运动联合阿仑膦酸钠对OVX大鼠骨质疏松的影响及机制研究
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摘要
目的
本实验通过雌性大鼠卵巢切除复制绝经后骨质疏松模型，观察运动是否可增强阿仑膦酸钠对骨质疏松的作用及机制，为临床治疗提供依据。
方法
90只6月龄雌性SD大鼠，随机分为假手术组（18只）和卵巢切除模型组（72只）。大鼠卵巢切除8周后，双能X线骨密度仪测定大鼠第四腰椎、左股骨、右股骨骨密度（BMD），ELISA法检测大鼠血清雌二醇含量。随后，存活的卵巢切除大鼠分为模型组、阿仑膦酸钠治疗组、运动治疗组、阿仑膦酸钠与运动联合治疗组，分别给予1mg/kg d阿仑膦酸钠灌胃和（或）跑台运动干预治疗12周后进行以下实验：
1．双能X线骨密度仪重新测定各组大鼠第四腰椎、左股骨、右股骨BMD；肌电图机检测大鼠双侧股神经传导速度（MCV）、运动末端潜伏期（ML）和复合肌肉动作电位（CMAP）。
2．ELISA法测定大鼠血清骨源性碱性磷酸酶（BALP）、骨钙素（BGP）、Ⅰ型前胶原羧基端前肽（PICP）及抗酒石酸酸性磷酸酶（TRAP）、Ⅰ型胶原羧基端交联端肽（ICTP）含量。
3．分析大鼠骨组织NF-κB受体活化因子配体（RANKL）和骨保护素（OPG）的mRNA和蛋白表达水平；western-blotting方法检测大鼠骨组织p38、ERK、JNK的磷酸化水平及c-Fos含量。
4．ELISA法检测大鼠血清IL-1β、TNFα含量；western-blotting方法分析大鼠骨组织NF-κB抑制蛋白IκB的磷酸化水平。
结果
1.去卵巢骨质疏松大鼠阿仑膦酸钠和（或）运动干预治疗12周后，模型组与假手术组比，BMD显著降低（P<0.05）；阿仑膦酸钠、运动均可显著提高骨质疏松大鼠BMD，且两者联用较单用效果明显（P<0.05）；阿仑膦酸钠、运动单独治疗两组间未见明显差异。
2.各组大鼠双侧股神经MCV未见明显差异。双侧股神经ML、CMAP模型组与假手术组比未见明显改变。阿仑膦酸钠对ML、CMAP无显著改善作用。运动单用、阿仑膦酸钠与运动联合运用可明显缩短模型组双侧ML（P<0.05），且左侧股神经ML两者联用较阿仑膦酸钠单用效果显著（P<0.05）。运动可显著增加模型组右侧CMAP，且运动和阿仑膦酸钠联合运用较阿仑膦酸钠单独应用作用强（P<0.05）。
3.去卵巢骨质疏松大鼠血清BALP、BGP、PICP和TRAP、ICTP显著增高；阿仑膦酸钠、运动、阿仑膦酸钠与运动联合运用均可显著降低上述指标（P<0.05）；阿仑膦酸钠和运动联合运用较阿仑膦酸钠和（或）运动单用治疗效果明显（P<0.05）。
4.去卵巢骨质疏松大鼠TRANKL mRNA及蛋白水平表达升高、OPGmRNA及蛋白水平表达降低，TRANKL/OPG升高；阿仑膦酸钠、运动均可显著逆转模型组的上述改变，且阿仑膦酸钠与运动联合运用较阿仑膦酸钠、运动单用治疗效果显著（P<0.05）。
5.去卵巢骨质疏松大鼠骨组织JNK磷酸化水平、c-Fos含量明显升高（P<0.05）；阿仑膦酸钠和（或）运动均可显著抑制JNK的磷酸化水平和c-Fos表达（P<0.05），但3种干预治疗组间未见明显差别。
6.去卵巢骨质疏松大鼠血清IL-1β、TNFα含量显著增高（P<0.05），阿仑膦酸钠和（或）运动可显著抑制IL-1β、TNFα表达，且二者联合运用较单用效果显著（P<0.05）。
7.去卵巢骨质疏松大鼠骨组织IκB磷酸化水平明显升高（P<0.05）；阿仑膦酸钠和（或）运动均可显著抑制IκB的磷酸化水平（P<0.05），但3种干预治疗组间见未见明显差别。
结论
阿仑膦酸钠、运动可能通过IκB/NF-κB通路抑制去卵巢骨质疏松大鼠血清细胞因子IL-1β和TNFα的释放，进而诱导成骨细胞OPG表达，抑制RANKL表达，使RANKL/OPG比值降低，从而抑制其下游信号通路JNK-c-fos的激活，抑制破骨细胞的骨吸收作用，最终治疗骨质疏松。
Objective
To observe the therapy effects of exercise (EX) combined with AlendronateSodium (FOX) on the treatment of ovariectomy-induced osteoporosis; then furtherresearch whether exercise can enhance the effects of Alendronate Sodium in theprotection against postmenopausal osteoporosis (PMOP) and its possible mechanism.
Methods
Ninety6months old female SD rats were randomly divided into2groups: sham(18rats) and ovariectomized group (72rats). Eight weeks after the ovariectomy,dual-energy x-ray absorptiometry (DEXA) scaned the bone mineral density (BMD) ofthe fourth lumbar vertebra, left femur and right femur. Then, the livingovariectomized rats were divided into4groups: ovariectomized model group (OVX),fosamax treatment group (OVX+FOX), exercise treatment group (OVX+EX), andexercise combined with fosamax treatment group (OVX+FOX+EX). Rats weretreated with1mg/kg fosamax intragastrically and/or exercise once a day for12weeks.
1. DEXA scaned the BMD of the fourth lumbar vertebra, left femur and rightfemur again; Electromyogram (EMG) detected the Motor Nerve Conduction Velocity(MCV), motor distal latency (ML) and compound muscle action potential (CMAP) ofbilateral femoral nerve.
2. ELISA analysed serum bone isoenzyme alkaline phosphatase (BALP),osteocalcin (BGP), carboxy terminal propeptideⅠprotection (PICP), tartrate-resistantacid phosphatase (TRAP), and type Ⅰcollagen cross-linked telopeptide (ICTP).
3. Real time PCR detected the mRNA expression of osteoprotegerin (OPG) andthe receptor activator of nuclear factor kappa B ligand (RANKL) in rat bone tissue;western-blotting analysed the protein expression of p38, ERK, JNK, and c-Fos.
4. ELISA analysed serum IL-1β, TNFα content; western-blotting analyzedNF-kappa B inhibitor IкB content in rat bone tissue.
Results
1. Twelve weeks after FOX and/or EX treatment towards ovariectomy rats,ovariectomized rats showed obviously lower BMD compared with sham group(P<0.05); FOX and/or EX can significantly increase BMD reduced by ovariectomy(P<0.05); BMD is significantly higher in the OVX+EX+FOX group than OVX+FOXor OVX+EX (P<0.05). However, no obvious difference was noticed betweenOVX+FOX and OVX+EX.
2. Comapared to sham group, there was no distinct difference among the5groups inMCV. Neither ovariectomy nor FOX can significantly affect ML or CMAP. EX, EX+FOX canshorter ML compared to OVX (P<0.05) and ML is remarkablely shorter in OVX+FOX+EX thanFOX alone on the left femoral nerve (P<0.05). EX can improve CMAP on the right femoralnerve compared to OVX and CMAP is obviously higher in OVX+FOX+EX is than FOX alone(P<0.05).
3. The serum BALP, BGP, PICP, TRAP, ICTP were significantly higher inovariectomized rats compared to sham group (P<0.05); FOX and/or EX cansignificantly reduce above parameters (P<0.05). OVX+EX+FOX group showed anobvious lowness than FOX or EX alone (P<0.05).
4. Compared to sham group, TRANKL mRNA and protein expression weresignificantly increased (P<0.05); OPG mRNA and protein were remarkablely lower inOVX group (P<0.05); the TRANKL/OPG ratio obviously increased (P<0.05). FOXand/or EX can significantly reduce RANKL/OPG ratio (P<0.05). OVX+EX+FOXgroup showed obviously lower TRANKL/OPG ratio than FOX or EX alone (P<0.05).
5. JNK phosphorylation level and c-Fos content were significantly increased inthe OVX group than sham in bone tissue (P<0.05); FOX and/or EX can significantlyinhibit the phosphorylation level of JNK and c-Fos content (P<0.05); however, nosignificant difference was observed among the OVX+FOX, OVX+EX, andOVX+FOX+EX.
6. The serum IL-1β and TNFα level were significantly increased in OVX groupthan sham (P<0.05); FOX and/or EX can significantly reduce IL-1β and TNFα level (P<0.05); OVX+EX+FOX group showed obvious lower IL-1β and TNFα than FOXor EX alone (P<0.05).
7. IκB phosphorylation level was remarkablely incread in OVX group than shamin bone tissue (P<0.05); FOX and/or EX can significantly inhibit the phosphorylationlevel of IκB (P<0.05); however, no significant difference was observed among theOVX+FOX, OVX+EX, and OVX+FOX+EX.
Conclusion
Fosamax and exercise may inhibit IL-1β and TNFα expression through theIκB/NF-κB pathway induced by ovariectomy, and then induce the OPG expression,inhibit the RANKL expression in osteoblas and decrease the RANKL/OPG ratio, thusinhibit the JNK-c-fos signal pathway and at last restrain bone absorption effect ofosteoclast.
本实验通过雌性大鼠卵巢切除复制绝经后骨质疏松模型，观察运动是否可增强阿仑膦酸钠对骨质疏松的作用及机制，为临床治疗提供依据。
方法
90只6月龄雌性SD大鼠，随机分为假手术组（18只）和卵巢切除模型组（72只）。大鼠卵巢切除8周后，双能X线骨密度仪测定大鼠第四腰椎、左股骨、右股骨骨密度（BMD），ELISA法检测大鼠血清雌二醇含量。随后，存活的卵巢切除大鼠分为模型组、阿仑膦酸钠治疗组、运动治疗组、阿仑膦酸钠与运动联合治疗组，分别给予1mg/kg d阿仑膦酸钠灌胃和（或）跑台运动干预治疗12周后进行以下实验：
1．双能X线骨密度仪重新测定各组大鼠第四腰椎、左股骨、右股骨BMD；肌电图机检测大鼠双侧股神经传导速度（MCV）、运动末端潜伏期（ML）和复合肌肉动作电位（CMAP）。
2．ELISA法测定大鼠血清骨源性碱性磷酸酶（BALP）、骨钙素（BGP）、Ⅰ型前胶原羧基端前肽（PICP）及抗酒石酸酸性磷酸酶（TRAP）、Ⅰ型胶原羧基端交联端肽（ICTP）含量。
3．分析大鼠骨组织NF-κB受体活化因子配体（RANKL）和骨保护素（OPG）的mRNA和蛋白表达水平；western-blotting方法检测大鼠骨组织p38、ERK、JNK的磷酸化水平及c-Fos含量。
4．ELISA法检测大鼠血清IL-1β、TNFα含量；western-blotting方法分析大鼠骨组织NF-κB抑制蛋白IκB的磷酸化水平。
结果
1.去卵巢骨质疏松大鼠阿仑膦酸钠和（或）运动干预治疗12周后，模型组与假手术组比，BMD显著降低（P<0.05）；阿仑膦酸钠、运动均可显著提高骨质疏松大鼠BMD，且两者联用较单用效果明显（P<0.05）；阿仑膦酸钠、运动单独治疗两组间未见明显差异。
2.各组大鼠双侧股神经MCV未见明显差异。双侧股神经ML、CMAP模型组与假手术组比未见明显改变。阿仑膦酸钠对ML、CMAP无显著改善作用。运动单用、阿仑膦酸钠与运动联合运用可明显缩短模型组双侧ML（P<0.05），且左侧股神经ML两者联用较阿仑膦酸钠单用效果显著（P<0.05）。运动可显著增加模型组右侧CMAP，且运动和阿仑膦酸钠联合运用较阿仑膦酸钠单独应用作用强（P<0.05）。
3.去卵巢骨质疏松大鼠血清BALP、BGP、PICP和TRAP、ICTP显著增高；阿仑膦酸钠、运动、阿仑膦酸钠与运动联合运用均可显著降低上述指标（P<0.05）；阿仑膦酸钠和运动联合运用较阿仑膦酸钠和（或）运动单用治疗效果明显（P<0.05）。
4.去卵巢骨质疏松大鼠TRANKL mRNA及蛋白水平表达升高、OPGmRNA及蛋白水平表达降低，TRANKL/OPG升高；阿仑膦酸钠、运动均可显著逆转模型组的上述改变，且阿仑膦酸钠与运动联合运用较阿仑膦酸钠、运动单用治疗效果显著（P<0.05）。
5.去卵巢骨质疏松大鼠骨组织JNK磷酸化水平、c-Fos含量明显升高（P<0.05）；阿仑膦酸钠和（或）运动均可显著抑制JNK的磷酸化水平和c-Fos表达（P<0.05），但3种干预治疗组间未见明显差别。
6.去卵巢骨质疏松大鼠血清IL-1β、TNFα含量显著增高（P<0.05），阿仑膦酸钠和（或）运动可显著抑制IL-1β、TNFα表达，且二者联合运用较单用效果显著（P<0.05）。
7.去卵巢骨质疏松大鼠骨组织IκB磷酸化水平明显升高（P<0.05）；阿仑膦酸钠和（或）运动均可显著抑制IκB的磷酸化水平（P<0.05），但3种干预治疗组间见未见明显差别。
结论
阿仑膦酸钠、运动可能通过IκB/NF-κB通路抑制去卵巢骨质疏松大鼠血清细胞因子IL-1β和TNFα的释放，进而诱导成骨细胞OPG表达，抑制RANKL表达，使RANKL/OPG比值降低，从而抑制其下游信号通路JNK-c-fos的激活，抑制破骨细胞的骨吸收作用，最终治疗骨质疏松。
Objective
To observe the therapy effects of exercise (EX) combined with AlendronateSodium (FOX) on the treatment of ovariectomy-induced osteoporosis; then furtherresearch whether exercise can enhance the effects of Alendronate Sodium in theprotection against postmenopausal osteoporosis (PMOP) and its possible mechanism.
Methods
Ninety6months old female SD rats were randomly divided into2groups: sham(18rats) and ovariectomized group (72rats). Eight weeks after the ovariectomy,dual-energy x-ray absorptiometry (DEXA) scaned the bone mineral density (BMD) ofthe fourth lumbar vertebra, left femur and right femur. Then, the livingovariectomized rats were divided into4groups: ovariectomized model group (OVX),fosamax treatment group (OVX+FOX), exercise treatment group (OVX+EX), andexercise combined with fosamax treatment group (OVX+FOX+EX). Rats weretreated with1mg/kg fosamax intragastrically and/or exercise once a day for12weeks.
1. DEXA scaned the BMD of the fourth lumbar vertebra, left femur and rightfemur again; Electromyogram (EMG) detected the Motor Nerve Conduction Velocity(MCV), motor distal latency (ML) and compound muscle action potential (CMAP) ofbilateral femoral nerve.
2. ELISA analysed serum bone isoenzyme alkaline phosphatase (BALP),osteocalcin (BGP), carboxy terminal propeptideⅠprotection (PICP), tartrate-resistantacid phosphatase (TRAP), and type Ⅰcollagen cross-linked telopeptide (ICTP).
3. Real time PCR detected the mRNA expression of osteoprotegerin (OPG) andthe receptor activator of nuclear factor kappa B ligand (RANKL) in rat bone tissue;western-blotting analysed the protein expression of p38, ERK, JNK, and c-Fos.
4. ELISA analysed serum IL-1β, TNFα content; western-blotting analyzedNF-kappa B inhibitor IкB content in rat bone tissue.
Results
1. Twelve weeks after FOX and/or EX treatment towards ovariectomy rats,ovariectomized rats showed obviously lower BMD compared with sham group(P<0.05); FOX and/or EX can significantly increase BMD reduced by ovariectomy(P<0.05); BMD is significantly higher in the OVX+EX+FOX group than OVX+FOXor OVX+EX (P<0.05). However, no obvious difference was noticed betweenOVX+FOX and OVX+EX.
2. Comapared to sham group, there was no distinct difference among the5groups inMCV. Neither ovariectomy nor FOX can significantly affect ML or CMAP. EX, EX+FOX canshorter ML compared to OVX (P<0.05) and ML is remarkablely shorter in OVX+FOX+EX thanFOX alone on the left femoral nerve (P<0.05). EX can improve CMAP on the right femoralnerve compared to OVX and CMAP is obviously higher in OVX+FOX+EX is than FOX alone(P<0.05).
3. The serum BALP, BGP, PICP, TRAP, ICTP were significantly higher inovariectomized rats compared to sham group (P<0.05); FOX and/or EX cansignificantly reduce above parameters (P<0.05). OVX+EX+FOX group showed anobvious lowness than FOX or EX alone (P<0.05).
4. Compared to sham group, TRANKL mRNA and protein expression weresignificantly increased (P<0.05); OPG mRNA and protein were remarkablely lower inOVX group (P<0.05); the TRANKL/OPG ratio obviously increased (P<0.05). FOXand/or EX can significantly reduce RANKL/OPG ratio (P<0.05). OVX+EX+FOXgroup showed obviously lower TRANKL/OPG ratio than FOX or EX alone (P<0.05).
5. JNK phosphorylation level and c-Fos content were significantly increased inthe OVX group than sham in bone tissue (P<0.05); FOX and/or EX can significantlyinhibit the phosphorylation level of JNK and c-Fos content (P<0.05); however, nosignificant difference was observed among the OVX+FOX, OVX+EX, andOVX+FOX+EX.
6. The serum IL-1β and TNFα level were significantly increased in OVX groupthan sham (P<0.05); FOX and/or EX can significantly reduce IL-1β and TNFα level (P<0.05); OVX+EX+FOX group showed obvious lower IL-1β and TNFα than FOXor EX alone (P<0.05).
7. IκB phosphorylation level was remarkablely incread in OVX group than shamin bone tissue (P<0.05); FOX and/or EX can significantly inhibit the phosphorylationlevel of IκB (P<0.05); however, no significant difference was observed among theOVX+FOX, OVX+EX, and OVX+FOX+EX.
Conclusion
Fosamax and exercise may inhibit IL-1β and TNFα expression through theIκB/NF-κB pathway induced by ovariectomy, and then induce the OPG expression,inhibit the RANKL expression in osteoblas and decrease the RANKL/OPG ratio, thusinhibit the JNK-c-fos signal pathway and at last restrain bone absorption effect ofosteoclast.
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