Ma Yun, Elefteriou Florent
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Department of Orthopedic Surgery, Baylor College of Medicine, Houston, TX, USA.
J Bone Miner Res. 2020 Aug;35(8):1562-1571. doi: 10.1002/jbmr.4024. Epub 2020 Apr 29.
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. © 2020 American Society for Bone and Mineral Research.
临床前和临床数据支持交感神经系统在骨重塑调节中的作用，但自主神经系统副交感神经分支对骨稳态的贡献仍研究较少。在本研究中，我们试图确定乙酰胆碱（ACh）在骨量峰值获取后是否有助于骨重塑的调节。我们发现，胆碱转运体（ChT）杂合小鼠中枢ACh合成减少导致年轻雌性小鼠骨量下降，从而独立证实了先前报道的ACh信号对骨量积累的有益作用。通过使用可透过血脑屏障（BBB）的乙酰胆碱酯酶抑制剂（AChEI）加兰他敏增加脑内ACh水平，可增加成年雌性小鼠的小梁骨量，而不可透过BBB的AChEI吡啶斯的明诱导的外周ACh水平升高则导致小梁骨丢失。AChEIs并未改变骨骼去甲肾上腺素水平，且诱导成骨细胞和破骨细胞密度总体增加，这两个发现不支持交感神经输出减少是加兰他敏对骨骼促合成代谢作用的机制。此外，我们未在AChEI处理的小鼠体内检测到骨骼祖细胞向成骨细胞谱系分化的变化，也未发现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有直接影响。最后，ChT杂合性和加兰他敏治疗仅在雌性小鼠中引发骨变化，从而揭示了对脑ACh水平存在性别特异性的骨骼反应。总之，本研究支持中枢ACh对骨量积累的刺激作用，表明其也促进成年小鼠骨量峰值的维持，并提示中枢ACh在生长小鼠和性成熟小鼠中通过不同机制调节骨量。© 2020美国骨与矿物质研究学会。
