Abstract
The objective of this study is to investigate the participation of inflammatory and oxidative stress mediators and the effects on the expression of matrix metalloproteinase (MMP)-2, MMP-9, and receptor activator of NF-κB ligand (RANKL)/receptor activator of NF-κB (RANK)/osteoprotegerin (OPG) pathway in the response to treatment with olmesartan, an angiotensin II type 1 receptor blocker. Male Wistar albino rats were randomly divided into five groups of ten rats each: (1) non-ligature with water, (2) ligature with water, (3) ligature with 1 mg/kg olmesartan, (4) ligature with 6 mg/kg olmesartan, and (5) ligature with 10 mg/kg olmesartan. All groups were treated with olmesartan or the vehicle by gavage daily for 10 days. Following the treatment course, the periodontal tissue of the animals was analyzed by histopathology and immunohistochemistry to determine the expression of cyclooxygenase-2 (COX-2), MMP-2, MMP-9, and members of the RANKL/RANK/OPG pathway and by ELISA and spectroscopic assay to determine the levels of interleukin (IL)-1β, IL-10, tumor necrosis factor (TNF)-α, myeloperoxidase (MPO), malonaldehyde (MDA), and glutathione. The concentrations of MPO and MDA were reduced in the group that received 6 mg/kg olmesartan (p < 0.05). In addition, the group that was treated with 6 mg/kg olmesartan showed a decreased level of IL-1β (p < 0.05), and all doses of olmesartan resulted in decreased levels of TNF-α. Furthermore, treatment with 6 mg/kg olmesartan led to downregulation of the expression of COX-2, MMP-2, MMP-9, RANKL, and RANK and to upregulation of the expression of OPG. These findings suggest that 6 mg/kg olmesartan reduces the inflammatory process and bone loss by downregulating MMPs and RANKL in osteoblasts and by upregulating OPG.
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References
Adams JL, Badger AM, Kumar S, Lee JC (2001) p38 MAP kinase: molecular target for the inhibition of pro-inflammatory cytokines. Prog Med Chem 38:1–60
Aki K, Shimizu A, Masuda Y, Kuwahara N, Arai T, Ishikawa A, Fujita E, Mii A, Natori Y, Fukunaga Y, Fukuda Y (2010) ANG II receptor blockade enhances anti-inflammatory macrophages in anti-glomerular basement membrane glomerulonephritis. Am J Physiol Renal Physiol 298(4):F870–F882
Carvalho Rde S, de Souza CM, Neves JC, Holanda-Pinto SA, Pinto LM, Brito GA, de Andrade GM (2013) Vitamin E does not prevent bone loss and induced anxiety in rats with ligature-induced periodontitis. Arch Oral Biol 58(1):50–58
Carvalho RS, de Souza CM, Neves JC, Holanda-Pinto SA, Pinto LM, Brito GA, de Andrade GM (2010) Effect of venlafaxine on bone loss associated with ligature-induced periodontitis in Wistar rats. J Negat Results Biomed 9:3
de Molon RS, de Avila ED, Cirelli JA (2012) Host responses induced by different animal models of periodontal disease: a literature review. J Investig Clin Den. doi:10.1111/jicd.12018t
Deo V, Bhongade ML (2010) Pathogenesis of periodontitis: role of cytokines in host response. Dent Today 29(9):60–62, 64–66; quiz 68–69
Gapski R, Barr JL, Sarment DP, Layher MG, Socransky SS, Giannobile WV (2004) Effect of systemic matrix metalloproteinase inhibition on periodontal wound repair: a proof of concept trial. J Periodontol 75(3):441–452
Gemmell E, Marshall RI, Seymour GJ (1997) Cytokines and prostaglandins in immune homeostasis and tissue destruction in periodontal disease. Periodontol 2000(14):112–143
Giannobile WV (2008) Host-response therapeutics for periodontal diseases. J Periodontol 79(8 Suppl):1592–1600
Graves D (2008) Cytokines that promote periodontal tissue destruction. J Periodontol 79(8 Suppl):1585–1591
Graves DT, Li J, Cochran DL (2011) Inflammation and uncoupling as mechanisms of periodontal bone loss. J Dent Res 90(2):143–153
Grenier D, Plamondon P, Sorsa T, Lee HM, McNamara T, Ramamurthy NS, Golub LM, Teronen O, Mayrand D (2002) Inhibition of proteolytic, serpinolytic, and progelatinase-b activation activities of periodontopathogens by doxycycline and the non-antimicrobial chemically modified tetracycline derivatives. J Periodontol 73(1):79–85
Harada S, Takahashi N (2011) Control of bone resorption by RANKL-RANK system. Clin Calcium 21(8):1121–1130
Kendall C, Ionescu-Matiu I, Dreesman GR (1983) Utilization of the biotin/avidin system to amplify the sensitivity of the enzyme-linked immunosorbent assay (ELISA). J Immunol Methods 56(3):329–339
Kirkwood KL, Cirelli JA, Rogers JE, Giannobile WV (2007) Novel host response therapeutic approaches to treat periodontal diseases. Periodontol 2000(43):294–315
Kurikawa N, Suga M, Kuroda S, Yamada K, Ishikawa H (2003) An angiotensin II type 1 receptor antagonist, olmesartan medoxomil, improves experimental liver fibrosis by suppression of proliferation and collagen synthesis in activated hepatic stellate cells. Br J Pharmacol 139(6):1085–1094
Kusano K, Miyaura C, Inada M, Tamura T, Ito A, Nagase H, Kamoi K, Suda T (1998) Regulation of matrix metalloproteinases (MMP-2, -3, -9, and -13) by interleukin-1 and interleukin-6 in mouse calvaria: association of MMP induction with bone resorption. Endocrinology 139(3):1338–1345
Leitao RF, Ribeiro RA, Chaves HV, Rocha FA, Lima V, Brito GA (2005) Nitric oxide synthase inhibition prevents alveolar bone resorption in experimental periodontitis in rats. J Periodontol 76(6):956–963
Li Z, Chen XD, Ni SK, Li JW, Lin MS (2004) Olmesartan inhibits the expression of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha and improves vascular remodeling after vascular injury in mouse. Chin J Traumatol 7(1):56–61
Lossdorfer S, Gotz W, Jager A (2011) PTH(1–34)-induced changes in RANKL and OPG expression by human PDL cells modify osteoclast biology in a co-culture model with RAW 264.7 cells. Clin Oral Investig 15(6):941–952
Lynch CC, Hikosaka A, Acuff HB, Martin MD, Kawai N, Singh RK, Vargo-Gogola TC, Begtrup JL, Peterson TE, Fingleton B, Shirai T, Matrisian LM, Futakuchi M (2005) MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell 7(5):485–496
Richards JB, Joseph L, Schwartzman K, Kreiger N, Tenenhouse A, Goltzman D (2006) The effect of cyclooxygenase-2 inhibitors on bone mineral density: results from the Canadian Multicentre Osteoporosis Study. Osteoporos Int 17(9):1410–1419
Rutkowski P, Bylina E, Klimczak A, Switaj T, Falkowski S, Kroc J, Lugowska I, Brzeskwiniewicz M, Melerowicz W, Osuch C, Mierzejewska E, Wasielewski K, Wozniak A, Grzesiakowska U, Nowecki ZI, Siedlecki JA, Limon J (2012) The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST) after imatinib failure - one institution study. BMC Cancer 12:107
Safieh-Garabedian B, Poole S, Allchorne A, Winter J, Woolf CJ (1995) Contribution of interleukin-1 beta to the inflammation-induced increase in nerve growth factor levels and inflammatory hyperalgesia. Br J Pharmacol 115(7):1265–1275
Sandmann S, Li J, Fritzenkotter C, Spormann J, Tiede K, Fischer JW, Unger T (2006) Differential effects of olmesartan and ramipril on inflammatory response after myocardial infarction in rats. Blood Press 15(2):116–128
Sanz M, van Winkelhoff AJ (2011) Periodontal infections: understanding the complexity–consensus of the Seventh European Workshop on Periodontology. J Clin Periodontol 38(Suppl 11):3–6
Shimizu H, Nakagami H, Osako MK, Hanayama R, Kunugiza Y, Kizawa T, Tomita T, Yoshikawa H, Ogihara T, Morishita R (2008) Angiotensin II accelerates osteoporosis by activating osteoclasts. FASEB J 22(7):2465–2475
Souza MH, Troncon LE, Cunha FQ, Oliveira RB (2003) Decreased gastric tone and delayed gastric emptying precede neutrophil infiltration and mucosal lesion formation in indomethacin-induced gastric damage in rats. Braz J Med Biol Res 36(10):1383–1390
Theoleyre S, Wittrant Y, Tat SK, Fortun Y, Redini F, Heymann D (2004) The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev 15(6):457–475
Vargova V, Pytliak M, Mechirova V (2012) Matrix metalloproteinases. EXS 103:1–33
Vestergaard P, Hermann P, Jensen JE, Eiken P, Mosekilde L (2012) Effects of paracetamol, non-steroidal anti-inflammatory drugs, acetylsalicylic acid, and opioids on bone mineral density and risk of fracture: results of the Danish Osteoporosis Prevention Study (DOPS). Osteoporos Int 23(4):1255–1265
Yamaguchi M, Kasai K (2005) Inflammation in periodontal tissues in response to mechanical forces. Arch Immunol Ther Exp (Warsz) 53(5):388–398
Yen CA, Damoulis PD, Stark PC, Hibberd PL, Singh M, Papas AS (2008) The effect of a selective cyclooxygenase-2 inhibitor (celecoxib) on chronic periodontitis. J Periodontol 79(1):104–113
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Araújo, A.A., Lopes de Souza, G., Souza, T.O. et al. Olmesartan decreases IL-1β and TNF-α levels; downregulates MMP-2, MMP-9, COX-2, and RANKL; and upregulates OPG in experimental periodontitis. Naunyn-Schmiedeberg's Arch Pharmacol 386, 875–884 (2013). https://doi.org/10.1007/s00210-013-0886-8
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DOI: https://doi.org/10.1007/s00210-013-0886-8