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BMC Musculoskeletal Disorders
Published in: BMC Musculoskeletal Disorders 1/2014

Open Access 01-12-2014 | Research article

Immune response associated with Toll-like receptor 4 signaling pathway leads to steroid-induced femoral head osteonecrosis

Authors: Lei Tian, Qi Wen, Xiaoqian Dang, Wulin You, Lihong Fan, Kunzheng Wang

Published in: BMC Musculoskeletal Disorders | Issue 1/2014

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Abstract

Background

Femoral head osteonecrosis is frequently observed in patients treated with excessive corticosteroids. The objective of the current study was to establish a rat model to investigate the disruption of immune response in steroid-induced femoral head osteonecrosis via Toll-like receptor 4 (TLR4) signaling pathway.

Methods

Male SD rats were divided into the treatment group (group A) and the model group (group B) consisting of 24 rats each, and were injected intramuscularly with 20 mg/kg methylprednisolone (MP) for 8 weeks, once a week. The rats in group A were injected intravenously with 7.5 mg/kg TAK242 before each MP administration. A control group (group N) consisted of 12 rats were received saline injection. All animals were sacrificed 8, 10 and 12 weeks from the first MP injection, respectively. Histopathological analysis was performed and the concentration of tartrate-resistant acid phosphatase (TRAP) in serum was tested. The signaling molecules including TLR4, MyD88, NF-κB p65 and MCP-1 were detected by immunohistochemistry, quantitative real-time PCR and Western blot.

Results

Femoral head osteonecrosis was observed in the model rats, and the concentration of TRAP and positive staining of all signaling molecules increased significantly in group B compared with that in group A and group N. Compare with the control group, the mRNA expressions and protein levels of all signaling molecules were enhanced significantly in group B, but no significant in group A.

Conclusions

Corticosteroids can induce femoral head osteonecrosis by disturbing the immune response via TLR4 signaling pathway. These findings suggest that the disruption of immune response play a role in the pathogenesis of osteonecrosis.
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Literature
1.
2.
Hougardy DM, Peterson GM, Bleasel MD, Randall CT: Is enough attention being given to the adverse effects of corticosteroid therapy?. J Clin Pharm Ther. 2000, 25: 227-234. 10.1046/j.1365-2710.2000.00284.x.CrossRefPubMed
3.
Mont MA, Jones LC, Hungerford DS: Nontraumatic osteonecrosis of the femoral head: ten years later. J Bone Joint Surg Am. 2006, 88: 1117-1132. 10.2106/JBJS.E.01041.CrossRefPubMed
4.
Fisher DE, Bickel WH: Corticosteroid-induced avascular necrosis. J Bone Joint Surg. 1971, 53A: 859-873.
5.
Mankin HJ: Nontraumatic necrosis of bone (osteonecrosis). N Engl J Med. 1992, 326: 1473-1479. 10.1056/NEJM199205283262206.CrossRefPubMed
6.
Chang CC, Greenspan A, Gershwin ME: Osteonecrosis: current perspectives on pathogenesis and treatment. Semin Arthritis Rheum. 1993, 23: 47-69. 10.1016/S0049-0172(05)80026-5.CrossRefPubMed
7.
Drescher W, Weigert KP, Bunger MH, Ingerslev J, Bunger C, Hansen ES: Femoral head blood flow reduction and hypercoagulability under 24h megadose steroid treatment in pigs. J Orthop Res. 2004, 22: 501-508. 10.1016/j.orthres.2003.10.002.CrossRefPubMed
8.
Zizic TM, Marcoux C, Hungerford DS, Stevens MB: The early diagnosis of ischemic necrosis of bone. Arthritis Rheum. 1986, 29: 1177-1186. 10.1002/art.1780291001.CrossRefPubMed
9.
Jones JP: Intravascular coagulation and osteonecrosis. Clin Orthop Relat Res. 1992, 277: 41-53.PubMed
10.
Zalavras C, Dailiana Z, Elisaf M, Bairaktari E, Vlachogiannopoulos P, Katsaraki A, Malizos KN: Potential aetiological factors concerning the development of osteonecrosis of the femoral head. Eur J Clin Invest. 2000, 30: 215-221. 10.1046/j.1365-2362.2000.00621.x.CrossRefPubMed
11.
Yamamoto T, Hirano K, Tsutsui H, Sugioka Y, Sueishi K: Corticosteroid enhances the experimental induction of osteonecrosis in rabbits with Schwartzman reaction. Clin Orthop Relat Res. 1995, 316: 235-243.PubMed
12.
Ichiseki T, Kaneuji A, Ueda Y, Nakagawa S, Mikami T, Fukui K, Matsumoto T: Osteonecrosis development in a novel rat model characterized by a single application of oxidative stress. Arthritis Rheum. 2011, 63 (7): 2138-2141. 10.1002/art.30365.CrossRefPubMed
13.
Okazaki S, Nagoya S, Tateda K, Katada R, Mizuo K, Watanabe S, Yamashita T, Matsumoto H: Weight bearing does not contribute to the development of osteonecrosis of the femoral head. Int J Exp Pathol. 2012, 93: 458-462.PubMedPubMedCentral
14.
Janke LJ, Liu CC, Vogel P, Kawedia J, Boyd KL, Funk AJ, Rellingy MV: Primary epiphyseal arteriopathy in a mouse model of steroid-induced osteonecrosis. Am J Pathol. 2013, 183 (1): 19-25. 10.1016/j.ajpath.2013.03.004.CrossRefPubMedPubMedCentral
15.
16.
Okazaki S, Nishitani Y, Nagoya S, Kaya M, Yamashita T, Matsumoto H: Femoral head osteonecrosis can be caused by disruption of the systemic immune response via the toll-like receptor 4 signalling pathway. Rheumatology. 2009, 48: 227-232.CrossRefPubMed
17.
Kanzler H, Barrat FJ, Hessel EM, Coffman RL: Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nat Med. 2007, 13 (5): 552-559. 10.1038/nm1589.CrossRefPubMed
18.
Barr TA, Brown S, Ryan G, Zhao J, Gray D: TLR-mediated stimulation of APC: Distinct cytokine responses of B cells and dendritic cells. Eur J Immunol. 2007, 37 (11): 3040-3053. 10.1002/eji.200636483.CrossRefPubMedPubMedCentral
19.
Takayanagi H: Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol. 2007, 7: 292-304. 10.1038/nri2062.CrossRefPubMed
20.
Mendonca DM, Chimelli L, Martinez AM: Quantitative evidence for neurofilament heavy subunit aggregation in motor neurons of spinal cords of patients with amyotrophic lateral sclerosis. Braz J Med Biol Res. 2005, 38: 925-933.CrossRefPubMed
21.
Sugano N, Kubo T, Takaoka K, Ohzono K, Hotokebuchi T, Matsumoto T, Igarashi H, Ninomiya S: Diagnostic criteria for non-traumatic osteonecrosis of the femoral head. A multicentre study. J Bone Joint Surg Br. 1999, 81: 590-595. 10.1302/0301-620X.81B4.9393.CrossRefPubMed
22.
Takeda K, Kaisho T, Akxra S: Toll-like receptors. Annu Rev Immunol. 2003, 21: 335-376. 10.1146/annurev.immunol.21.120601.141126.CrossRefPubMed
23.
Janeway CA, Medzhltov JR: Innate immune recognition. Annu Rev Immunol. 2002, 20: 197-216. 10.1146/annurev.immunol.20.083001.084359.CrossRefPubMed
24.
Goldring SR, Gravallese EM: Pathogenesis of bone lesions in rheumatoid arthritis. Curr Rheumatol Rep. 2002, 4 (3): 226-231. 10.1007/s11926-002-0069-y.CrossRefPubMed
25.
Romas E, Sims NA, Hards DK, Lindsay M, Quinn JWM, Ryan PFJ, Dunstan CR, Martin TJ, Gillespie MT: Osteoprotegerin reduces osteoelast numbers and prevents bone erosion in collagen-induced arthritis. Am J Pathol. 2002, 161 (4): 1419-1427. 10.1016/S0002-9440(10)64417-3.CrossRefPubMedPubMedCentral
26.
Xu Y, Tao X, Shen B, Horng T, Medzhitov R, Manley JL, Tong L: Structural basis for signal transduction by the Toll/ interleukin-l recptor domains. Nature. 2000, 408 (6808): 111-115. 10.1038/35040600.CrossRefPubMed
27.
Bar-Shavit Z: Taking a toll on the bones: regulation of bone metabolism by innate immune regulators. Autoimmunity. 2008, 41: 195-203. 10.1080/08916930701694469.CrossRefPubMed
28.
Loré K, Betts MR, Brenchley JM, Kuruppu J: Toll-like receptor ligands modulate dendritic cells to augment cytomegalovirus and HIV-1-specific T cell responses. J Immunol. 2003, 171 (8): 4320-4328.CrossRefPubMed
29.
Coimbra R, Melbostad H, Loomis W, Porcides RD, Wolf P, Tobar M, Hoyt DB: LPS-induced acute lung injury is attenuated by phosphodiesterase inhibition:effects on proinflammatory mediators metalloproteinases NF-kappa B and ICAM-1 expression. Trauma. 2006, 60: 115-125. 10.1097/01.ta.0000200075.12489.74.CrossRef
30.
Cominacini L, Fratta Pasini A, Garbin U, Davoli A, Tosetti ML, Campagnola M, Rigoni A, Pastorino AM, Lo Cascio V, Sawamura T: Oxidized low density lipoprotein (ox-LDL) binding to Ox-LDL receptor-1 in endothelial cells induces the activation of NF-kB through an increaded production of intracellular reaetive oxygen species. J Biol Chem. 2000, 275: 12633-12638. 10.1074/jbc.275.17.12633.CrossRefPubMed
31.
Frantz S, Kobzik L, Kim YD, Fukazawa R, Medzhitov R, Lee RT, Kelly RA: Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. J Clin Invest. 1999, 104: 271-280. 10.1172/JCI6709.CrossRefPubMedPubMedCentral
32.
Ii M, Matsunaga N, Hazeki K, Nakamura K, Takashima K, Seya T, Hazeki O, Kitazaki T, Iizawa Y: A novel cyclohexene derivative, ethyl (6R)-6-[N- (2-Chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate (TAK-242), selectively inhibits toll-like receptor 4-mediated cytokine production through suppression of intracellular signaling. Mol Pharmacol. 2006, 69: 1288-1295. 10.1124/mol.105.019695.CrossRefPubMed
33.
Kawamoto T, Ii M, Kitazaki T, Iizawa Y, Kimura H: TAK-242 selectively suppresses Toll-like receptor 4-signaling mediated by the intracellular domain. Eur J Pharmacol. 2008, 584: 40-48. 10.1016/j.ejphar.2008.01.026.CrossRefPubMed
34.
Takashima K, Matsunaga N, Yoshimatsu M, Hazeki K, Kaisho T, Uekata M, Hazeki O, Akira S, Iizawa Y, Ii M: Analysis of binding site for the novel small-molecule TLR4 signal transduction inhibitor TAK-242 and its therapeutic effect on mouse sepsis model. Br J Pharmacol. 2009, 157: 1250-1262. 10.1111/j.1476-5381.2009.00297.x.CrossRefPubMedPubMedCentral
35.
Hirano T, Iwasaki K, Oda J, Kumashiro T: Osteonecrosis of the femoral head in spontaneously hypertensive rats. Relation to ossific nuclei during growth. Acta Orthop Scand. 1992, 63: 37-40. 10.3109/17453679209154846.CrossRefPubMed
36.
Ichiseki T, Ueda Y, Katsuda S, Kitamura K, Kaneuji A, Matsumoto T: Oxidative stress by glutathione depletion induces osteonecrosis in rats. Rheumatology. 2006, 45: 287-290.CrossRefPubMed
37.
Kim YY, Kim SH, Oh S, Sul OJ, Lee HY, Kim HJ, Kim SY, Choi HS: Increased fat due to estrogen deficiency induces bone loss by elevating monocyte chemoattractant protein-1 (MCP-1) production. Mol Cells. 2010, 29: 277-282. 10.1007/s10059-010-0027-x.CrossRefPubMed
38.
Aaron RK: Osteonecrosis: etiology, pathophysiology and diagnosis. The adult hip. Edited by: Callaghan JJ, Rosenberg AG, Rubash HE. 1998, Philadelphia: Lippincott-Raven, 451-466.
39.
Parsons SJ, Steeleb N: Osteonecrosis of the femoral head: Part 1—Aetiology, pathogenesis, investigation, classification. Curr Orthop. 2007, 21: 457-463. 10.1016/j.cuor.2007.11.004.CrossRef
40.
Vink A, Schoneveld AH, van der Meer JJ, van Middelaar BJ, Sluijter JP, Smeets MB, Quax PH, Lim SK, Borst C, Pasterkamp G, de Kleijn DP: In vivo evidence for a role of toll-like receptor 4 in the development of intimal lesions. Circulation. 2002, 106 (15): 1985-1990. 10.1161/01.CIR.0000032146.75113.EE.CrossRefPubMed
41.
Takayanagi H: The unexpected link between osteoclasts and the immune system. Adv Exp Med Biol. 2010, 658: 61-68.CrossRefPubMed
42.
Metadata
Title
Immune response associated with Toll-like receptor 4 signaling pathway leads to steroid-induced femoral head osteonecrosis
Authors
Lei Tian
Qi Wen
Xiaoqian Dang
Wulin You
Lihong Fan
Kunzheng Wang
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2014
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/1471-2474-15-18

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