)
Yu TY, Kondo T, Matsumoto T, Fujii-Kuriyama Y, Imai Y. Aryl hydrocarbon receptor catabolic activity in bone metabolism is osteoclast dependent in vivo. Biochem Biophys Res Commun. 2014;450(1):416–22. (PMID: 2493813010.1016/j.bbrc.2014.05.114)
Szymczyk KH, Freeman TA, Adams CS, Srinivas V, Steinbeck MJ. Active caspase-3 is required for osteoclast differentiation. J Cell Physiol. 2006;209(3):836–44. (PMID: 1697225610.1002/jcp.20770)
Izawa T, Arakaki R, Mori H, Tsunematsu T, Kudo Y, Tanaka E, et al. The nuclear receptor AhR controls bone homeostasis by regulating osteoclast differentiation via the RANK/c-Fos signaling Axis. J Immunol. 2016;197(12):4639–50. (PMID: 27849171513367110.4049/jimmunol.1600822)
Kinjyo I, Hanada T, Inagaki-Ohara K, Mori H, Aki D, Ohishi M, et al. SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity. 2002;17(5):583–91. (PMID: 1243336510.1016/S1074-7613(02)00446-6)
Kimura A, Naka T, Muta T, Takeuchi O, Akira S, Kawase I, et al. Suppressor of cytokine signaling-1 selectively inhibits LPS-induced IL-6 production by regulating JAK-STAT. Proc Natl Acad Sci U S A. 2005;102(47):17089–94. (PMID: 16287972128800410.1073/pnas.0508517102)
Huang S, Liu K, Cheng A, Wang M, Cui M, Huang J, et al. SOCS proteins participate in the regulation of innate immune response caused by viruses. Front Immunol. 2020;25(11): 558341. (PMID: 10.3389/fimmu.2020.558341)
Posselt G, Schwarz H, Duschl A, Horejs-Hoeck J. Suppressor of cytokine signaling 2 is a feedback inhibitor of TLR-induced activation in human monocyte-derived dendritic cells. J Immunol. 2011;187(6):2875–84. (PMID: 2184438910.4049/jimmunol.1003348)
Madeira MFM, Queiroz-Junior CM, Costa GM, Santos PC, Silveira EM, Garlet GP, et al. MIF induces osteoclast differentiation and contributes to progression of periodontal disease in mice. Microbes Infect. 2012;14(2):198–206. (PMID: 2201600710.1016/j.micinf.2011.09.005)

APQ-03606-17 National Institute for Science and Technology in Dengue and Host-microbial interactions; REDE-00140-16 Fundação de Amparo a Pesquisa de Minas Gerais; 408433/2018-3 Conselho Nacional de Desenvolvimento Científico e Tecnológico; 307981/2014-2 Conselho Nacional de Desenvolvimento Científico e Tecnológico

Keywords: Aggregatibacter actinomycetemcomitans; Immunoregulation; Osteoclastogenesis; Periodontitis; SOCS2

0 (Cytokines)
0 (Socs2 protein, mouse)
0 (Suppressor of Cytokine Signaling Proteins)

Date Created: 20230313 Date Completed: 20230427 Latest Revision: 20230427

20230427

10.1007/s00011-023-01711-5

36912916