Involvement of toll-like receptor 2 and 4 in association between dyslipidemia and osteoclast differentiation in apolipoprotein E deficient rat periodontium

Lipids in Health and Disease

Manabu Morita¹  Toshiki Yoneda¹  Kenta Kasuyama¹  Yasumasa Endo¹  Koichiro Irie¹  Tetsuji Azuma¹  Daisuke Ekuni¹  Takaaki Tomofuji¹ 

[1] Department of Preventive Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, 700-8558, Okayama, Kita-ku, Japan

关键词: Osteoclast differentiation;    Toll-like receptor 4;    Toll-like receptor 2;    Alveolar bone;    Apolipoprotein E-deficient model;   

Others  :  1160107
DOI  :  10.1186/1476-511X-12-1

 received in 2012-09-11, accepted in 2013-01-05,  发布年份 2013

【 摘 要 】

Background

Dyslipidemia increases circulating levels of oxidized low-density lipoprotein (OxLDL) and this may induce alveolar bone loss through toll-like receptor (TLR) 2 and 4. The purpose of this study was to investigate the effects of dyslipidemia on osteoclast differentiation associated with TLR2 and TLR4 in periodontal tissues using a rat dyslipidemia (apolipoprotein E deficient) model.

Methods

Levels of plasma OxLDL, and the cholesterol and phospholipid profiles in plasma lipoproteins were compared between apolipoprotein E-deficient rats (16-week-old males) and wild-type (control) rats. In the periodontal tissue, we evaluated the changes in TLR2, TLR4, receptor activator of nuclear factor kappa B ligand (RANKL) and tartrate resistant acid phosphatase (TRAP) expression.

Results

Apolipoprotein E-deficient rats showed higher plasma levels of OxLDL than control rats (p<0.05), with higher plasma levels of total cholesterol (p<0.05) and LDL-cholesterol (p<0.05) and lower plasma levels of high-density lipoprotein cholesterol (p<0.05). Their periodontal tissue also exhibited a higher ratio of RANKL-positive cells and a higher number of TRAP-positive osteoclasts than control rats (p<0.05). Furthermore, periodontal gene expression of TLR2, TLR4 and RANKL was higher in apolipoprotein E-deficient rats than in control rats (p<0.05).

Conclusion

These findings underscore the important role for TLR2 and TLR4 in mediating the osteoclast differentiation on alveolar bone response to dyslipidemia.

【 授权许可】

   
2013 Tomofuji et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Noack B, Jachmann I, Roscher S, Sieber L, Kopprasch S, Lück C, Hanefeld M, Hoffmann T: Metabolic diseases and their possible link to risk indicators of periodontitis. J Periodontol 2000, 71(6):898-903.
• [2]Fentoğlu Ö, Köroğlu BK, Hiçyılmaz H, Sert T, Özdem M, Sütçü R, Tamer MN, Orhan H, Ay ZY, Öztürk Tonguç M, Kırzıoğlu FY: Pro-inflammatory cytokine levels in association between periodontal disease and hyperlipidaemia. J Clin Periodontol 2011, 38(1):8-16.
• [3]Bastos AS, Graves DT, Loureiro AP, Rossa Júnior C, Abdalla DS, Faulin Tdo E, Olsen Câmara N, Andriankaja OM, Orrico SR: Lipid peroxidation is associated with the severity of periodontal disease and local inflammatory markers in patients with type 2 diabetes. J Clin Endocrinol Metab 2012, 97(8):E1353-E1362.
• [4]Oliveira HC, Cosso RG, Alberici LC, Maciel EN, Salerno AG, Dorighello GG, Velho JA, de Faria EC, Vercesi AE: Oxidative stress in atherosclerosis-prone mouse is due to low antioxidant capacity of mitochondria. FASEB J 2005, 19(2):278-280.
• [5]Vasconcelos EM, Degasperi GR, de Oliveira HC, Vercesi AE, de Faria EC, Castilho LN: Reactive oxygen species generation in peripheral blood monocytes and oxidized LDL are increased in hyperlipidemic patients. Clin Biochem 2009, 42(12):1222-1227.
• [6]Xu XH, Shah PK, Faure E, Equils O, Thomas L, Fishbein MC, Luthringer D, Xu XP, Rajavashisth TB, Yano J, Kaul S, Arditi M: Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL. Circulation 2001, 104(25):3103-3108.
• [7]Su X, Ao L, Shi Y, Johnson TR, Fullerton DA, Meng X: Oxidized low density lipoprotein induces bone morphogenetic protein-2 in coronary artery endothelial cells via Toll-like receptors 2 and 4. J Biol Chem 2011, 286(14):12213-12220.
• [8]Sun Y, Shu R, Li CL, Zhang MZ: Gram-negative periodontal bacteria induce the activation of Toll-like receptors 2 and 4, and cytokine production in human periodontal ligament cells. J Periodontol 2010, 81(10):1488-1496.
• [9]Ding PH, Wang CY, Darveau RP, Jin L: Porphyromonas gingivalis LPS stimulates the expression of LPS-binding protein in human oral keratinocytes in vitro. Innate Immun 2012. in press
• [10]Tang Y, Sun F, Li X, Zhou Y, Yin S, Zhou X: Porphyromonas endodontalis lipopolysaccharides induce RANKL by mouse osteoblast in a way different from that of Escherichia coli lipopolysaccharide. J Endod 2011, 37(12):1653-1658.
• [11]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(2):166-169.
• [12]Tomofuji T, Kusano H, Azuma T, Ekuni D, Yamamoto T, Watanabe T: Effects of a high-cholesterol diet on cell behavior in rat periodontitis. J Dent Res 2005, 84(8):752-756.
• [13]Sanbe T, Tomofuji T, Ekuni D, Azuma T, Tamaki N, Yamamoto T: Oral administration of vitamin C prevents alveolar bone resorption induced by high dietary cholesterol in rats. J Periodontol 2007, 78(11):2165-2170.
• [14]Sanbe T, Tomofuji T, Ekuni D, Azuma T, Irie K, Tamaki N, Yamamoto T, Morita M: Vitamin C intake inhibits serum lipid peroxidation and osteoclast differentiation on alveolar bone in rats fed on a high-cholesterol diet. Arch Oral Biol 2009, 54(3):235-240.
• [15]Bagavant H, Scindia Y, Nackiewicz D, Nandula SR, Doran A, Cutchins A, Oldham S, Deshmukh U, McNamara C: Deficiency of a transcriptional regulator, inhibitor of differentiation 3, induces glomerulonephritis in apolipoprotein E-deficient mice: a model linking hyperlipidemia and renal disease. Am J Pathol 2011, 179(2):651-660.
• [16]Ohshiro T, Matsuda D, Sakai K, Degirolamo C, Yagyu H, Rudel LL, Omura S, Ishibashi S, Tomoda H: Pyripyropene A, an acyl-coenzyme A:cholesterol acyltransferase 2-selective inhibitor, attenuates hypercholesterolemia and atherosclerosis in murine models of hyperlipidemia. Arterioscler Thromb Vasc Biol 2011, 31(5):1108-1115.
• [17]Lima LC, Porto ML, Campagnaro BP, Tonini CL, Nogueira BV, Pereira TM, Vasquez EC, Meyrelles SS: Mononuclear cell therapy reverts cuff-induced thrombosis in apolipoprotein E-deficient mice. Lipids Health Dis 2012, 11(1):96. BioMed Central Full Text
• [18]Kasuyama K, Tomofuji T, Ekuni D, Tamaki N, Azuma T, Irie K, Endo Y, Morita M: Hydrogen-rich water attenuates experimental periodontitis in a rat model. J Clin Periodontol 2011, 38(12):1085-1090.
• [19]Ekuni D, Tomofuji T, Endo Y, Kasuyama K, Irie K, Azuma T, Tamaki N, Mizutani S, Kojima A, Morita M: Hydrogen-rich water prevents lipid deposition in the descending aorta in a rat periodontitis model. Arch Oral Biol 2012. in press
• [20]Miida T, Seino U, Miyazaki O, Hanyu O, Hirayama S, Saito T, Ishikawa Y, Akamatsu S, Nakano T, Nakajima K, Okazaki M, Okada M: Probucol markedly reduces HDL phospholipids and elevated prebeta1-HDL without delayed conversion into alpha-migrating HDL: putative role of angiopoietin-like protein 3 in probucol-induced HDL remodeling. Atherosclerosis 2008, 200(2):329-335.
• [21]Bullon P, Morillo JM, Ramirez-Tortosa MC, Quiles JL, Newman HN, Battino M: Metabolic syndrome and periodontitis: is oxidative stress a common link? J Dent Res 2009, 88(6):503-518.
• [22]Ramirez-Tortosa MC, Quiles JL, Battino M, Granados S, Morillo JM, Bompadre S, Newman HN, Bullon P: Periodontitis is associated with altered plasma fatty acids and cardiovascular risk markers. Nutr Metab Cardiovasc Dis 2010, 20(2):133-139.
• [23]Pejcic A, Kesic L, Brkic Z, Pesic Z, Mirkovic D: Effect of periodontal treatment on lipoproteins levels in plasma in patients with periodontitis. South Med J 2011, 104(8):547-552.
• [24]Tomofuji T, Ekuni D, Azuma T, Irie K, Endo Y, Yamamoto T, Ishikado A, Sato T, Harada K, Suido H, Morita M: Supplementation of broccoli or Bifidobacterium longum-fermented broccoli suppresses serum lipid peroxidation and osteoclast differentiation on alveolar bone surface in rats fed a high-cholesterol diet. Nutr Res 2012, 32(4):301-307.
• [25]Devaraj S, Tobias P, Jialal I: Knockout of toll-like receptor-4 attenuates the pro-inflammatory state of diabetes. Cytokine 2011, 55(3):441-445.
• [26]Wang H, Wu Y, Ojcius DM, Yang XF, Zhang C, Ding S, Lin X, Yan J: Leptospiral hemolysins induce proinflammatory cytokines through toll-like receptor 2-and 4-mediated JNK and NF-κB signaling pathways. PLoS One 2012, 7(8):e42266.
• [27]Yang S, Takahashi N, Yamashita T, Sato N, Takahashi M, Mogi M, Uematsu T, Kobayashi Y, Nakamichi Y, Takeda K, Akira S, Takada H, Udagawa N, Furusawa K: Muramyl dipeptide enhances osteoclast formation induced by lipopolysaccharide, IL-1 alpha, and TNF-alpha through nucleotide-binding oligomerization domain 2-mediated signaling in osteoblasts. J Immunol 2005, 175(3):1956-1964.
• [28]Garlet GP: Destructive and protective roles of cytokines in periodontitis: a re-appraisal from host defense and tissue destruction viewpoints. J Dent Res 2010, 89(12):1349-1363.
• [29]Kushiyama M, Shimazaki Y, Yamashita Y: Relationship between metabolic syndrome and periodontal disease in Japanese adults. J Periodontol 2009, 80(10):1610-1615.
• [30]Nakarai H, Yamashita A, Takagi M, Adachi M, Sugiyama M, Noda H, Katano M, Yamakawa R, Nakayama K, Takumiya H, Nakai Y, Taniguchi A, Nishimura F: Periodontal disease and hypertriglyceridemia in Japanese subjects: potential association with enhanced lipolysis. Metabolism 2011, 60(6):823-829.