Identification and Functional Characterization of Metabolites for Bone Mass in Peri- and Postmenopausal Chinese Women

Abstract Context 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. Objective We aimed to systematically identify metabolites associated with B...

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Published in:The journal of clinical endocrinology and metabolism 2021-08, Vol.106 (8), p.e3159-e3177
Main Authors: 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
Format: Article
Language:English
Subjects:
Absorptiometry, Photon
Adult
Animals
Biomarkers - blood
Bone Density - physiology
Bone loss
Bone mass
Bone mineral density
Bone turnover
Bones
Cell Line
China
Clinical s
Cross-Sectional Studies
Density
Dietary supplements
DNA sequencing
Fatty acids
Female
Genomes
Genomics
Humans
Lauric acid
Lauric Acids - blood
Menopause
Metabolites
Metabolome
Metabolomics
Mice
Middle Aged
Nucleotide sequencing
Osteoblastogenesis
Osteoblasts
Osteoclastogenesis
Osteogenesis - physiology
Osteoporosis
Osteoporosis, Postmenopausal - blood
Osteoporosis, Postmenopausal - diagnostic imaging
Ovariectomy
Post-menopause
Postmenopausal women
Postmenopause - blood
Type 2 diabetes
Variation
Whole genome sequencing
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Summary:Abstract Context 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. Objective We aimed to systematically identify metabolites associated with BMD variation and their potential functional mechanisms in peri- and postmenopausal women. Design and Methods 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. Results 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). Conclusions 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.
ISSN:0021-972X
1945-7197
DOI:10.1210/clinem/dgab146