The Role of Parathyroid Hormone-Related Protein (PTHrP) in Osteoblast Response to Microgravity: Mechanistic Implications for Osteoporosis Development.
The Role of Parathyroid Hormone-Related Protein (PTHrP) in Osteoblast Response to Microgravity: Mechanistic Implications for Osteoporosis Development.
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DOI：
10.1371/journal.pone.0160034
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Karaplis A
中科院分区：
文献类型：
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作者：
Camirand A;Goltzman D;Gupta A;Kaouass M;Panda D;Karaplis A
通过卧床休息延长的骨骼卸载导致骨丢失，类似于在老年骨质疏松患者中观察到的骨丢失，但时间范围加快。在宇航员身上也观察到了这种对承重骨骼的快速影响，他们在太空中每个月会失去多达2%的骨量。尽管对航天旅行者和卧床不起的患者有重要意义，但废用性骨质疏松症的确切机制尚未阐明。甲状旁腺激素相关蛋白（PTHrP）调节包括骨骼发育在内的许多生理过程，并已被提议作为一种机械传感器。为了研究PTHrP在微重力诱导的骨丢失中的作用，使来自PTHrp +/+和-/-小鼠的小梁和颅骨成骨细胞（TO和CO）经受实际的航天飞行6天（Foton M3卫星）。PTHRP +/+、+/-和-/-成骨细胞也暴露于模拟微重力，时间从6天到6周不等。虽然CO在0 g中的活力几乎没有变化，但所有TO的活力与PTHrP表达水平成反比迅速下降。此外，Pthrp+/+ TO在Og下2周后显示出急剧的活力下降。Pthrp+/+ TO在模拟0 g中6天后的微阵列分析揭示了编码催乳素、凋亡/存活分子、骨代谢和细胞外基质组成蛋白、趋化因子、胰岛素样生长因子家族成员和Wnt相关信号分子的基因的表达变化。在正常重力条件下，0 g诱导的Pthrp+/+细胞表达变化的88%与Pthrp消融引起的变化重叠，PTHrP 1 -36脉冲治疗不仅逆转了大部分0 g诱导的Pthrp+/+ TO效应，而且在6周的微重力暴露中保持了活力。我们的研究结果证实PTHrP作为合成代谢剂预防TO微重力诱导的细胞死亡的功效。
Prolonged skeletal unloading through bedrest results in bone loss similar to that observed in elderly osteoporotic patients, but with an accelerated timeframe. This rapid effect on weight-bearing bones is also observed in astronauts who can lose up to 2% of their bone mass per month spent in Space. Despite the important implications for Spaceflight travelers and bedridden patients, the exact mechanisms involved in disuse osteoporosis have not been elucidated. Parathyroid hormone-related protein (PTHrP) regulates many physiological processes including skeletal development, and has been proposed as a mechanosensor. To investigate the role of PTHrP in microgravity-induced bone loss, trabecular and calvarial osteoblasts (TOs and COs) from Pthrp +/+ and -/- mice were subjected to actual Spaceflight for 6 days (Foton M3 satellite). Pthrp +/+, +/- and -/- osteoblasts were also exposed to simulated microgravity for periods varying from 6 days to 6 weeks. While COs displayed little change in viability in 0g, viability of all TOs rapidly decreased in inverse proportion to PTHrP expression levels. Furthermore, Pthrp+/+ TOs displayed a sharp viability decline after 2 weeks at 0g. Microarray analysis of Pthrp+/+ TOs after 6 days in simulated 0g revealed expression changes in genes encoding prolactins, apoptosis/survival molecules, bone metabolism and extra-cellular matrix composition proteins, chemokines, insulin-like growth factor family members and Wnt-related signalling molecules. 88% of 0g-induced expression changes in Pthrp+/+ cells overlapped those caused by Pthrp ablation in normal gravity, and pulsatile treatment with PTHrP1-36 not only reversed a large proportion of 0g-induced effects in Pthrp+/+ TOs but maintained viability over 6-week exposure to microgravity. Our results confirm PTHrP efficacy as an anabolic agent to prevent microgravity-induced cell death in TOs.