Brain-Derived Acetylcholine Maintains Peak Bone Mass in Adult Female Mice.
Brain-Derived Acetylcholine Maintains Peak Bone Mass in Adult Female Mice.
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DOI：
10.1002/jbmr.4024
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发表时间：
2020-08
期刊：
影响因子：
--
通讯作者：
Elefteriou F
中科院分区：
文献类型：
--
作者：
Ma Y;Elefteriou F
临床前和临床数据支持交感神经系统在骨重建的调节中的作用，但自主神经系统的副交感神经臂对骨稳态的贡献仍然研究较少。在这项研究中，我们试图确定乙酰胆碱（ACh）是否有助于调节峰值骨量获得后的骨重建。我们发现，胆碱转运蛋白（ChT）杂合子小鼠中枢乙酰胆碱合成减少导致年轻雌性小鼠骨量减少，从而独立证实了先前报道的乙酰胆碱信号传导对骨量增加的有益作用。通过使用血脑屏障（BBB）渗透性乙酰胆碱酯酶抑制剂（AChEI）加兰他敏增加脑ACh水平增加成年雌性小鼠的骨小梁质量，而外周ACh水平的增加由BBB渗透性AChEI吡啶斯的明引起的骨小梁丢失。乙酰胆碱酯酶抑制剂不改变骨骼去甲肾上腺素水平，并诱导成骨细胞和破骨细胞密度的总体增加，这两个发现不支持交感神经流出减少作为加兰他敏对骨骼的促合成代谢作用的机制。此外，我们没有检测到AChEI治疗小鼠体内骨骼祖细胞向成骨细胞谱系的承诺的变化，也没有这些药物在体外对成骨细胞和破骨细胞祖细胞的存活和分化的直接影响。最后，ChT杂合性和加兰他敏治疗引发的骨的变化只在雌性小鼠，从而揭示了存在的性别特异性骨骼脑乙酰胆碱水平的反应。总之，这项研究支持中枢ACh对骨量增加的刺激作用，表明它也促进成年小鼠峰值骨量的维持，并表明中枢ACh通过不同的机制调节生长与性成熟小鼠的骨量。
Preclinical and clinical data support a role of the sympathetic nervous system in the regulation of bone remodeling, but the contribution of parasympathetic arm of the autonomic nervous system to bone homeostasis remains less studied. In this study, we sought to determine whether acetylcholine (ACh) contributes to the regulation of bone remodeling after peak bone mass acquisition. We show that reduced central ACh synthesis in mice heterozygous for the choline transporter (ChT) leads to a decrease in bone mass in young female mice, thus independently confirming the previously reported beneficial effect of ACh signaling on bone mass accrual. Increasing brain ACh levels through the use of the blood brain barrier (BBB)-permeable acetylcholinesterase inhibitor (AChEI) galantamine increased trabecular bone mass in adult female mice, whereas a peripheral increase in ACh levels induced by the BBB-impermeable AChEI pyridostigmine caused trabecular bone loss. AChEIs did not alter skeletal norepinephrine level, and induced an overall increase in osteoblast and osteoclast densities, two findings that do not support a reduction in sympathetic outflow as the mechanism involved in the pro-anabolic effect of galantamine on the skeleton. In addition, we did not detect changes in the commitment of skeletal progenitor cells to the osteoblast lineage in vivo in AChEI-treated mice, nor a direct impact of these drugs in vitro on the survival and differentiation of osteoblast and osteoclast progenitors. Last, ChT heterozygosity and galantamine treatment triggered bone changes in female mice only, thus revealing the existence of a gender-specific skeletal response to brain ACh level. In conclusion, this study supports the stimulatory effect of central ACh on bone mass accrual, shows that it also promotes peak bone mass maintenance in adult mice, and suggests that central ACh regulates bone mass via different mechanisms in growing versus sexually mature mice.
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影响因子：
3.3
作者：
Castañeda-Corral G;Jimenez-Andrade JM;Bloom AP;Taylor RN;Mantyh WG;Kaczmarska MJ;Ghilardi JR;Mantyh PW
通讯作者：
Mantyh PW
影响因子：
3.2
作者：
Fan, Wei;Bouwense, Stefan A. W.;Crawford, Ross;Xiao, Yin
通讯作者：
Xiao, Yin
影响因子：
2.9
作者：
Geerts, H;Guillaumat, PO;Sachak, S
通讯作者：
Sachak, S
影响因子：
5.8
作者：
Farr, Joshua N.;Charkoudian, Nisha;Khosla, Sundeep
通讯作者：
Khosla, Sundeep
影响因子：
5.3
作者：
Gibbs, RB
通讯作者：
Gibbs, RB