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首页> 外文期刊>International journal of molecular medicine >Fluvastatin improves osteoporosis in fructose-fed insulin resistant model rats through blockade of the classical mevalonate pathway and antioxidant action.
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Fluvastatin improves osteoporosis in fructose-fed insulin resistant model rats through blockade of the classical mevalonate pathway and antioxidant action.

机译：氟伐他汀通过阻断经典的甲羟戊酸途径和抗氧化作用，改善了果糖喂养的胰岛素抵抗模型大鼠的骨质疏松症。

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Feeding rats with a high-fructose diet induced insulin resistance, leading to hypertension or metabolic disorders. Although hypertension is known to accelerate osteoporosis, it is not obvious whether insulin resistance would accelerate osteoporosis. In this study, we evaluated whether osteoporosis might accelerate in fructose-fed rats (FFR), and examined the effect of fluvastatin through a blockade of the mevalonate pathway and an antioxidant action. Stimulation of recombinant receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) expressed by osteoblasts/ stromal cells and macrophage-colony stimulating factor (M-CSF) significantly increased TRAP-positive multinuclear osteoclasts and pit formation, accompanied by an increase in reactive oxygen species as assessed by dichlorodihydrofluorescein (DCF) staining. Interestingly, it was completely abolished by treatment with fluvastatin, pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC), but not pravastatin. These actions of fluvastatin were partially abolished by co-treatment with geranylgeranylpyrophosphate (GGPP), but not farnesylpyrophosphate (FPP). In the estrogen-deficient model by ovariectomy, FFR exhibited a decrease in bone mineral density, activation of osteoclasts, and an increase in urinary deoxypyridinoline. Importantly, the treatment of fluvastatin, but not pravastatin, attenuated FFR-induced osteoporosis. The present study demonstrates that fructose fed to rats induced insulin resistance and accelerated osteoporosis, while fluvastatin, but not pravastatin, significantly attenuated osteoclast differentiation and activation through a blockade of the classical mevalonate pathway and an antioxidant action, leading to prevention of osteoporosis.
机译：用高果糖饮食喂养大鼠会引起胰岛素抵抗，从而导致高血压或代谢紊乱。尽管已知高血压会加速骨质疏松症，但胰岛素抵抗是否会加速骨质疏松症尚不清楚。在这项研究中，我们评估了果糖喂养大鼠（FFR）中骨质疏松症是否会加速，并通过甲羟戊酸途径的阻断和抗氧化作用检查了氟伐他汀的作用。成骨细胞/基质细胞和巨噬细胞集落刺激因子（M-CSF）表达的核因子-κB（NF-kappaB）配体（RANKL）重组受体激活剂的刺激显着增加了TRAP阳性的多核破骨细胞和凹坑的形成，并伴有通过二氯二氢荧光素（DCF）染色评估，活性氧增加。有趣的是，用氟伐他汀，吡咯烷二硫代氨基甲酸酯（PDTC）和N-乙酰半胱氨酸（NAC）治疗可完全废除，而普伐他汀则不能。氟伐他汀的这些作用通过与香叶基香叶基焦磷酸酯（GGPP）共同处理而被部分消除，但与法呢基焦磷酸酯（FPP）不共同消除。在通过卵巢切除术的雌激素缺乏模型中，FFR表现出骨矿物质密度降低，破骨细胞活化和尿中脱氧吡啶啉的增加。重要的是，氟伐他汀而不是普伐他汀的治疗减弱了FFR引起的骨质疏松。本研究表明，喂食大鼠的果糖可诱导胰岛素抵抗并加速骨质疏松，而氟伐他汀而非普伐他汀则可通过阻断经典的甲羟戊酸途径和抗氧化作用而显着减弱破骨细胞的分化和激活，从而预防骨质疏松。

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