Gong Rui, Xiao Hong-Mei, Zhang Yin-Hua, Zhao Qi, Su Kuan-Jui, Lin Xu, Mo Cheng-Lin, Zhang Qiang, Du Ya-Ting, Lyu Feng-Ye, Chen Yuan-Cheng, Peng Cheng, Liu Hui-Min, Hu Shi-Di, Pan Dao-Yan, Chen Zhi, Li Zhang-Fang, Zhou Rou, Wang Xia-Fang, Lu Jun-Min, Ao Zeng-Xin, Song Yu-Qian, Weng Chan-Yan, Tian Qing, Schiller Martin R, Papasian Christopher J, Brotto Marco, Shen Hui, Shen Jie, Deng Hong-Wen
Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
Tulane Center for Biomedical Informatics and Genomics, School of Medicine, Tulane University, New Orleans, LA, USA.
J Clin Endocrinol Metab. 2021 Jul 13;106(8):e3159-e3177. doi: 10.1210/clinem/dgab146.
Although metabolic profiles appear to play an important role in menopausal bone loss, the functional mechanisms by which metabolites influence bone mineral density (BMD) during menopause are largely unknown.
We aimed to systematically identify metabolites associated with BMD variation and their potential functional mechanisms in peri- and postmenopausal women.
We performed serum metabolomic profiling and whole-genome sequencing for 517 perimenopausal (16%) and early postmenopausal (84%) women aged 41 to 64 years in this cross-sectional study. Partial least squares regression and general linear regression analysis were applied to identify BMD-associated metabolites, and weighted gene co-expression network analysis was performed to construct co-functional metabolite modules. Furthermore, we performed Mendelian randomization analysis to identify causal relationships between BMD-associated metabolites and BMD variation. Finally, we explored the effects of a novel prominent BMD-associated metabolite on bone metabolism through both in vivo/in vitro experiments.
Twenty metabolites and a co-functional metabolite module (consisting of fatty acids) were significantly associated with BMD variation. We found dodecanoic acid (DA), within the identified module causally decreased total hip BMD. Subsequently, the in vivo experiments might support that dietary supplementation with DA could promote bone loss, as well as increase the osteoblast and osteoclast numbers in normal/ovariectomized mice. Dodecanoic acid treatment differentially promoted osteoblast and osteoclast differentiation, especially for osteoclast differentiation at higher concentrations in vitro (eg,10, 100 μM).
This study sheds light on metabolomic profiles associated with postmenopausal osteoporosis risk, highlighting the potential importance of fatty acids, as exemplified by DA, in regulating BMD.
尽管代谢谱似乎在绝经后骨质流失中起重要作用，但代谢物在绝经期间影响骨密度（BMD）的功能机制在很大程度上尚不清楚。
我们旨在系统地识别与围绝经期和绝经后女性骨密度变化相关的代谢物及其潜在的功能机制。
在这项横断面研究中，我们对517名年龄在41至64岁的围绝经期（16%）和绝经早期（84%）女性进行了血清代谢组学分析和全基因组测序。应用偏最小二乘回归和一般线性回归分析来识别与骨密度相关的代谢物，并进行加权基因共表达网络分析以构建共功能代谢物模块。此外，我们进行了孟德尔随机化分析，以确定与骨密度相关的代谢物和骨密度变化之间的因果关系。最后，我们通过体内/体外实验探索了一种新的突出的与骨密度相关的代谢物对骨代谢的影响。
20种代谢物和一个共功能代谢物模块（由脂肪酸组成）与骨密度变化显著相关。我们发现，在已识别的模块中，十二烷酸（DA）因果性地降低了全髋骨密度。随后，体内实验可能支持补充DA饮食会促进骨质流失，并增加正常/去卵巢小鼠的成骨细胞和破骨细胞数量。十二烷酸处理差异地促进了成骨细胞和破骨细胞的分化，特别是在体外较高浓度（如10、100μM）下对破骨细胞分化的促进作用。
本研究揭示了与绝经后骨质疏松风险相关的代谢组学特征，突出了脂肪酸（如DA）在调节骨密度方面的潜在重要性。
