劉 洋,陳 臖,翟玉瑩,葉小天,肖 珊,柯詩韻,李青南,楊國柱,盧 麗,陸幸妍
(廣東藥科大學(xué)生命科學(xué)與生物制藥學(xué)院/廣東省生物技術(shù)候選藥物研究重點(diǎn)實(shí)驗(yàn)室,廣東廣州 510006)
阿魏酸鈉治療糖皮質(zhì)激素性骨質(zhì)疏松的實(shí)驗(yàn)研究
劉 洋,陳 臖,翟玉瑩,葉小天,肖 珊,柯詩韻,李青南,楊國柱,盧 麗,陸幸妍
(廣東藥科大學(xué)生命科學(xué)與生物制藥學(xué)院/廣東省生物技術(shù)候選藥物研究重點(diǎn)實(shí)驗(yàn)室,廣東廣州 510006)
目的 探討阿魏酸鈉對(duì)于大鼠糖皮質(zhì)激素性骨質(zhì)疏松癥的治療作用。方法 3月齡Wistar大鼠隨機(jī)均分5組:對(duì)照組、模型組、治療組(阿魏酸鈉低、中、高劑量組)。動(dòng)物處死前進(jìn)行鈣黃綠素雙熒光標(biāo)記。采用骨組織形態(tài)計(jì)量學(xué)方法測量脛骨的靜態(tài)參數(shù)、動(dòng)態(tài)參數(shù)、骨組織細(xì)胞和生長板變化。結(jié)果 ①靜態(tài)參數(shù):與對(duì)照組相比,模型組骨小梁面積百分?jǐn)?shù)、骨小梁厚度、骨小梁數(shù)量明顯減少,骨小梁分離度增大;與模型組相比,阿魏酸鈉中、高劑量組骨小梁面積百分?jǐn)?shù)、骨小梁厚度、骨小梁數(shù)量明顯增加,骨小梁分離度明顯減小。低劑量組骨小梁厚度明顯增加。②動(dòng)態(tài)參數(shù):與對(duì)照組相比,模型組標(biāo)記周長百分?jǐn)?shù)、骨轉(zhuǎn)化率、骨表面新骨形成率明顯增大;與模型組相比,中、高劑量組新骨年形成率增加。③骨組織細(xì)胞:與對(duì)照組相比,模型組單位骨小梁面積成骨細(xì)胞數(shù)量、破骨細(xì)胞數(shù)量以及成骨細(xì)胞周長占骨小梁周長百分率均明顯增加。與模型組相比:各個(gè)實(shí)驗(yàn)組均沒有明顯變化。④生長板:與對(duì)照組相比,模型組生長板寬明顯增大;與模型組相比,各實(shí)驗(yàn)組生長板退行細(xì)胞高度、生長板寬均沒有明顯變化。結(jié)論 阿魏酸鈉對(duì)糖皮質(zhì)激素性骨質(zhì)疏松的治療作用主要體現(xiàn)在增加骨量和改善骨小梁結(jié)構(gòu),并促進(jìn)骨形成。
糖皮質(zhì)激素性骨質(zhì)疏松;阿魏酸鈉;骨組織形態(tài)計(jì)量學(xué);骨組織細(xì)胞;生長板;骨小梁;松質(zhì)骨
糖皮質(zhì)激素性骨質(zhì)疏松癥(glucocorticoid-in-duced osteoporosis,GIOP)是目前發(fā)病率最高最常見的繼發(fā)性骨質(zhì)疏松癥。糖皮質(zhì)激素誘導(dǎo)的細(xì)胞氧化應(yīng)激反應(yīng),損傷成骨細(xì)胞、使成骨細(xì)胞凋亡增加[1]。但由于其強(qiáng)大抗炎和免疫抑制作用,很多患者必須長期甚至終生大劑量使用糖皮質(zhì)激素[2]?,F(xiàn)有研究多是針對(duì)糖皮質(zhì)激素用藥時(shí)骨骼的變化,而對(duì)停藥后及停藥后藥物治療對(duì)大鼠骨骼變化的研究較少。
阿魏酸鈉(sodium ferulate,SF)是一種穩(wěn)定的、低毒性、水溶性內(nèi)皮素受體拮抗劑,具有防止DNA的損傷,抗細(xì)胞凋亡,保護(hù)內(nèi)皮細(xì)胞,促進(jìn)血管平滑肌細(xì)胞增殖,改善局部血液供給等多種生理功能[3]。已有研究發(fā)現(xiàn)SF具有刺激體外培養(yǎng)的成骨細(xì)胞(osteoblast,Ob)增殖、分化和礦化的功能,可以促進(jìn)成骨相關(guān)基因的表達(dá)[4]。近來有國外學(xué)者報(bào)道,應(yīng)用阿魏酸鈉來治療骨關(guān)節(jié)炎、軟骨退變?nèi)〉昧溯^好的療效[5]。阿魏酸鈉有較強(qiáng)的舒張血管的作用,可有效減輕血流瘀滯狀態(tài)[6],減少骨壞死的發(fā)生率;另據(jù)報(bào)道,阿魏酸鈉可以有效地促進(jìn)去卵巢大鼠的骨重建作用,抑制去卵巢大鼠骨吸收作用[7-8]。但是對(duì)于糖皮質(zhì)激素性骨質(zhì)疏松癥干預(yù)治療的研究,尚未見報(bào)道。
1.1 材料
1.1.1 實(shí)驗(yàn)動(dòng)物 3月齡♀Wistar大鼠30只(SPF級(jí),中山大學(xué)動(dòng)物中心提供),許可證號(hào):44008500006272,體質(zhì)量(220±15)g,標(biāo)準(zhǔn)飼料,室溫。
1.1.2 藥品與試劑 地塞米松磷酸鈉注射液(辰欣藥業(yè)股份有限公司,批號(hào):1405216421,規(guī)格1 ml:2 mg)、熒光標(biāo)記物Calcein(Sigma Chemcal Co.USA);2-Methyloxethyl acetate(Sigma Chemcal Co.USA);甲基丙烯酸甲酯(成都市新都區(qū)木蘭鎮(zhèn)工業(yè)開發(fā)區(qū));鄰苯二甲酸二丁酯(成都市科龍化工試劑廠);過氧化苯甲酰(天津市福晨化學(xué)試劑廠)。
1.1.3 儀器 硬組織切片機(jī)(德國Leica RM2255);骨組織形態(tài)計(jì)量學(xué)測量系統(tǒng)(美國BIOQUANT OS-TEO公司)。
1.2 動(dòng)物分組和實(shí)驗(yàn)處理
1.2.1 動(dòng)物分組 Wistar大鼠隨機(jī)分成5組:對(duì)照組(Con組肌肉注射生理鹽水120 d);模型組[Mod組肌注地塞米松(Dex)1 mg·kg-1每周5次,90 d,停藥肌注生理鹽水恢復(fù)30 d];阿魏酸鈉治療組[低、中、高劑量組(Low、Mid、Hig組),肌注Dex 1 mg·kg-1,每周5次,90 d,停藥10 d,分別肌注阿魏酸鈉(20、40、80 mg·kg-1·d-1,20 d)]。
1.2.2 動(dòng)物處理 所有大鼠每周稱體重1次。并按體重變化調(diào)整給藥量。所有動(dòng)物處死前d 14、13 和d 4、3分別皮下注射鈣黃綠素,進(jìn)行雙熒光標(biāo)記。取實(shí)驗(yàn)組大鼠脛骨,經(jīng)不脫鈣包埋后,根據(jù)文獻(xiàn)方法[9],用Leica RM2255型切片機(jī)(Leica Co.Germa-ny)將PTM松質(zhì)骨切出5 μm薄片和9 μm厚片,5 μm薄片經(jīng)脫塑后采用甲苯胺藍(lán)染色法對(duì)切片染色,9 μm經(jīng)脫塑后熒光下觀察。
1.3 骨組織形態(tài)計(jì)量學(xué) 采用骨組織形態(tài)計(jì)量學(xué)方法進(jìn)行靜態(tài)參數(shù)測量,通過相關(guān)靜態(tài)參數(shù)包括骨小梁面積百分?jǐn)?shù)(%Tb.Ar)、骨小梁厚度(Tb.Th)、骨小梁數(shù)量(Tb.N)、骨小梁分離度(Tb.Sp),分析各組大鼠脛骨近心端松質(zhì)骨骨量和骨結(jié)構(gòu)變化情況。通過相關(guān)動(dòng)態(tài)參數(shù)包括骨礦化沉積率(MAR)、標(biāo)記周長百分?jǐn)?shù)(%L.Pm)、新骨年形成率(BFR/TV)、骨轉(zhuǎn)化率(BFR/BV)、骨表面新骨形成率(BFR/BS),分析各組大鼠脛骨近心端松質(zhì)骨骨形成和骨代謝的變化情況[10-11];通過相關(guān)骨細(xì)胞參數(shù)包括單位骨小梁面積成骨細(xì)胞數(shù)量(Ob.N/BS)、破骨細(xì)胞數(shù)量(Oc.N/BS);以及成骨細(xì)胞周長占骨小梁周長百分率(%Ob.S/BS)和破骨細(xì)胞周長占骨小梁周長百分率(%Oc.S/BS)。松質(zhì)骨生長板變化情況測量其生長板寬(G.P.Wi)和退行細(xì)胞高度(D.C.H)。
Tab 1 Comparison of static parameters of cancellous bone proximal tibia in different groups(±s,n=6)
Tab 1 Comparison of static parameters of cancellous bone proximal tibia in different groups(±s,n=6)
*P<0.05,**P<0.01 vs control;#P<0.05,##P<0.01 vs model
4.78 Mod 19.13±2.26** 25.31±0.48** 7.52±0.75** 111.81±14.08**Low 32.63±1.84* 39.82±1.67## 8.22±0.51* 83.21±7.04 Mid 38.10±2.69## 36.69±1.38## 10.39±0.71# 60.88±6.70##Hig 36.68±3.36## 38.55±1.59### 9.49±0.64# 68.12±7.11 Group %Tb.Ar/% Tb.Th/μm Tb.N/No·mm-1 Tb.Sp/μm Con 45.51±3.24 40.13±1.67 11.32±0.52 48.76± #
2.1 PTM骨量骨結(jié)構(gòu)變化 如Fig 1、Tab 1所示:與對(duì)照組相比,模型組%Tb.Ar減小(P<0.01),Tb.Th明顯減?。≒<0.01),Tb.N明顯減少(P< 0.01),Tb.Sp明顯增大(P<0.01)。與模型組相比,阿魏酸鈉中、高劑量組%Tb.Ar增大(P<0.01),Tb.Th明顯增加(P<0.01),Tb.Sp明顯增大(P<0.05)。Tb.Sp明顯減少(高劑量組P<0.05,中劑量組P<0.01)。
Tab 2 Comparison of dynamic parameters of cancellous bone proximal tibia in different groups(±s,n=6)
Tab 2 Comparison of dynamic parameters of cancellous bone proximal tibia in different groups(±s,n=6)
*P<0.05,**P<0.01 vs control;#P<0.05,##P<0.01 vs model
Group MAR/μm %L.Pm/% BFR/TV/%·y-1 BFR/BV/%·y-1 BFR/BS/%·y -1 Con 1.22±0.08 2.63±0.29 21.21±1.84 61.34±5.24 1151±64.83 Mod 1.14±0.05 6.13±0.92* 28.57±3.50 202.4±32.39** 2557±403.1*Low 1.17±0.08 7.59±0.62** 46.31±5.40** 155.1±20.00** 3320±511.9**Mid 1.49±0.16 7.56±1.03** 65.40±5.09**## 217.8±18.83** 4014±439.4**Hig 1.39±0.14 6.57±1.09* 51.53±9.94*# 175.8±33.95* 3446±719.0*
Tab 3 Comparison of bone formation and resorption parameters of cancellous bone proximal tibia in different groups(±s,n=6)
Tab 3 Comparison of bone formation and resorption parameters of cancellous bone proximal tibia in different groups(±s,n=6)
*P<0.05,**P<0.01 vs control.
Group Ob.N/BS/N·mm-1 %Ob.S/BS/% Oc.N/BS/No·mm-1%Oc.S/BS/% Con 3.61±0.55 97.07±16.92 3.43±0.60 46.68±9.85 Mod 8.41±1.46* 336.0±83.14* 8.19±1.432* 219.9±45.37**Low 7.96±1.43* 248.0±63.42* 7.034±1.77 153.2±16.39**Mid 6.18±1.08 355.5±94.49* 8.59±1.53* 134.3±15.53**Hig 8.98±0.47** 323.9±57.40** 7.77±0.97** 220.6±14.33**
Fig 1 Effects of dexametha-sone and dexamethasone plus SF at different doses on bone histomorphometry of cancel-lous bone proximal tibia in Toluidine blue-stained(5 μm,×20)
Fig 2 Fluorescent Calcein markers in bone formation of proximal tibia(9 μm,×100)
2.2 PTM骨形成骨代謝影響 如Fig 2、Tab 2所示:與對(duì)照組相比,模型組%L.Pm明顯增大(P<0.05),BFR/BV明顯增大(P<0.01),BFR/BS明顯增大(P<0.05)。與模型組相比,阿魏酸鈉中、高劑量組新骨年形成率明顯增大(中劑量組P<0.01,高劑量組P<0.05)。
2.3 PTM骨組織細(xì)胞 骨小梁表面成骨細(xì)胞和破骨細(xì)胞如Fig 3、Tab 3所示:與對(duì)照組相比,模型組Ob.N/BS、%Ob.S/BS、Oc.N/BS明顯增加(P<0.05),%Oc.S/BS明顯增加(P<0.01)。與模型組相比,各個(gè)實(shí)驗(yàn)組均沒有明顯變化。
Fig 3 Osteoblast(dashed lines)and osteoclast(solid lines)in adjacent trabecular bone labeled in Toluidine blue-stained(5 μm,×200)
2.4 PTM生長板影響 如Fig 4、Tab 4所示:與對(duì)照組相比,模型組生長板寬明顯增大(P<0.05)。與模型組相比,阿魏酸鈉各組生長板退行細(xì)胞高度、生長板寬均沒有明顯變化。
Fig 4 Effects of dexametha-sone and dexamethasone plus SF in different dose on bone histomorphometry of growth plate(5 μm,×200)
Tab 4 Comparison of histomorphometry parameter of growth plate in different groups(±s,n=6)
Tab 4 Comparison of histomorphometry parameter of growth plate in different groups(±s,n=6)
*P<0.05,**P<0.01 vs control
Group G.P.Wi/μm D.C.H/μm Con 73.21±2.93 11.97±0.73 Mod 89.38±4.61* 15.39±1.96 Low 95.37±8.56* 15.52±1.37 Mid 93.15±7.51* 15.66±1.33 Hig 95.27±4.45** 18.18±1.37***
骨代謝平衡是指成骨細(xì)胞的骨形成作用生成新骨,破骨細(xì)胞的骨吸收作用吸收舊骨,骨形成和骨吸收動(dòng)態(tài)平衡[12],而骨量的改變是骨代謝平衡的結(jié)果。目前研究普遍認(rèn)為,糖皮質(zhì)激素給藥,抑制了腸鈣吸收及骨鈣、磷重吸收,會(huì)促進(jìn)成骨細(xì)胞和骨細(xì)胞的凋亡,使成骨細(xì)胞失活,抑制成骨細(xì)胞的功能[13]。停用糖皮質(zhì)激素,成骨細(xì)胞的功能可逐漸恢復(fù),隨著停用時(shí)間的延長,骨質(zhì)疏松癥狀有所恢復(fù)[14]。本實(shí)驗(yàn)結(jié)果顯示模型組骨形成明顯增加,在細(xì)胞水平發(fā)現(xiàn)模型組成骨細(xì)胞和破骨細(xì)胞都增加,但骨量和骨小梁結(jié)構(gòu)沒有恢復(fù),原因可能是停藥30 d的時(shí)間增加骨轉(zhuǎn)換,但不足以大鼠骨質(zhì)疏松癥狀完全恢復(fù)。
有研究表明,阿魏酸鈉通過抑制炎癥反應(yīng),可以維護(hù)缺血區(qū)域神經(jīng)元的基本結(jié)構(gòu)功能[15];同時(shí)阿魏酸鈉還可以提高VEGF以及其它骨生長因子,如TGF-13、BMP等表達(dá),從而促進(jìn)了局部血管增生和成骨細(xì)胞分化,使成骨細(xì)胞活性增強(qiáng)[16];本研究中阿魏酸鈉促進(jìn)成骨細(xì)胞增殖作用不明顯,但是其明顯增強(qiáng)成骨細(xì)胞的骨形成作用。另外阿魏酸鈉上的酚羥基結(jié)構(gòu)可使氧自由基發(fā)生還原反應(yīng),降低氧自由基水平,減少氧自由基對(duì)細(xì)胞和組織的損害等作用[17-18]。本研究發(fā)現(xiàn)與模型組相比,阿魏酸鈉組骨轉(zhuǎn)化明顯增加,這可能是由于阿魏酸鈉對(duì)細(xì)胞的保護(hù)從而使成骨細(xì)胞在骨的形成和修復(fù)中發(fā)揮作用。
生長板是位于長骨兩端骨骺和骨干之間的軟骨組織??煞至?、成熟、肥大,以軟骨內(nèi)成骨的方式對(duì)于長骨生長具有重要作用[19]。大鼠成熟后,軟骨增殖潛能逐漸下降[20],本實(shí)驗(yàn)所用大鼠為7月齡,糖皮質(zhì)激素使用90 d,停藥30 d后模型組軟骨細(xì)胞增殖區(qū)面積增大,這顯示停用糖皮質(zhì)激素后刺激軟骨增殖能力。
綜上所述:本研究發(fā)現(xiàn)糖皮質(zhì)激素使用90 d,停藥30 d后,模型組的骨量減少和骨結(jié)構(gòu)被破壞的情況沒有恢復(fù);而應(yīng)用阿魏酸鈉治療可以通過促進(jìn)骨轉(zhuǎn)化增加骨量和改善骨小梁結(jié)構(gòu)。
(致謝:本研究相關(guān)實(shí)驗(yàn)主要在廣東藥科大學(xué)生命科學(xué)與生物制藥學(xué)院骨骼與骨骼肌疾病研究室和廣東省生物技術(shù)候選藥物研究重點(diǎn)實(shí)驗(yàn)室完成,感謝以上實(shí)驗(yàn)室的老師對(duì)本研究給予的支持。)
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Effect of Sodium ferulate on glucocorticoid-induced osteoporosis
LIU Yang,CHEN Jun,ZHAI Yu-ying,YE Xiao-tian,XIAO Shan,KE Shi-yun,LI Qing-nan,YANG Guo-zhu,LU Li,LU Xing-yan
(School of Life Science and Biopharmacy,Guangdong Pharmaceutical University/Guangdong Provincial Key Laboratory of Biotechnology Candidate Drug Research,Guangzhou 510006,China)
Aim To study the influence of Sodium fer-ulate(SF)on bone metabolism in glucocorticoidin-duced osteoporosis rats.Methods Thirty cases of fe-male Wistar Rats(3-month-old)were divided into con-trol group,model group and SF group(low-dose group,middle-dose group,high-dose group)by ran-domized block design.Double fluorochrome labeling with calcein was performed before necropsy.The left tibia was taken for bone histomorphometry.Results In static parameters,the proximal tibia cancellous bone trabecular thickness,trabecular quantity and area ratio were significantly reduced in model group compared with control group;while compared with model group,those were increased in middle and high-dose SF group.Trabecular separation degree was increased in model group compared with control group,while it was decreased in middle and high-dose SF group compared with model group.In dynamic parameters,the calcula-tion parameters of cancellous bone mark perimeter rate and the bone formation rate were increased in model group compared with control group,in middle and high-dose SF group the bone formation rate was in-creased compared with model group.In bone cells,os-teoclast number per mm,osteoblast number per mm,percent osteoblast surface perimeter and percent osteo-clast surface perimeter were increased in model group compared with control group.In growth-plate,the thickness of growth-plate was increased in model group compared with control group.In bone cells and growth-plate there was no statistical significance between treat-ment group and model group.Conclusion This study demonstrates that SF can increase bone mass and im-prove bone structure,which may be related to the im-provement of bone formation.SF is effective for GIOP in rats.
GIOP;Sodium ferulate;bone histomor-phometry studies;bone cell;growth-plate;bone tra-becula;cancellous bone
時(shí)間:2016-2-26 10:20 網(wǎng)絡(luò)出版地址:http://www.cnki.net/kcms/detail/34.1086.R.20160226.1020.038.html
10.3969/j.issn.1001-1978.2016.03.019
A
1001-1978(2016)03-0394-05
R-332;R323.72;R336;R681.05;R977.11
2015-10-04,
2015-11-24
國家自然科學(xué)基金面上項(xiàng)目(No 30971172);廣東省科技計(jì)劃項(xiàng)目(No 2013B060300022)
劉 洋(1989-),女,碩士生,研究方向:骨骼疾病藥理藥效學(xué),Tel:020-39352201,E-mail:15817148003@139.com;李青南(1956-),女,博士,教授,研究員,研究方向:骨代謝病理生理及藥理藥效學(xué),Tel:020-39352589,E-mail:qingnanli@sina.com;陸幸妍(1963-),女,副教授,研究方向:骨和骨骼肌代謝性疾病分子機(jī)制及藥物靶點(diǎn)發(fā)現(xiàn),通訊作者,Tel:020-39352201,E-mail:xingyanlu2005@126.com