血管紧张素Ⅱ可促进小鼠激素诱导的缺血性股骨头坏死
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摘要
背景:关于激素性股骨头坏死的发病机制的研究很多,但目前相关机制仍未阐述清楚。股骨头局部血运障碍被认为是股骨头坏死的一个重要原因。目的:观察血管紧张素Ⅱ对激素诱导的缺血性股骨头坏死的影响。方法:实验将Balb/c雄性小鼠随机分为3组:地塞米松联合血管紧张素Ⅱ组,将地塞米松置于饮水中(2 mg/L),实验开始第1天皮下植入胶囊渗透泵,按照0.28 mg/(kg·d)持续泵入血管紧张素Ⅱ共4周;地塞米松组,地塞米松用量、用法同地塞米松联合血管紧张素Ⅱ组;对照组正常饲养。全部动物饲养6周。结果与结论:①一般情况及病理改变显示,地塞米松联合血管紧张素Ⅱ组小鼠较其他两组体质量增长程度明显较低,血清总胆固醇水平、总三酰甘油水平、小鼠股骨头空骨陷窝率及骨小梁占有率(BV/TV)较其他2组明显升高(P <0.05),骨坏死程度更加明显;②免疫组织化学染色显示,地塞米松联合血管紧张素Ⅱ组骨保护素蛋白表达明显大于其他2组(P <0.05),破骨行为更活跃;③结果证实,血管紧张素Ⅱ能够明显促进小鼠激素诱导的股骨头坏死。
BACKGROUND: There are many studies on the pathogenesis of steroid-induced avascular necrosis of the femoral head, but the relevant mechanisms remain unclear. Local obstruction of blood flow to the femoral head is an important cause of avascular necrosis of the femoral head. OBJECTIVE: To investigate the effect of angiotensin Ⅱ on avascular necrosis of the femoral head. METHODS: Male Balb/c mice were randomly divided into three groups. In the dexamethasone plus angiotensin Ⅱ group, 2 mg/L dexamethasone was added in drinking water, subcutaneous implantatian with osmotic pump capsules began on the first day, followed by pumping with 0.28 mg/(kg?d) angiotensin Ⅱ for 4 weeks. Dexamethasone group dosage and usage were the same as dexamethasone plus angiotensin Ⅱ group. Control group had normal feed. All mice were fed for 6 weeks. RESULTS AND CONCLUSION:(1) General condition and pathological changes showed that compared with the dexamethasone and control groups, the body mass increase was significantly decreased, and the serum total cholesterol, total triglyceride, empty lacunae rate and bone volume/tissue volume were significantly increased in the dexamethasone plus angiotensin Ⅱ group(P < 0.05), and the degree of osteonecrosis was more obvious.(2) Immunohistochemical results showed that the osteoprotegerin protein expression level in the dexamethasone plus angiotensin Ⅱ group was significantly higher than that in the other two groups(P < 0.05), indicating that the osteoclast was more active.(3) In summary, angiotensin Ⅱ can obviously promote steroid-induced avascular necrosis of the femoral head in mice.
BACKGROUND: There are many studies on the pathogenesis of steroid-induced avascular necrosis of the femoral head, but the relevant mechanisms remain unclear. Local obstruction of blood flow to the femoral head is an important cause of avascular necrosis of the femoral head. OBJECTIVE: To investigate the effect of angiotensin Ⅱ on avascular necrosis of the femoral head. METHODS: Male Balb/c mice were randomly divided into three groups. In the dexamethasone plus angiotensin Ⅱ group, 2 mg/L dexamethasone was added in drinking water, subcutaneous implantatian with osmotic pump capsules began on the first day, followed by pumping with 0.28 mg/(kg?d) angiotensin Ⅱ for 4 weeks. Dexamethasone group dosage and usage were the same as dexamethasone plus angiotensin Ⅱ group. Control group had normal feed. All mice were fed for 6 weeks. RESULTS AND CONCLUSION:(1) General condition and pathological changes showed that compared with the dexamethasone and control groups, the body mass increase was significantly decreased, and the serum total cholesterol, total triglyceride, empty lacunae rate and bone volume/tissue volume were significantly increased in the dexamethasone plus angiotensin Ⅱ group(P < 0.05), and the degree of osteonecrosis was more obvious.(2) Immunohistochemical results showed that the osteoprotegerin protein expression level in the dexamethasone plus angiotensin Ⅱ group was significantly higher than that in the other two groups(P < 0.05), indicating that the osteoclast was more active.(3) In summary, angiotensin Ⅱ can obviously promote steroid-induced avascular necrosis of the femoral head in mice.
引文
[1]王傲,王金成.激素性股骨头坏死发病机制的研究进展[J].中国骨与关节损伤杂志,2016,31(4):445-446.
[2]Dinh QN, Drummond GR, Kemp-Harper BK, et al. Pressor response to angiotensin II is enhanced in aged mice and associated with inflammation, vasoconstriction and oxidative stress. Aging. 2017;9(6):1595-1606.
[3]Yang L, Boyd K, Kaste SC, et al. A mouse model for glucocorticoid-induced osteonecrosis:effect of a steroid holiday. J Orthop Res. 2009;27(2):169-175.
[4]Qin L, Zhang G, Sheng H, et al. Multiple bioimaging modalities in evaluation of an experimental osteonecrosis induced by a combination of lipopolysaccharide and methylprednisolone. Bone. 2006;39(4):863-871.
[5]Okazaki S, Nishitani Y, Nagoya S, et al. Femoral head osteonecrosis can be caused by disruption of the systemic immune response via the toll-like receptor 4 signalling pathway. Rheumatology(Oxford). 2009;48(3):227-232.
[6]Yamamoto T, Hirano K, Tsutsui H, et al. Corticosteroid enhances the experimental induction of osteonecrosis in rabbits with Shwartzman reaction. Clin Orthop Relat Res.1995;(316):235-243.
[7]Yamamoto T, Irisa T, Sugioka Y, et al. Effects of pulse methylprednisolone on bone and marrow tissues:Corticosteroid-induced osteonecrosis in rabbits. Arthritis Rheum. 1997;40(11):2055-2064,.
[8]Blair JM, Zheng Y, Dunstan CR. RANK ligand. Int J Biochem Cell Biol. 2007;39(6):1077-1081.
[9]Yamada Y, Ando F, Niino N:et al. Association of polymorphisms of the osteoprotegerin gene with bone mineral density in Japanese women but not men. Mol Genet Metab.2003;80(3):344-349.
[10]Gori F, Hofbauer LC, Dunstan CR, et al. The expression of osteoprotegerin and RANK ligand and the support of osteoclast formation by stromal-osteoblast lineage cells is developmentally regulated. Endocrinology. 2000;141(12):4768-4776.
[11]Zeng X, Zhan K, Zhang L, et al. The impact of high total cholesterol and high low-density lipoprotein on avascular necrosis of the femoral head in low-energy femoral neck fractures. J Orthop Surg Res. 2017;12(1):30.
[12]Mukisi M, Bashoun K, Burny F. Sickle-cell hip necrosis and intraosseous pressure. Orthop Traumatol Surg Res. 2009;95(2):134-138.
[13]Wang G, Zhang CQ, Sun Y, et al. Changes in femoral head blood supply and vascular endothelial growth factor in rabbits with steroid-induced osteonecrosis. J Int Med Res. 2010;38(3):1060-1069.
[14]Zheng L, Wang W, Ni J, et al. The association of e NOS gene polymorphism with avascular necrosis of femoral head. PLoS One. 2014;9(2):e87583.
[15]Tian L, Wen Q, Dang X, et al. Immune response associated with Toll-like receptor 4 signaling pathway leads to steroidinduced femoral head osteonecrosis. BMC Musculoskelet Disord. 2014;15:18.
[16]Assouline-Dayan Y, Chang C, Greenspan A, et al.Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum. 2002;32(2):94-124.
[17]Mont MA, Jones LC, Hungerford DS.Nontraumaticosteonecrosis of the femoral head:ten years later. J Bone Joint Surg Am. 2006;88(5):1117-1132.
[18]Lieberman JR, Berry DJ, Mont MA, et al. Osteonecrosis of the hip:management in the 21st century. Instr Course Lect. 2003;52:337-355.
[19]Law RK, Lee EW, Poon PY, et al. The functional capacity of healthcare workers with history of severe acute respiratory distress syndrome(SARS)complicated with avascular necrosis-case report. Work. 2008;30(1):17-26.
[20]Chan MH, Chan PK, Griffith JF, et al. Steroid-induced osteonecrosis in severe acute respiratory syndrome:a retrospective analysis of biochemicalmarkers of bone metabolism and corticosteroid therapy. Pathology. 2006;38(3):229-235.
[21]Kerachian MA, Seguin C, Harvey EJ. Glucocorticoids in osteonecrosis of the femoral head:a new understanding of the mechanisms of action. J Steroid Biochem Mol Biol.2009;114(3-5):121-128.
[22]Weinstein RS. Glucocorticoid-induced osteonecrosis.Endocrine. 2012;41(2):183-190.
[23]Kerachian MA, Harvey EJ, Cournoyer D, et al. Avascular necrosis of the femoral head:vascular hypotheses.Endothelium. 2006;13:237-244.
[24]Ong SL, Whitworth JA. How do glucocorticoids cause hypertension:role of nitric oxide deficiency, oxidative stress,and eicosanoids. Endocrinol Metab Clin North Am.2011;40(2):393-407.
[25]Kerachian MA, Harvey EJ, Cournoyer D, et al. Avascular necrosis of the femoral head:vascular hypotheses.Endothelium. 2006;13(4):237-244.
[26]Touyz RM, Montezano AC. Angiotensin-(1-7)and vascular function:the clinical context. Hypertension. 2018;71(1):68-69.
[27]Hofbauer LC, Neubauer A, Heufelder AE. Receptor activator of nuclear factor-kappa B ligand and osteoprotegerin:potential implications for the pathogenesis and treatment of malignant bone diseases. Cancer. 2001;92(3):460-470.
[28]Singh PP, van der Kraan AG, Xu J, et al. Membrane-bound receptor activator of NFκB ligand(RANKL)activity displayed by osteoblasts is differentially regulated by osteolytic factors.Biochem Biophys Res Commun. 2012;422(1):48-53.
[29]Boyce BF, Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys. 2008;473(2):139-146.
[30]Theoleyre S, Wittrant Y, Tat SK, et al. The molecular triad OPG/RANK/RANKL:Involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev. 2004;15(6):457-475.
[2]Dinh QN, Drummond GR, Kemp-Harper BK, et al. Pressor response to angiotensin II is enhanced in aged mice and associated with inflammation, vasoconstriction and oxidative stress. Aging. 2017;9(6):1595-1606.
[3]Yang L, Boyd K, Kaste SC, et al. A mouse model for glucocorticoid-induced osteonecrosis:effect of a steroid holiday. J Orthop Res. 2009;27(2):169-175.
[4]Qin L, Zhang G, Sheng H, et al. Multiple bioimaging modalities in evaluation of an experimental osteonecrosis induced by a combination of lipopolysaccharide and methylprednisolone. Bone. 2006;39(4):863-871.
[5]Okazaki S, Nishitani Y, Nagoya S, et al. Femoral head osteonecrosis can be caused by disruption of the systemic immune response via the toll-like receptor 4 signalling pathway. Rheumatology(Oxford). 2009;48(3):227-232.
[6]Yamamoto T, Hirano K, Tsutsui H, et al. Corticosteroid enhances the experimental induction of osteonecrosis in rabbits with Shwartzman reaction. Clin Orthop Relat Res.1995;(316):235-243.
[7]Yamamoto T, Irisa T, Sugioka Y, et al. Effects of pulse methylprednisolone on bone and marrow tissues:Corticosteroid-induced osteonecrosis in rabbits. Arthritis Rheum. 1997;40(11):2055-2064,.
[8]Blair JM, Zheng Y, Dunstan CR. RANK ligand. Int J Biochem Cell Biol. 2007;39(6):1077-1081.
[9]Yamada Y, Ando F, Niino N:et al. Association of polymorphisms of the osteoprotegerin gene with bone mineral density in Japanese women but not men. Mol Genet Metab.2003;80(3):344-349.
[10]Gori F, Hofbauer LC, Dunstan CR, et al. The expression of osteoprotegerin and RANK ligand and the support of osteoclast formation by stromal-osteoblast lineage cells is developmentally regulated. Endocrinology. 2000;141(12):4768-4776.
[11]Zeng X, Zhan K, Zhang L, et al. The impact of high total cholesterol and high low-density lipoprotein on avascular necrosis of the femoral head in low-energy femoral neck fractures. J Orthop Surg Res. 2017;12(1):30.
[12]Mukisi M, Bashoun K, Burny F. Sickle-cell hip necrosis and intraosseous pressure. Orthop Traumatol Surg Res. 2009;95(2):134-138.
[13]Wang G, Zhang CQ, Sun Y, et al. Changes in femoral head blood supply and vascular endothelial growth factor in rabbits with steroid-induced osteonecrosis. J Int Med Res. 2010;38(3):1060-1069.
[14]Zheng L, Wang W, Ni J, et al. The association of e NOS gene polymorphism with avascular necrosis of femoral head. PLoS One. 2014;9(2):e87583.
[15]Tian L, Wen Q, Dang X, et al. Immune response associated with Toll-like receptor 4 signaling pathway leads to steroidinduced femoral head osteonecrosis. BMC Musculoskelet Disord. 2014;15:18.
[16]Assouline-Dayan Y, Chang C, Greenspan A, et al.Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum. 2002;32(2):94-124.
[17]Mont MA, Jones LC, Hungerford DS.Nontraumaticosteonecrosis of the femoral head:ten years later. J Bone Joint Surg Am. 2006;88(5):1117-1132.
[18]Lieberman JR, Berry DJ, Mont MA, et al. Osteonecrosis of the hip:management in the 21st century. Instr Course Lect. 2003;52:337-355.
[19]Law RK, Lee EW, Poon PY, et al. The functional capacity of healthcare workers with history of severe acute respiratory distress syndrome(SARS)complicated with avascular necrosis-case report. Work. 2008;30(1):17-26.
[20]Chan MH, Chan PK, Griffith JF, et al. Steroid-induced osteonecrosis in severe acute respiratory syndrome:a retrospective analysis of biochemicalmarkers of bone metabolism and corticosteroid therapy. Pathology. 2006;38(3):229-235.
[21]Kerachian MA, Seguin C, Harvey EJ. Glucocorticoids in osteonecrosis of the femoral head:a new understanding of the mechanisms of action. J Steroid Biochem Mol Biol.2009;114(3-5):121-128.
[22]Weinstein RS. Glucocorticoid-induced osteonecrosis.Endocrine. 2012;41(2):183-190.
[23]Kerachian MA, Harvey EJ, Cournoyer D, et al. Avascular necrosis of the femoral head:vascular hypotheses.Endothelium. 2006;13:237-244.
[24]Ong SL, Whitworth JA. How do glucocorticoids cause hypertension:role of nitric oxide deficiency, oxidative stress,and eicosanoids. Endocrinol Metab Clin North Am.2011;40(2):393-407.
[25]Kerachian MA, Harvey EJ, Cournoyer D, et al. Avascular necrosis of the femoral head:vascular hypotheses.Endothelium. 2006;13(4):237-244.
[26]Touyz RM, Montezano AC. Angiotensin-(1-7)and vascular function:the clinical context. Hypertension. 2018;71(1):68-69.
[27]Hofbauer LC, Neubauer A, Heufelder AE. Receptor activator of nuclear factor-kappa B ligand and osteoprotegerin:potential implications for the pathogenesis and treatment of malignant bone diseases. Cancer. 2001;92(3):460-470.
[28]Singh PP, van der Kraan AG, Xu J, et al. Membrane-bound receptor activator of NFκB ligand(RANKL)activity displayed by osteoblasts is differentially regulated by osteolytic factors.Biochem Biophys Res Commun. 2012;422(1):48-53.
[29]Boyce BF, Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys. 2008;473(2):139-146.
[30]Theoleyre S, Wittrant Y, Tat SK, et al. The molecular triad OPG/RANK/RANKL:Involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev. 2004;15(6):457-475.