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

Author:

Gong Rui123ORCID,Xiao Hong-Mei4ORCID,Zhang Yin-Hua1,Zhao Qi5,Su Kuan-Jui2,Lin Xu12,Mo Cheng-Lin6,Zhang Qiang27,Du Ya-Ting68,Lyu Feng-Ye9,Chen Yuan-Cheng1,Peng Cheng1,Liu Hui-Min4,Hu Shi-Di1,Pan Dao-Yan1,Chen Zhi1,Li Zhang-Fang1,Zhou Rou1,Wang Xia-Fang1,Lu Jun-Min1,Ao Zeng-Xin1,Song Yu-Qian1,Weng Chan-Yan1,Tian Qing2,Schiller Martin R10,Papasian Christopher J11,Brotto Marco6,Shen Hui2,Shen Jie112ORCID,Deng Hong-Wen24ORCID

Affiliation:

1. Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China

2. Tulane Center for Biomedical Informatics and Genomics, School of Medicine, Tulane University, New Orleans, LA, USA

3. Cadre Ward Endocrinology Department, Gansu Provincial Hospital, Lanzhou, Gansu, China

4. Center of System Biology, Data Information and Reproductive Health, School of Basic Medical Science, Central South University, Changsha, China

5. Department of Preventive Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA

6. Bone-Muscle Research Center, College of Nursing and Health Innovation, The University of Texas-Arlington, Arlington, TX, USA

7. School of Nursing and Health, Zhengzhou University, Zhengzhou, China

8. Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China

9. LC-Bio Technologies (Hangzhou) CO.LTD, Hangzhou, China

10. Nevada Institute of Personalized Medicine, University of Nevada Las Vegas, Las Vegas, NV, USA

11. Department of Biomedical Sciences, University of Missouri-Kansas City, School of Medicine, Kansas City, MO, USA

12. Shunde Hospital of Southern Medical University (The First People’s Hospital of Shunde), Foshan, China

Abstract

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.

Funder

National Institutes of Health

Science and Technology Program of Guangzhou, China

National Natural Science Foundation of China

National Key R&D Program of China

National Institutes of Aging

Publisher

The Endocrine Society

Subject

Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

Reference72 articles.

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