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GDF11 Inhibits Bone Formation by Activating Smad2/3 in Bone Marrow Mesenchymal Stem Cells

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Abstract

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor-β superfamily. Recent studies confirmed that GDF11 plays an important role in regulating the regeneration of brain, skeletal muscle, and heart during aging; however, its role in bone metabolism remains unclear. Thus, the aim of this study was to determine the effects of GDF11 on bone metabolism, including bone formation and bone resorption, both in vitro and in vivo. Our results showed that GDF11 inhibited osteoblastic differentiation of bone marrow mesenchymal stem cells in vitro. Mechanistically, GDF11 repressed Runx2 expression by inducing SMAD2/3 phosphorylation during osteoblast differentiation. Moreover, intraperitoneal injection of GDF11 inhibited bone formation and accelerated age-related bone loss in mice. Our results also showed that GDF11 had no effect on osteoclast differentiation or bone resorption both in vitro and in vivo. These results provide a further rationale for the therapeutic targeting of GDF11 for the treatment of age-related osteoporosis.

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References

  1. Loffredo FS, Steinhauser ML, Jay SM et al (2013) Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153:828–839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Katsimpardi L, Litterman NK, Schein PA et al (2014) Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344:630–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sinha M, Jang YC, Oh J et al (2014) Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344:649–652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Smith SC, Zhang X, Zhang X et al (2015) GDF11 does not rescue aging-related pathological hypertrophy. Circ Res 117:926–932

    Article  CAS  PubMed  Google Scholar 

  5. Mendelsohn AR, Larrick JW (2014) Systemic factors mediate reversible age-associated brain dysfunction. Rejuvenation Res 17:525–528

    Article  CAS  PubMed  Google Scholar 

  6. Egerman MA, Cadena SM, Gilbert JA et al (2015) GDF11 increases with age and inhibits skeletal muscle regeneration. Cell Metab 22:164–174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Raisz L (2005) Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest 115:3318–3325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ettinger B, Black DM, Nevitt MC et al (1992) Contribution of vertebral deformities to chronic pain and disability. The Study of Osteoporotic Fractures Research Group. J Bone Miner Res 7:449–456

    Article  CAS  PubMed  Google Scholar 

  9. Cauley JA, Thompson DE, Ensrud KC et al (2000) Risk of mortality following clinical fractures. Osteoporos Int 11:556–561

    Article  CAS  PubMed  Google Scholar 

  10. Eriksen EF (2010) Cellular mechanisms of bone remodeling. Rev Endocr Metab Disord. 11:219–227

    Article  PubMed  PubMed Central  Google Scholar 

  11. Zhang Y, Shao J, Wang Z et al (2015) Growth differentiation factor 11 is a protective factor for osteoblast genesis by targeting PPAR gamma. Gene 557:209–214

    Article  CAS  PubMed  Google Scholar 

  12. Shoback D (2007) Update in osteoporosis and metabolic bone disorders. J Clin Endocrinol Metab 92:747–753

    Article  CAS  PubMed  Google Scholar 

  13. Li H, Xie H, Liu W et al (2009) A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. J Clin Invest 119:3666–3677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shim JH, Greenblatt MB, Zou W et al (2013) Schnurri-3 regulates ERK downstream of WNT signaling in osteoblasts. J Clin Invest. 123:4010–4022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Li Z, Kawasumi M, Zhao B et al (2010) Transgenic over-expression of growth differentiation factor 11 propeptide in skeleton results in transformation of the seventh cervical vertebra into a thoracic vertebra. Mol Reprod Dev. 77:990–997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Li CJ, Cheng P, Liang MK et al (2015) MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation. J Clin Invest 125:1509–1522

    Article  PubMed  PubMed Central  Google Scholar 

  17. Liu Y, Berendsen AD, Jia S et al (2012) Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation. J Clin Invest. 122:3101–3113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cao Y, Gomes SA, Rangel EB et al (2015) S-nitrosoglutathione reductase-dependent PPARγ denitrosylation participates in MSC-derived adipogenesis and osteogenesis. J Clin Invest 125:1679–1691

    Article  PubMed  PubMed Central  Google Scholar 

  19. Nishikawa K, Nakashima T, Takeda S et al (2010) Maf promotes osteoblast differentiation in mice by mediating the age-related switch in mesenchymal cell differentiation. J Clin Invest 120:3455–3465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Iyer S, Ambrogini E, Bartell SM et al (2013) FOXOs attenuate bone formation by suppressing Wnt signaling. J Clin Invest. 123:3409–3419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wu MY, Hill CS (2009) TGF—beta superfamily signaling in embryonic development and homeostasis. Dev Cell 16:329–343

    Article  CAS  PubMed  Google Scholar 

  22. Wu JY, Aarnisalo P, Bastepe M et al (2011) Gsα enhances commitment of mesenchymal progenitors to the osteoblast lineage but restrains osteoblast differentiation in mice. J Clin Invest. 121:3492–3504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sartori R, Milan G, Patron M et al (2009) Smad2 and 3 transcription factors control muscle mass in adulthood. Am J Physiol Cell Physiol 296:C1248–C1257

    Article  CAS  PubMed  Google Scholar 

  24. Kang JS, Alliston T, Delston R et al (2005) Repression of Runx2 function by TGF -beta through recruitment of class II histone deacetylases by Smad3. EMBO J 24:2543–2555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chen G, Deng C, Li YP et al (2012) TGF- β and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci. 8:272–288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hamrick MW (2003) Increased bone mineral density in the of GDF8 knockout mice. Anat Rec A DiscovMol Cell Evol Biol 272:388–391

    Article  Google Scholar 

  27. Hamrick MW, Shi X, Zhang W et al (2007) Loss of myostatin (gdf8) function increases osteogenic differentiation of bone marrow-derived mesenchymal stem cells but the osteogenic effect is ablated with unloading. Bone 40:1544–1553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hamrick MW, McPherron AC, Lovejoy CO (2002) Bone mineral content and density in the humerus of adult myostatin-deficient mice. Calcif Tissue Int 71:63–68

    Article  CAS  PubMed  Google Scholar 

  29. McPherron AC, Lawler AM, Lee SJ (1999) Regulation of anterior/posterior patterning of the axial skeleton by growth differentiation factor 11. Nat Genet 22:260–264

    Article  CAS  PubMed  Google Scholar 

  30. Hamrick MW, Arounleut P, Kellum E et al (2010) Recombinant myostatin (GDF-8) propeptide enhances the repair and regeneration of both muscle and bone in a model of deep penetrant musculoskeletal injury. J Trauma 69:579–583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by Grant No. 81520108008 from the Major International (Regional) Joint Research Project of China National Natural Scientific Foundation (NSFC), Grant No. 81125006 from the Distinguished Young Scientists of China National Natural Scientific Foundation, Grant No. U1301222 from the NSFC-Guangdong Joint Project, and Grant No. 81570806 from the China National Natural Scientific Foundation.

Author Contributions

Study design: XHL; Study conduct: QL, MLT, CJL, ZL, TL, and XHL; Data collection: QL, MLT, CJL, and ZL; Data analysis: XHL, QL, MLT, and CJL; Data interpretation: XHL, QL, MLT, CJL, and LZ; Drafting manuscript: XHL, QL, MLT, and CJL; Revising manuscript content: XHL and QL; Approval of the final manuscript: QL, MLT, CJL, ZL, TL and XHL; XHL and QL are primarily responsible for integrity of the data analysis, and all authors take responsibility for and attest to the integrity of the data analysis. XHL is responsible for transmitting the editors’ comments to the other authors.

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Authors and Affiliations

  1. Department of Metabolism & Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People’s Republic of China

    Qiong Lu, Man-Li Tu, Chang-Jun Li, Li Zhang & Xiang-Hang Luo

  2. National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People’s Republic of China

    Qiong Lu, Man-Li Tu, Chang-Jun Li, Li Zhang & Xiang-Hang Luo

  3. Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People’s Republic of China

    Qiong Lu

  4. Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Qiong Lu

  5. Department of Orthopaedics Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Man-Li Tu

  6. Department of Endocrinology, The Xiangya Hospital of Central South University, Changsha, 410008, Hunan, People’s Republic of China

    Tie-Jian Jiang

  7. Department of Orthopaedics Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People’s Republic of China

    Tang Liu

Authors
  1. Qiong Lu
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  2. Man-Li Tu
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  3. Chang-Jun Li
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  4. Li Zhang
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  5. Tie-Jian Jiang
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  6. Tang Liu
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  7. Xiang-Hang Luo
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Corresponding author

Correspondence to Xiang-Hang Luo.

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Conflict of Interest

Xiang-Hang Luo, Qiong Lu, Man-Li Tu, Chang-Jun Li, Li Zhang, Tie-Jian Jiang, and Tang Liu declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

Mouse cell line and mice were used in this study. All animal experiments were approved by the Animal Care and Use Committee of the Laboratory Animal Research Center at Xiangya Medical School of Central South University (Changsha, Hunan, China). Strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals. No human specimen was used in this study.

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Lu, Q., Tu, ML., Li, CJ. et al. GDF11 Inhibits Bone Formation by Activating Smad2/3 in Bone Marrow Mesenchymal Stem Cells. Calcif Tissue Int 99, 500–509 (2016). https://doi.org/10.1007/s00223-016-0173-z

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  • DOI: https://doi.org/10.1007/s00223-016-0173-z

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