Skip to main content

Advertisement

SpringerLink
Log in

Bone–fat linkage via interleukin-11 in response to mechanical loading

  • Invited Review
  • Published:
Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Positive regulators of bone formation, such as mechanical loading and PTH, stimulate and negative regulators, such as aging and glucocorticoid excess, suppress IL-11 gene transcription in osteoblastic cells. Signal transduction from mechanical loading and PTH stimulation involves two pathways: one is Ca2+–ERK–CREB pathway which facilitates binding of ∆FosB/JunD to the AP-1 site to enhance IL-11 gene transcription, and the other is Smad1/5 phosphorylation that promotes IL-11 gene transcription via SBE binding and complex formation with ∆FosB/JunD. The increased IL-11 suppresses Sost expression via IL-11Rα–STAT1/3–HDAC4/5 pathway and enhances Wnt signaling in the bone to stimulate bone formation. Thus, IL-11 mediates stimulatory and inhibitory signals of bone formation by affecting Wnt signaling. Physiologically important stimulation of bone formation is exercise-induced mechanical loading, but exercise simultaneously requires energy source for muscle contraction. Exercise-induced stimulation of IL-11 expression in the bone increases the secretion of IL-11 from the bone. The increased circulating IL-11 acts like a hormone to enhance adipolysis as an energy source with a reduction in adipogenic differentiation via a suppression of Dkk1/2 expression in the adipose tissue. Such bone–fat linkage can be a mechanism whereby exercise increases bone mass and, at the same time, maintains energy supply from the adipose tissue.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Kinoshita Y, Fukumoto S (2018) X-linked hypophosphatemia and FGF23-related hypophosphatemic diseases: prospect for new treatment. Endocr Rev 39:274–291

    Article  PubMed  Google Scholar 

  2. Takashi Y, Kosako H, Sawatsubashi S, Kinoshita Y, Ito N, Tsoumpra MK, Nangaku M, Abe M, Matsuhisa M, Kato S, Matsumoto T, Fukumoto S (2019) Activation of unliganded FGF receptor by extracellular phosphate potentiates proteolytic protection of FGF23 by its O-glycosylation. Proc Natl Acad Sci USA 116:11418–11427

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wei J, Karsenty G (2015) An overview of the metabolic functions of osteocalcin. Rev Endocr Metab Disord 16:93–98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kido S, Kuriwaka-Kido R, Imamura T, Ito Y, Inoue D, Matsumoto T (2009) Mechanical stress induces Interleukin-11 expression to stimulate osteoblast differentiation. Bone 45:1125–1132

    Article  CAS  PubMed  Google Scholar 

  5. Kawashima I, Ohsumi J, Mita-Honjo K, Shimoda-Takano K, Ishikawa H, Sakakibara S, Miyadai K, Takiguchi Y (1991) Molecular cloning of cDNA encoding adipogenesis inhibitory factor and identity with interleukin-11. FEBS Lett 283:199–202

    Article  CAS  PubMed  Google Scholar 

  6. Dong B, Hiasa M, Higa Y, Ohnishi Y, Endo I, Kondo T, Takashi Y, Tsoumpra M, Kainuma R, Sawatsubashi S, Kiyonari H, Shioi G, Sakaue H, Nakashima T, Kato S, Abe M, Fukumoto S, Matsumoto T (2022) Osteoblast/osteocyte-derived interleukin-11 regulates osteogenesis and systemic adipogenesis. Nat Commun 13:7194

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bennett CN, Longo KA, Wright WS, Suva LJ, Lane TF, Hankenson KD, MacDougald OA (2005) Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci USA 102:3324–3329

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  8. Levi G, Narboux-Nême N, Cohen-Solal M (2022) DLX Genes in the development and maintenance of the vertebrate skeleton: implications for human pathologies. Cells 11:3277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19:179–192

    Article  CAS  PubMed  Google Scholar 

  10. Kim J, Han W, Park T, Kim EJ, Bang I, Lee HS, Jeong Y, Roh K, Kim J, Kim JS, Kang C, Seok C, Han JK, Choi HJ (2020) Sclerostin inhibits Wnt signaling through tandem interaction with two LRP6 ectodomains. Nat Commun 11:5357

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kuriwaka-Kido R, Kido S, Miyatani Y, Ito Y, Kondo T, Omatsu T, Dong B, Endo I, Miyamoto K, Matsumoto T (2013) Parathyroid hormone (1–34) counteracts the suppression of interleukin-11 expression by glucocorticoid in murine osteoblasts: a possible mechanism for stimulating osteoblast differentiation against glucocorticoid excess. Endocrinology 154:1156–1167

    Article  CAS  PubMed  Google Scholar 

  12. Rauch A, Seitz S, Baschant U, Schilling AF, Illing A et al (2010) Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor. Cell Metab 11:517–531

    Article  CAS  PubMed  Google Scholar 

  13. Tohjima E, Inoue D, Yamamoto N, Kido S, Ito Y, Kato S, Takeuchi Y, Fukumoto S, Matsumoto T (2003) Decreased AP-1 activity and interleukin-11 expression by bone marrow stromal cells may be associated with impaired bone formation in aged mice. J Bone Miner Res 18:1461–1470

    Article  CAS  PubMed  Google Scholar 

  14. Jenkins BJ, Roberts AW, Greenhill CJ, Najdovska M, Lundgren-May T, Robb L, Grail D, Ernst M (2007) Pathologic consequences of STAT3 hyperactivation by IL-6 and IL-11 during hematopoiesis and lymphopoiesis. Blood 109:2380–2388

    Article  CAS  PubMed  Google Scholar 

  15. Johnstone CN, Chand A, Putoczki TL, Ernst M (2015) Emerging roles for IL-11 signaling in cancer development and progression: focus on breast cancer. Cytokine Growth Factor Rev 26:489–498

    Article  CAS  PubMed  Google Scholar 

  16. Girasole G, Passeri G, Jilka RL, Manolagas SC (1994) Interleukin-11: a new cytokine critical for osteoclast development. J Clin Invest 93:1516–1524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Taguchi Y, Yamamoto M, Yamate T, Lin SC, Mocharla H, DeTogni P, Nakayama N, Boyce BF, Abe E, Manolagas SC (1998) Interleukin-6-type cytokines stimulate mesenchymal progenitor differentiation toward the osteoblastic lineage. Proc Assoc Am Physicians 110:559–574

    CAS  PubMed  Google Scholar 

  18. Kespohl B, Schumertl T, Bertrand J, Lokau J, Garbers C (2021) The cytokine interleukin-11 crucially links bone formation, remodeling and resorption. Cytokine Growth Factor Rev 60:18–27

    Article  CAS  PubMed  Google Scholar 

  19. Ng B, Widjaja AA, Viswanathan S, Dong J, Chothani SP, Lim S, Shekeran SG, Tan J, McGregor NE, Walker EC, Sims NA, Schafer S, Cook SA (2021) Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis. Sci Rep 11:14088

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sims NA, Jenkins BJ, Nakamura A, Quinn JM, Li R, Gillespie MT, Ernst M, Robb L, Martin TJ (2005) Interleukin-11 receptor signaling is required for normal bone remodeling. J Bone Miner Res 20:1093–1102

    Article  CAS  PubMed  Google Scholar 

  21. Takeuchi Y, Watanabe S, Ishii G, Takeda S, Nakayama K, Fukumoto S, Kaneta Y, Inoue D, Matsumoto T, Harigaya K, Fujita T (2002) Interleukin-11 as a stimulatory factor for bone formation prevents bone loss with advancing age in mice. J Biol Chem 277:49011–49018

    Article  CAS  PubMed  Google Scholar 

  22. Watanabe Y, Ohshima H, Mizuno K, Sekiguchi C, Fukunaga M, Kohri K, Rittweger J, Felsenberg D, Matsumoto T, Nakamura T (2004) Intravenous pamidronate prevents femoral bone loss and renal stone formation during 90-day bed rest. J Bone Miner Res 19:1771–1778

    Article  CAS  PubMed  Google Scholar 

  23. Sibonga J, Matsumoto T, Jones J, Shapiro J, Lang T, Shackelford L, Smith SM, Young M, Keyak J, Kohri K, Ohshima H, Spector E, LeBlanc A (2019) Resistive exercise in astronauts on prolonged spaceflights provides partial protection against spaceflight-induced bone loss. Bone 128:112037

    Article  CAS  PubMed  Google Scholar 

  24. Morey ER, Baylink DJ (1978) Inhibition of bone formation during space flight. Science 201:1138–1141

    Article  ADS  CAS  PubMed  Google Scholar 

  25. Kodama Y, Nakayama K, Fuse H, Fukumoto S, Kawahara H, Takahashi H, Kurokawa T, Sekiguchi C, Nakamura T, Matsumoto T (1997) Inhibition of bone resorption by pamidronate cannot restore normal gain in cortical bone mass and strength in tail-suspended rapidly growing rats. J Bone Miner Res 12:1058–1067

    Article  CAS  PubMed  Google Scholar 

  26. Robling AG, Turner CH (2009) Mechanical signaling for bone modeling and remodeling. Crit Rev Eukaryot Gene Expr 19:319–338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Inoue D, Kido S, Matsumoto T (2004) Transcriptional induction of FosB/∆FosB gene by mechanical stress in osteoblasts. J Biol Chem 279:49795–49803

    Article  CAS  PubMed  Google Scholar 

  28. Sasaki F, Hayashi M, Mouri Y, Nakamura S, Adachi T, Nakashima T (2020) Mechanotransduction via the Piezo1-Akt pathway underlies Sost suppression in osteocytes. Biochem Biophys Res Commun 521:806–813

    Article  CAS  PubMed  Google Scholar 

  29. Liu D, Genetos DC, Shao Y, Geist DJ, Li J, Ke HZ, Turner CH, Duncan RL (2008) Activation of extracellular-signal regulated kinase (ERK1/2) by fluid shear is Ca(2+)- and ATP-dependent in MC3T3-E1 osteoblasts. Bone 42:644–652

    Article  CAS  PubMed  Google Scholar 

  30. Sabatakos G, Sims NA, Chen J, Aoki K, Kelz MB, Amling M, Bouali Y, Mukhopadhyay K, Ford K, Nestler EJ, Baron R (2000) Overexpression of DeltaFosB transcription factor(s) increases bone formation and inhibits adipogenesis. Nat Med 6:985–990

    Article  CAS  PubMed  Google Scholar 

  31. Kido S, Kuriwaka-Kido R, Umino-Miyatani Y, Endo I, Inoue D, Taniguchi H, Inoue Y, Imamura T, Matsumoto T (2010) Mechanical stress activates Smad pathway through PKCδ to enhance interleukin-11 gene transcription in osteoblasts. PLoS ONE 5:e13090

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  32. Miyazono K, Maeda S, Imamura T (2005) BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev 16:251–263

    Article  CAS  PubMed  Google Scholar 

  33. Zhou S, Dai Q, Huang X, Jin A, Yang Y, Gong X, Xu H, Gao X, Jiang L (2021) STAT3 is critical for skeletal development and bone homeostasis by regulating osteogenesis. Nat Commun 12:6891

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sato T, Verma S, Andrade CDC, Omeara M, Campbell N, Wang JS, Cetinbas M, Lang A, Ausk BJ, Brooks DJ, Sadreyev RI, Kronenberg HM, Lagares D, Uda Y, Pajevic PD, Bouxsein ML, Gross TS, Wein MN (2020) A FAK/HDAC5 signaling axis controls osteocyte mechanotransduction. Nat Commun 11:3282

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Studies presented in this review were supported in part by Grants-in-Aid for Scientific Research from Japan Society for the Promotion of Science to MH (#17H05104, #19K22719, and #23H03101) and to IE (#21K07339) and the JSBMR Rising Stars Grant 2022 and Nishiyama Dental Academy General Foundation Grant to MH.

Funding

This study was supported by Japan Society for the Promotion of Science, 17H05104, Masahiro Hiasa, 19K22719, Masahiro Hiasa, 23H03101, Masahiro Hiasa, 21K07339, Itsuro Endo, The Japanese Society for Bone and Mineral Research, JSBMR Rising Stars Grant 2022, Masahiro Hiasa, Nishiyama Dental Academy, Nishiyama Dental Academy General Foundation Grant, Masahiro Hiasa.

Author information

Authors and Affiliations

  1. Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Dentistry, Tokushima, 770-8503, Japan

    Masahiro Hiasa

  2. Department of Endocrinology, Metabolism and Hematology, Tokushima University Graduate School of Medical Sciences, 3-18-15 Kuramoto-Cho, Tokushima, 770-8503,, Japan

    Itsuro Endo & Toshio Matsumoto

Authors
  1. Masahiro Hiasa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Itsuro Endo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toshio Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toshio Matsumoto.

Ethics declarations

Conflict of interest

The authors have no conflict of interest related to this work.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hiasa, M., Endo, I. & Matsumoto, T. Bone–fat linkage via interleukin-11 in response to mechanical loading. J Bone Miner Metab (2024). https://doi.org/10.1007/s00774-023-01493-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00774-023-01493-0

Keywords

Search

Navigation