Decreased oxidative stress and greater bone anabolism in the aged, when compared to the young, murine skeleton with parathyroid hormone administration.
Decreased oxidative stress and greater bone anabolism in the aged, when compared to the young, murine skeleton with parathyroid hormone administration.
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DOI：
10.1111/j.1474-9726.2010.00616.x
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发表时间：
2010-10
期刊：
影响因子：
7.8
通讯作者：
Manolagas SC
中科院分区：
文献类型：
--
作者：
Jilka RL;Almeida M;Ambrogini E;Han L;Roberson PK;Weinstein RS;Manolagas SC
由于最近对年龄相关性骨丢失发病机制的深入研究，我们调查了间歇性甲状旁腺激素(PTH)是否拮抗衰老对骨的不利影响的分子机制。与6月龄雌性C57BL/6小鼠相比，PTH使26只雌性C57BL/6小鼠股骨的椎体松质骨密度和骨体积有较大的增加，皮质内骨面也有较大的扩张。此外，PTH增加了椎骨中的小梁连通性，并增加了老年(但不是年轻)小鼠椎骨和股骨的韧性。甲状旁腺素还能更大程度地增加老龄小鼠的骨形成率，减少成骨细胞的凋亡。最显著的是，PTH降低了老龄小鼠骨骼中的ROS、p66Shc的磷酸化和脂氧合酶Alox15的表达，增加了GSH，并刺激了Wnt信号转导。体外实验中，PTH还拮抗氧化应激对p66Shc磷酸化、FoxO转录活性、成骨细胞凋亡和Wnt信号转导的影响。相反，给予抗氧化剂N-乙酰半胱氨酸或聚乙二醇化过氧化氢酶减少成骨细胞前体细胞，并减弱增殖和Wnt信号。这些结果表明，PTH在老年具有更大的骨合成代谢功效，因为除了它对骨形成的其他积极作用外，它还对抗与年龄相关的氧化应激增加及其对成骨细胞的出生和存活的不利影响。另一方面，普通抗氧化剂不能在老年时恢复骨量，因为它们通过干扰Wnt信号来减缓重塑和减弱成骨细胞的形成。
Because of recent insights into the pathogenesis of age-related bone loss, we investigated whether intermittent parathyroid hormone (PTH) administration antagonizes the molecular mechanisms of the adverse effects of aging on bone. PTH produced a greater increase in vertebral trabecular bone mineral density and bone volume as well as a greater expansion of the endocortical bone surface in the femur of 26 as compared to 6 month old female C57BL/6 mice. Moreover, PTH increased trabecular connectivity in vertebrae and the toughness of both vertebrae and femora in old, but not young, mice. PTH also increased the rate of bone formation and reduced osteoblast apoptosis to a greater extent in the old mice. Most strikingly, PTH reduced reactive oxygen species (ROS), p66Shc phosphorylation and expression of the lipoxygenase Alox15; and it increased glutathione and stimulated Wnt signaling in bone of old mice. PTH also antagonized the effects of oxidative stress on p66Shc phosphorylation, FoxO transcriptional activity, osteoblast apoptosis, and Wnt signaling in vitro. In contrast, administration of the antioxidants N-acetyl cysteine or pegylated catalase reduced osteoblast progenitors, and attenuated proliferation and Wnt signaling. These results suggest that PTH has a greater bone anabolic efficacy in old age because in addition to its other positive actions on bone formation it antagonizes the age-associated increase in oxidative stress and its adverse effects on the birth and survival of osteoblasts. On the other hand, ordinary antioxidants cannot restore bone mass in old age because they slow remodeling and attenuate osteoblastogenesis by interfering with Wnt signaling.
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影响因子：
29
作者：
Ambrogini E;Almeida M;Martin-Millan M;Paik JH;Depinho RA;Han L;Goellner J;Weinstein RS;Jilka RL;O'Brien CA;Manolagas SC
通讯作者：
Manolagas SC
影响因子：
64.5
作者：
Giorgio, M;Migliaccio, E;Pelicci, PG
通讯作者：
Pelicci, PG
影响因子：
4.8
作者：
Guo, Jun;Liu, Minlin;Kronenberg, Henry M.
通讯作者：
Kronenberg, Henry M.
影响因子：
4.8
作者：
Galli, Carlo;Fu, Qiang;O'Brien, Charles A.
通讯作者：
O'Brien, Charles A.
影响因子：
56.9
作者：
He, TC;Sparks, AB;Kinzler, KW
通讯作者：
Kinzler, KW