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首页> 外文期刊>Calcified Tissue International >A Comparison between the Effects of Hydrophobic and Hydrophilic Statins on Osteoclast Function In Vitro and Ovariectomy-Induced Bone Loss In Vivo
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A Comparison between the Effects of Hydrophobic and Hydrophilic Statins on Osteoclast Function In Vitro and Ovariectomy-Induced Bone Loss In Vivo

机译：疏水性和亲水性他汀类药物对破骨细胞功能的体外作用和卵巢切除术引起的体内骨丢失影响的比较

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摘要

Statins potently inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase, blocking downstream biosynthesis of isoprenoid lipids and causing inhibition of protein prenylation. Prenylated signaling molecules are essential for osteoclast function, consistent with our previous observation that mevastatin can inhibit osteoclast activity in vitro. Several reports suggest that statins may also have an anabolic effect on bone and stimulate osteoblast differentiation. This study sought to determine the effects of both hydrophobic and hydrophilic statins, particularly rosuvastatin (RSV), on osteoclast function in vitro and in vivo. All statins tested (RSV, pravastatin [PRA], cerivastatin [CER], and simvastatin [SIM]) caused accumulation of unprenylated Rap-1A in rabbit osteoclast-like cells and J774 macrophages in vitro and inhibited osteoclast-mediated resorption. The order of potency for inhibiting prenylation in vitro (at concentrations of 0.01–50 μM) was CER > SIM > RSV > PRA. The most potent hydrophilic statin (CER, 0.05 and 0.3 mg/kg) inhibited prenylation in rabbit osteoclasts 24 hours after a single subcutaneous (s.c.) injection more effectively than the most potent hydrophobic statin (RSV, 20 mg/kg). However, in a mouse model of osteoporosis, s.c. 0.05 mg/kg/day CER and 2 or 20 mg/kg/day RSV for 3 weeks only mildly prevented loss of cortical and trabecular bone induced by ovariectomy. No increase in bone formation rate was observed with statin treatment, suggesting that this effect was due to inhibition of osteoclast-mediated resorption rather than increased bone formation.
机译：他汀类药物有效抑制3-羟基-3-甲基戊二酰辅酶A还原酶，阻止类异戊二烯脂质的下游生物合成，并引起蛋白质异戊二烯化的抑制。烯丙基化的信号分子对于破骨细胞功能必不可少，这与我们以前的观察结果一致，美伐他汀可以在体外抑制破骨细胞的活性。一些报道表明他汀类药物也可能对骨骼有合成代谢作用并刺激成骨细胞分化。这项研究试图确定疏水性和亲水性他汀类药物，特别是瑞舒伐他汀（RSV）在体外和体内对破骨细胞功能的影响。在体外测试的所有他汀类药物（RSV，普伐他汀[PRA]，西立伐他汀[CER]和辛伐他汀[SIM]）都会在兔破骨细胞样细胞和J774巨噬细胞中引起未异戊酸化的Rap-1A积聚，并抑制破骨细胞介导的吸收。体外抑制烯丙基化的效力顺序（浓度为0.01–50μM）为CER> SIM> RSV> PRA。最有效的亲水性他汀类药物（CER，0.05和0.3 mg / kg）在单次皮下（s.c.）注射后24小时抑制兔破骨细胞的异戊二烯化效果比最有效的疏水性他汀类药物（RSV，20 mg / kg）更有效。但是，在骨质疏松症的小鼠模型中0.05 mg / kg / day CER和2或20 mg / kg / day RSV持续3周，仅能轻度预防卵巢切除术引起的皮质和小梁骨丢失。他汀类药物治疗未观察到骨形成速率增加，表明该作用是由于抑制破骨细胞介导的吸收而不是增加骨形成。

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  • 来源
    《Calcified Tissue International》 |2007年第5期|403-413|共11页
  • 作者

    Alun Hughes; Michael J. Rogers; Aymen I. Idris; Julie C. Crockett;

  • 作者单位

    Department of Medicine and Therapeutics University of Aberdeen Institute of Medical Sciences Foresterhill Aberdeen AB25 2ZD UK;

    Department of Medicine and Therapeutics University of Aberdeen Institute of Medical Sciences Foresterhill Aberdeen AB25 2ZD UK;

    Department of Medicine and Therapeutics University of Aberdeen Institute of Medical Sciences Foresterhill Aberdeen AB25 2ZD UK;

    Department of Medicine and Therapeutics University of Aberdeen Institute of Medical Sciences Foresterhill Aberdeen AB25 2ZD UK;

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  • 正文语种 eng
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  • 关键词

    Osteoclast; Bone resorption; Statin; Prenylation; Anabolic;

    机译：破骨细胞;骨吸收;他汀;异戊烯酸酯;合成代谢;

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