Rapamycin impairs trabecular bone acquisition from high-dose but not low-dose intermittent parathyroid hormone treatment.
Rapamycin impairs trabecular bone acquisition from high-dose but not low-dose intermittent parathyroid hormone treatment.
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DOI：
10.1002/jcp.21887
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发表时间：
2009-12
影响因子：
5.6
通讯作者：
Robling, A. G.
中科院分区：
文献类型：
--
作者：
Niziolek, P. J.;Murthy, S.;Ellis, S. N.;Sukhija, K. B.;Hornberger, T. A.;Turner, C. H.;Robling, A. G.
间歇性甲状旁腺激素(PTH)治疗的骨合成代谢效应需要胰岛素样生长因子(IGF)通过IGF-I受体传递信号。IGF-I受体的一个主要下游靶点(通过Akt)是哺乳动物雷帕霉素(MTOR)的靶点，雷帕霉素是一种参与蛋白质合成的激酶。我们调查了间歇性甲状旁腺激素的成骨效应是否需要功能性的mTOR信号。小鼠每天给予甲状旁腺素1-34(0、10、30或90μg/kg)，在有或没有mTOR选择性抑制剂雷帕霉素的情况下连续6周。我们发现，无论是否存在雷帕霉素，所有剂量的甲状旁腺素都能有效地提高骨量。雷帕霉素对低剂量(10μg)甲状旁腺素的合成代谢反应几乎没有影响，在中剂量(30μg)的少数合成代谢措施中影响很小，但高剂量甲状旁腺素(90μg)的合成代谢效应可被雷帕霉素持续显著抑制(~4-36%)。雷帕霉素可显著提高血清中作为吸收标志物的TRap5b水平，但无论甲状旁腺激素是否存在，均可观察到这种影响。我们的数据表明，间歇性甲状旁腺激素，特别是在较低剂量下，在雷帕霉素存在的情况下，在建立骨量方面是有效的。然而，高剂量甲状旁腺素的完全合成代谢效应被雷帕霉素显著抑制，这表明甲状旁腺素可能激活了其他途径(包括mTOR)，从而增强了高剂量的合成代谢效应。临床剂量的间歇性甲状旁腺激素可能是一种有效的治疗方法，可以维持或增加服用雷帕霉素类似物的患者的骨量，以解决与健康无关的问题。
The osteo-anabolic effects of intermittent parathyroid hormone (PTH) treatment require insulin-like growth factor (IGF) signaling through the IGF-I receptor. A major downstream target of the IGF-I receptor (via Akt) is the mammalian target of rapamycin (mTOR), a kinase involved in protein synthesis. We investigated whether the bone-building effects of intermittent PTH require functional mTOR signaling. Mice were treated with daily PTH 1-34 (0, 10, 30, or 90 μg/kg) for 6 weeks in the presence or absence of rapamycin, a selective inhibitor of mTOR. We found that all PTH doses were effective in enhancing bone mass, whether rapamycin was present or not. Rapamycin had little to no effect on the anabolic response at low (10 μg) PTH doses, small effects in a minority of anabolic measures at moderate doses (30 μg), but the anabolic effects of high dose PTH (90 μg) were consistently and significantly suppressed by rapamycin (~4-36% reduction). Serum levels of Trap5b, a marker of resorption, were significantly enhanced by rapamycin, but these effects were observed whether PTH was absent or present. Our data suggest that intermittent PTH, particularly at lower doses, is effective in building bone mass in the presence of rapamycin. However, the full anabolic effects of higher doses of PTH are significantly suppressed by rapamycin, suggesting that PTH might normally activate additional pathways (including mTOR) for its enhanced high-dose anabolic effects. Clinical doses of intermittent PTH could be an effective treatment for maintaining or increasing bone mass among patients taking rapamycin analogs for unrelated health issues.
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影响因子：
16
作者：
Loewith, R;Jacinto, E;Hall, MN
通讯作者：
Hall, MN
影响因子：
6.2
作者：
Wang, Yongmei;Nishida, Shigeki;Bikle, Daniel D.
通讯作者：
Bikle, Daniel D.
影响因子：
3.8
作者：
Mann, Anita;Khan, Meraj Alam;Ganguli, Munia
通讯作者：
Ganguli, Munia
影响因子：
37.8
作者：
Lindenfeld, J;Miller, GG;Kobashigawa, J
通讯作者：
Kobashigawa, J
影响因子：
4.2
作者：
JOFFE, I;KATZ, I;EPSTEIN, S
通讯作者：
EPSTEIN, S