Rui Gong1,2,3, Hong-Mei Xiao4, Yin-Hua Zhang1, Qi Zhao5, Kuan-Jui Su2, Xu Lin1,2, Cheng-Lin Mo6, Qiang Zhang2,7, Ya-Ting Du6,8, Feng-Ye Lyu9, Yuan-Cheng Chen1, Cheng Peng1, Hui-Min Liu4, Shi-Di Hu1, Dao-Yan Pan1, Zhi Chen1, Zhang-Fang Li1, Rou Zhou1, Xia-Fang Wang1, Jun-Min Lu1, Zeng-Xin Ao1, Yu-Qian Song1, Chan-Yan Weng1, Qing Tian2, Martin R Schiller10, Christopher J Papasian11, Marco Brotto6, Hui Shen2, Jie Shen1,12, Hong-Wen Deng2,4. 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
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.
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.
Authors: Serena Sanna; Natalie R van Zuydam; Anubha Mahajan; Alexander Kurilshikov; Arnau Vich Vila; Urmo Võsa; Zlatan Mujagic; Ad A M Masclee; Daisy M A E Jonkers; Marije Oosting; Leo A B Joosten; Mihai G Netea; Lude Franke; Alexandra Zhernakova; Jingyuan Fu; Cisca Wijmenga; Mark I McCarthy Journal: Nat Genet Date: 2019-02-18 Impact factor: 38.330
Authors: S A Kliewer; S S Sundseth; S A Jones; P J Brown; G B Wisely; C S Koble; P Devchand; W Wahli; T M Willson; J M Lenhard; J M Lehmann Journal: Proc Natl Acad Sci U S A Date: 1997-04-29 Impact factor: 11.205
Authors: Hou-Feng Zheng; Vincenzo Forgetta; Yi-Hsiang Hsu; Karol Estrada; Alberto Rosello-Diez; Paul J Leo; Chitra L Dahia; Kyung Hyun Park-Min; Jonathan H Tobias; Charles Kooperberg; Aaron Kleinman; Unnur Styrkarsdottir; Ching-Ti Liu; Charlotta Uggla; Daniel S Evans; Carrie M Nielson; Klaudia Walter; Ulrika Pettersson-Kymmer; Shane McCarthy; Joel Eriksson; Tony Kwan; Mila Jhamai; Katerina Trajanoska; Yasin Memari; Josine Min; Jie Huang; Petr Danecek; Beth Wilmot; Rui Li; Wen-Chi Chou; Lauren E Mokry; Alireza Moayyeri; Melina Claussnitzer; Chia-Ho Cheng; Warren Cheung; Carolina Medina-Gómez; Bing Ge; Shu-Huang Chen; Kwangbom Choi; Ling Oei; James Fraser; Robert Kraaij; Matthew A Hibbs; Celia L Gregson; Denis Paquette; Albert Hofman; Carl Wibom; Gregory J Tranah; Mhairi Marshall; Brooke B Gardiner; Katie Cremin; Paul Auer; Li Hsu; Sue Ring; Joyce Y Tung; Gudmar Thorleifsson; Anke W Enneman; Natasja M van Schoor; Lisette C P G M de Groot; Nathalie van der Velde; Beatrice Melin; John P Kemp; Claus Christiansen; Adrian Sayers; Yanhua Zhou; Sophie Calderari; Jeroen van Rooij; Chris Carlson; Ulrike Peters; Soizik Berlivet; Josée Dostie; Andre G Uitterlinden; Stephen R Williams; Charles Farber; Daniel Grinberg; Andrea Z LaCroix; Jeff Haessler; Daniel I Chasman; Franco Giulianini; Lynda M Rose; Paul M Ridker; John A Eisman; Tuan V Nguyen; Jacqueline R Center; Xavier Nogues; Natalia Garcia-Giralt; Lenore L Launer; Vilmunder Gudnason; Dan Mellström; Liesbeth Vandenput; Najaf Amin; Cornelia M van Duijn; Magnus K Karlsson; Östen Ljunggren; Olle Svensson; Göran Hallmans; François Rousseau; Sylvie Giroux; Johanne Bussière; Pascal P Arp; Fjorda Koromani; Richard L Prince; Joshua R Lewis; Bente L Langdahl; A Pernille Hermann; Jens-Erik B Jensen; Stephen Kaptoge; Kay-Tee Khaw; Jonathan Reeve; Melissa M Formosa; Angela Xuereb-Anastasi; Kristina Åkesson; Fiona E McGuigan; Gaurav Garg; Jose M Olmos; Maria T Zarrabeitia; Jose A Riancho; Stuart H Ralston; Nerea Alonso; Xi Jiang; David Goltzman; Tomi Pastinen; Elin Grundberg; Dominique Gauguier; Eric S Orwoll; David Karasik; George Davey-Smith; Albert V Smith; Kristin Siggeirsdottir; Tamara B Harris; M Carola Zillikens; Joyce B J van Meurs; Unnur Thorsteinsdottir; Matthew T Maurano; Nicholas J Timpson; Nicole Soranzo; Richard Durbin; Scott G Wilson; Evangelia E Ntzani; Matthew A Brown; Kari Stefansson; David A Hinds; Tim Spector; L Adrienne Cupples; Claes Ohlsson; Celia M T Greenwood; Rebecca D Jackson; David W Rowe; Cynthia A Loomis; David M Evans; Cheryl L Ackert-Bicknell; Alexandra L Joyner; Emma L Duncan; Douglas P Kiel; Fernando Rivadeneira; J Brent Richards Journal: Nature Date: 2015-09-14 Impact factor: 49.962