Skip to main content
Springer Nature Link
Log in

Association between fibroblast growth factor 21 and bone mineral density in adults

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Purpose

Animal-based studies have reported a decrease in bone mass resulting from high level of fibroblast growth factor 21 (FGF21). However, the correlation between plasma FGF21 levels and bone mineral density (BMD) is paradoxical in previous human-based studies, and the associations between FGF21 gene polymorphisms and BMD haven’t been reported yet. Therefore, here, we evaluated plasma FGF21 levels with sufficient study samples, and performed genetic association test to reveal the physiological and genetic role of FGF21 on BMD in adults.

Methods

Plasma and genetic samples containing 168 and 569 Han Chinese subjects, respectively, were employed in this study. Fasting plasma FGF21 levels were determined using enzyme-linked immunosorbent assay (ELISA). Regional BMD values were measured by dual energy X-ray absorptiometry (DXA). Five variants of FGF21 gene were successfully genotyped.

Results

Physiological association suggested that plasma FGF21 levels were inversely correlated with BMD in femoral neck (Neck-BMD: P = 0.039) and Ward’s triangle (Ward’s-BMD: P = 0.002) of hip region. A FGF21 gene variant, rs490942, was significantly associated with the increase of Ward’s-BMD in total (P = 0.027) and female (P = 0.016) cohorts, as well as Neck-BMD in female cohort (P = 7.45 × 10−3). Meanwhile, eQTL results indicated that this SNP was related to the decreased level of FGF21 gene expression.

Conclusions

Taking together from both physiological and genetic levels, we suggest that FGF21 is inversely associated with regional BMD. And we haven’t observed sex-specific effect in this study.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. N.C. Wright, A.C. Looker, K.G. Saag, J.R. Curtis, E.S. Delzell, S. Randall, B. Dawson-Hughes, The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J. Bone Miner. Res. 29(11), 2520–2526 (2014)

    Article  PubMed  PubMed Central  Google Scholar 

  2. S. Harada, G.A. Rodan, Control of osteoblast function and regulation of bone mass. Nature 423(6937), 349–355 (2003)

    Article  CAS  PubMed  Google Scholar 

  3. S.C. Manolagas, Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr. Rev. 21(2), 115–137 (2000)

    CAS  PubMed  Google Scholar 

  4. P. Arner, A. Pettersson, P.J. Mitchell, J.D. Dunbar, A. Kharitonenkov, M. Ryden, FGF21 attenuates lipolysis in human adipocytes—a possible link to improved insulin sensitivity. FEBS Lett. 582(12), 1725–1730 (2008)

    Article  CAS  PubMed  Google Scholar 

  5. X.F. Li, H.F. Ge, J. Weiszmann, R. Hecht, Y.S. Li, M.M. Veniant, J. Xu, X.L. Wu, R. Lindberg, Y. Li, Inhibition of lipolysis may contribute to the acute regulation of plasma FFA and glucose by FGF21 in ob/ob mice. FEBS Lett. 583(19), 3230–3234 (2009)

    Article  CAS  PubMed  Google Scholar 

  6. M.K. Badman, P. Pissios, A.R. Kennedy, G. Koukos, J.S. Flier, E. Maratos-Flier, Hepatic fibroblast growth factor 21 is regulated by PPAR alpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 5(6), 426–437 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. X. Wang, W. Wei, J.Y. Krzeszinski, Y. Wang, Y. Wan, A liver-bone endocrine relay by IGFBP1 promotes osteoclastogenesis and mediates FGF21-induced bone resorption. Cell. Metab. 22(5), 811–824 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. W. Wei, P.A. Dutchak, X.D. Wang, X.S. Ding, X.Q. Wang, A.L. Bookout, R. Goetz, M. Mohammadi, R.D. Gerard, P.C. Dechow, D.J. Mangelsdorf, S.A. Kliewer, Y.H. Wan, Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor gamma. Proc. Natl. Acad. Sci. USA 109(8), 3143–3148 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. P. Lee, J. Linderman, S. Smith, R.J. Brychta, R. Perron, C. Idelson, C.D. Werner, K.Y. Chen, F.S. Celi, Fibroblast growth factor 21 (FGF21) and bone: is there a relationship in humans? Osteoporos. Int. 24(12), 3053–3057 (2013)

    Article  CAS  PubMed  Google Scholar 

  10. S.H. Ralston, A.G. Uitterlinden, Genetics of osteoporosis. Endocr. Rev. 31(5), 629–662 (2010)

    Article  CAS  PubMed  Google Scholar 

  11. F. Rivadeneira, U. Styrkarsdottir, K. Estrada, B.V. Halldorsson, Y.H. Hsu, J.B. Richards, M.C. Zillikens, F.K. Kavvoura, N. Amin, Y.S. Aulchenko, L.A. Cupples, P. Deloukas, S. Demissie, E. Grundberg, A. Hofman, A. Kong, D. Karasik, J.B. van Meurs, B. Oostra, T. Pastinen, H.A. Pols, G. Sigurdsson, N. Soranzo, G. Thorleifsson, U. Thorsteinsdottir, F.M. Williams, S.G. Wilson, Y. Zhou, S.H. Ralston, C.M. van Duijn, T. Spector, D.P. Kiel, K. Stefansson, J.P. Ioannidis, A.G. Uitterlinden, Genetic factors for osteoporosis, C.: twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat. Genet. 41(11), 1199–1206 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. J.B. Richards, F. Rivadeneira, M. Inouye, T.M. Pastinen, N. Soranzo, S.G. Wilson, T. Andrew, M. Falchi, R. Gwilliam, K.R. Ahmadi, A.M. Valdes, P. Arp, P. Whittaker, D.J. Verlaan, M. Jhamai, V. Kumanduri, M. Moorhouse, J.B. van Meurs, A. Hofman, H.A. Pols, D. Hart, G. Zhai, B.S. Kato, B.H. Mullin, F. Zhang, P. Deloukas, A.G. Uitterlinden, T.D. Spector, Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 371(9623), 1505–1512 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. U. Styrkarsdottir, B.V. Halldorsson, S. Gretarsdottir, D.F. Gudbjartsson, G.B. Walters, T. Ingvarsson, T. Jonsdottir, J. Saemundsdottir, S. Snorradottir, J.R. Center, T.V. Nguyen, P. Alexandersen, J.R. Gulcher, J.A. Eisman, C. Christiansen, G. Sigurdsson, A. Kong, U. Thorsteinsdottir, K. Stefansson, New sequence variants associated with bone mineral density. Nat. Genet. 41(1), 15–17 (2009)

    Article  CAS  PubMed  Google Scholar 

  14. U. Styrkarsdottir, B.V. Halldorsson, S. Gretarsdottir, D.F. Gudbjartsson, G.B. Walters, T. Ingvarsson, T. Jonsdottir, J. Saemundsdottir, J.R. Center, T.V. Nguyen, Y. Bagger, J.R. Gulcher, J.A. Eisman, C. Christiansen, G. Sigurdsson, A. Kong, U. Thorsteinsdottir, K. Stefansson, Multiple genetic loci for bone mineral density and fractures. N. Engl. J. Med. 358(22), 2355–2365 (2008)

    Article  CAS  PubMed  Google Scholar 

  15. Q.D.R Hologic. 4500 X-ray Bone Densitometer User’s Guide. (Hologic, Bedford, MA, 1996)

  16. K.G. Faulkner, The tale of the T-score: review and perspective. Osteoporos. Int. 16(4), 347–352 (2005)

    Article  PubMed  Google Scholar 

  17. S. Purcell, B. Neale, K. Todd-Brown, L. Thomas, M.A. Ferreira, D. Bender, J. Maller, P. Sklar, P.I. de Bakker, M.J. Daly, P.C. Sham, PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81(3), 559–575 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. G.T. Consortium, Human genomics. The genotype-tissue expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348(6235), 648–660 (2015)

    Article  Google Scholar 

  19. P.K. Fazeli, A.T. Faje, E.J. Cross, H. Lee, C.J. Rosen, M.L. Bouxsein, A. Klibanski, Serum FGF-21 levels are associated with worsened radial trabecular bone microarchitecture and decreased radial bone strength in women with anorexia nervosa. Bone 77, 6–11 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. L.T. Ho-Pham, U.D. Nguyen, T.V. Nguyen, Association between lean mass, fat mass, and bone mineral density: a meta-analysis. J. Clin. Endocrinol. Metab. 99(1), 30–38 (2014)

    Article  CAS  PubMed  Google Scholar 

  21. X. Zhang, D.C. Yeung, M. Karpisek, D. Stejskal, Z.G. Zhou, F. Liu, R.L. Wong, W.S. Chow, A.W. Tso, K.S. Lam, A. Xu, Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 57(5), 1246–1253 (2008)

    Article  CAS  PubMed  Google Scholar 

  22. J. Dushay, P.C. Chui, G.S. Gopalakrishnan, M. Varela-Rey, M. Crawley, F.M. Fisher, M.K. Badman, M.L. Martinez-Chantar, E. Maratos-Flier, Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology 139(2), 456–463 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We wish to thank all the blood donors who participated in the study.

Funding

This work was supported by the National Natural Science Foundation of China (81573241, 31471188, 31771399), China Postdoctoral Science Foundation (2016M602797), Natural Science Basic Research Program Shaanxi Province (2016JQ3026), and the Fundamental Research Funds for the Central Universities.

Author contributions

Y.G. conceived and supervised the project. RH.H. and SS.D. conducted data analysis. M.L., W.H., HN.Y. and DL.Z. contributed to experiments. RH.H wrote the manuscript. JL.G. reproduced data analysis and revised manuscript. All authors discussed the results and commented on the manuscript. All authors agree to be accountable for the work and to ensure that any questions relating to the accuracy and integrity of the paper are investigated and properly resolved.

Author information

Authors and Affiliations

  1. Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, 710049, China

    Ruo-Han Hao, Jun-Ling Gao, Dong-Li Zhu, Hlaing Nwe Thynn, Shan-Shan Dong & Yan Guo

  2. Departments of Orthopaedics, the First Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, 710061, China

    Meng Li

  3. Department of Trauma Surgery, Honghui Hospital, College of Medicine, Xi’an Jiaotong University, Xi’an, 710054, China

    Wei Huang

Authors
  1. Ruo-Han Hao
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Jun-Ling Gao
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Meng Li
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Wei Huang
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Dong-Li Zhu
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Hlaing Nwe Thynn
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Shan-Shan Dong
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Yan Guo
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Yan Guo.

Ethics declarations

Conflict of interest

The authors declare that they have no coonflict of interests.

Ethical approval

This study was approved by the Institutional Review Board and Ethics Committee of Xi’an Jiaotong University. All procedures performed in the study involving human participants were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hao, RH., Gao, JL., Li, M. et al. Association between fibroblast growth factor 21 and bone mineral density in adults. Endocrine 59, 296–303 (2018). https://doi.org/10.1007/s12020-017-1507-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-017-1507-y

Keywords