二氢青蒿素对系统性红斑狼疮小鼠继发性骨损害的防治作用初探
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摘要
目的:观察自发性系统性红斑狼疮(SLE)小鼠的继发性骨损害及初步探讨二氢青蒿素的干预作用。方法:15周龄B6.Mrl-Faslpr/J发病雌性小鼠随机分成红斑狼疮组、醋酸泼尼松6mg/kg组和二氢青蒿素150mg/kg组,8只C57BL/6J野生型同龄小鼠为空白对照。每日灌胃给药共90天。实验结束,胫骨显微CT扫描和不脱钙切片、染色后进行形态计量学分析,股骨力学检测,观察SLE小鼠骨代谢和骨质量变化。结果:与空白对照组相比,红斑狼疮组的骨量显著减少、连接密度和小梁密度均明显下降,小梁变薄,分离度增加,板状小梁向杆状小梁转变(SMI)增加,骨形成率下降而骨吸收明显增加,股骨弹性载荷、最大载荷和断裂载荷均下降;醋酸泼尼松组骨形成率进一步下降;二氢青蒿素150mg/kg组与红斑狼疮组相比,骨量、连接密度和小梁密度均明显增加,小梁结构改善,骨吸收显著抑制且骨形成比醋酸泼尼松组明显增加;二氢青蒿素组弹性载荷及最大载荷、断裂载荷均比红斑狼疮组和醋酸泼尼松治疗组明显增加。结论:二氢青蒿素既可显著降低SLE导致的小鼠骨吸收增加且不降低骨形成,并阻止骨量丢失,改善骨微结构和生物力学性能。
Objective: To observe the secondary bone damage in mice with systemic lupus erythematosus and explore the intervention effect of dihydroartemisinin. Methods:15-week-old female B6.MRL-Faslpr/J mice were divided into three groups:6 mg/kg prednisone group,150 mg/kg dihydroartemisinin group and lupus erythematosus group, 8 matched female C57 BL/6 J wild type mice were used for the blank control group. Mice in all groups were orally administered with corresponding drugs for 90 days. Micro-computed tomography assessments and bone histomorphometric analysis of both sites of proximal tibia,femur biomechanics testing were performed to study the bone metabolism and mass change in SLE mice. Results: The results showed that, compared with the blank control group, the bone mass, trabecular connectivity density and trabecular mineral density were decreased, the degree of trabecular separation and structure model index(SMI)were increased. Moreover,compared with prednisone group, the bone formation rate(BFR/TV) was increased while bone resorption was significantly inhibited in SLE group. Compared with SLE and prednisone group, the Elastic load, maximum load and fracture load of femur were significantly increased in dihydroartemisinin group. Conclusions:Dihydroartemisinin may inhibit high bone resorption without reducing bone formation,it may also prevent bone loss and improve bone microstructure and biomechanical properties induced by SLE.
Objective: To observe the secondary bone damage in mice with systemic lupus erythematosus and explore the intervention effect of dihydroartemisinin. Methods:15-week-old female B6.MRL-Faslpr/J mice were divided into three groups:6 mg/kg prednisone group,150 mg/kg dihydroartemisinin group and lupus erythematosus group, 8 matched female C57 BL/6 J wild type mice were used for the blank control group. Mice in all groups were orally administered with corresponding drugs for 90 days. Micro-computed tomography assessments and bone histomorphometric analysis of both sites of proximal tibia,femur biomechanics testing were performed to study the bone metabolism and mass change in SLE mice. Results: The results showed that, compared with the blank control group, the bone mass, trabecular connectivity density and trabecular mineral density were decreased, the degree of trabecular separation and structure model index(SMI)were increased. Moreover,compared with prednisone group, the bone formation rate(BFR/TV) was increased while bone resorption was significantly inhibited in SLE group. Compared with SLE and prednisone group, the Elastic load, maximum load and fracture load of femur were significantly increased in dihydroartemisinin group. Conclusions:Dihydroartemisinin may inhibit high bone resorption without reducing bone formation,it may also prevent bone loss and improve bone microstructure and biomechanical properties induced by SLE.
引文
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[2]An J,Minie M,Sasaki T,et al.Antimalarial Drugs as Immune Modulators:New Mechanisms for Old Drugs.Annu Rev Med.2017,68 (1) :317～330.
[3]Liu Y,Cui Y,Zhang X,et al.Effects of salvianolate on bone metabolism in glucocorticoid-treated lupus-prone B6.MRL-Fas (lpr) /J mice.Drug Des Devel Ther,2016,10 (1) ∶2535～2546.
[4]Bozec A,Zaiss MM.T Regulatory Cells in Bone Remodelling.Current Osteoporosis Reports,2017,15 (3) ∶121～125.
[5]何瑶,曾玉萍,孟妍明,等.白细胞介素-21对B细胞信号调节及与系统性红斑狼疮发病机制的研究.华西医学,2017,32 (12) ∶1972～1976.
[6]Srivastava R K,Dar H Y,Mishra P K.Immunoporosis:Immunology of Osteoporosis-Role of T Cells.Frontiers in Immunology,2018,9 (1) ∶657～670.
[7]Zha L,He L,Liang Y,et al.TNF-alpha contributes to postmenopausal osteoporosis by synergistically promoting RANKL-induced osteoclast formation.Biomedicine & Pharmacotherapy,2018,102 (1) ∶369～374.
[8]Blaschke M,Koepp R,Cortis J,et al.IL-6,IL-1beta,and TNF-alpha only in combination influence the osteoporotic phenotype in Crohn's patients via bone formation and bone resorption.Advances in Clinical and Experimental Medicine,2018,27 (1) ∶45～56.
[9]薛明,杨谛,李任.肿瘤坏死因子-α和白细胞介素-2对成骨细胞增殖的影响.微生物学杂志,2010,30 (3) ∶100～102.
[10]刘佳,罗映红,龙昱,等.IL-4,IL-6和TNF-α 对脐带血来源的间充质干细胞成骨分化的影响.中国骨质疏松杂志,2017,23 (9) ∶1136～1139.
[11]宋冬明,崔婷,裘影影,等.肿瘤坏死因子-α抑制狼疮鼠(MPL/lpr)骨髓间充质干细胞成骨分化参与骨质疏松机制的体内研究.中华风湿病学杂志,2015,19 (6) ∶364～368.
[12]刘连勇,郑胜喜,甄燕,等.原发性骨质疏松的骨骼免疫机制研究进展.中国骨质疏松杂志,2016,22 (7) ∶912～917.
[13]Bugatti S,Bogliolo L,Montecucco C,et al.B cell autoimmunity and bone damage in rheum-atoid arthritis.Reumatismo,2016,68 (3) ∶117～125.
[14]Ruiz-Irastorza G,Danza A,Khamashta M.Glucocorticoid use and abuse in SLE.Rheumatology,2012,51 (7) ∶1145～1153.
[15]Krasselt M,Baerwald C.An update on glucocorticoid-induced osteoporosis.Dtsch Med Wochenschr,2016,141 (5) ∶352～357.
[16]Conaway H H,Henning P,Lie A,et al.Activation of dimeric glucocorticoid receptors in osteoclast progenitors potentiates RANKL induced mature osteoclast bone resorbing activity.Bone,2016,93 (1) ∶43～54.
[17]Teitelbaum S L.Glucocorticoids and the osteoclast.Clin Exp Rheumatol,2015,33 (Suppl.92) ∶37～39.
[18]王子见,李怡瑞,吴文成,等.青蒿素及其衍生物的药理学作用研究进展.广西医学,2018,40 (10) ∶1222～1224.
[19]肖黎辉,冯学兵.青蒿素类药物与自身免疫性疾病.辽宁中医药大学学报,2011,13 (1) ∶130～133.
[20]齐磊,段永刚,丁英奇,等.Notch-1下调对双氢青蒿素抗人骨肉瘤细胞株U-2OS存活率的影响.中国病理生理杂志,2015,31 (12) ∶2120～2125.
[21]刘洪伟,梅基雄.双氢青蒿素通过Wnt/β-catenin信号通路抑制胃癌细胞的增殖和侵袭.第三军医大学学报,2018,5 (1) ∶1～7.
[22]Wang C,Zholudov Y T,Nsabimana A,et al.Sensitive and selective electrochemical detection of artemisinin based on its reaction with p-aminophenylboronic acid.Analytica Chimica Acta,2016,937 (1) ∶39～42.