Log in

KLF9 regulates osteogenic differentiation of mesenchymal stem cells

  • Original Paper
  • Published:
Journal of Molecular Histology Aims and scope Submit manuscript

This article has been updated

Abstract

Osteoporosis is a progressive skeletal disease which is characterized by reduced bone mass and degradation of bone microstructure. Mesenchymal stem cells (MSCs) have the potential to inhibit osteoporosis since they are multipotent stem cells that can differentiate into multiple types of cells including osteoblasts. Hence the mechanism of osteogenic differentiation of MSCs deserves comprehensive study. Here we report that KLF9 is a novel regulator in osteogenic differentiation of MSCs. We observed that depletion of KLF9 can largely compromise the osteogenic differentiation ability of MSCs. In addition, we revealed that inhibition of the PI3K-Akt pathway could also affect osteogenic differentiation since KLF9 depletion inhibits PI3K expression. Finally, we discovered that KLF9 expression can be induced by dexamethasone which is an essential component in osteogenic induction medium. Taken together, our study provides new insights into the regulatory role of KLF9 in osteogenic differentiation of MSCs.

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

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /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 includes VAT (Germany)

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

Not applicable.

Change history

  • 08 June 2024

    The affiliation of the author was updated.

References

  • Chen J (2011) Multiple signal pathways in obesity-associated cancer. Obes Rev 12(12):1063–1070

    Article  PubMed  Google Scholar 

  • Chen J et al (2013) The key regulatory roles of the PI3K/Akt signaling pathway in the functionalities of mesenchymal stem cells and applications in tissue regeneration. Tissue Eng Part B Rev 19(6):516–528

    Article  CAS  PubMed  Google Scholar 

  • Chen G, Yang L, Lv Y (2016) Cell-free scaffolds with different stiffness but same microstructure promote bone regeneration in rabbit large bone defect model. J Biomed Mater Res, Part A 104(4):833–841

    Article  CAS  Google Scholar 

  • Compston J (2004) Action Plan for the prevention of osteoporotic fractures in the European Community. Osteoporos Int 15(4):259–262

    Article  PubMed  Google Scholar 

  • Cui A et al (2019) Dexamethasone-induced Krüppel-like factor 9 expression promotes hepatic gluconeogenesis and hyperglycemia. J Clin Investig 129(6):2266–2278

    Article  PubMed  PubMed Central  Google Scholar 

  • Curtis JR, Adachi JD, Saag KG (2009) Bridging the osteoporosis quality chasm. J Bone Miner Res 24(1):3–7

    Article  PubMed  Google Scholar 

  • Di Luca A et al (2016) Gradients in pore size enhance the osteogenic differentiation of human mesenchymal stromal cells in three-dimensional scaffolds. Sci Rep 6(1):22898

    Article  PubMed  PubMed Central  Google Scholar 

  • Dominici M et al (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8(4):315

    Article  CAS  PubMed  Google Scholar 

  • Engler AJ et al (2006) Matrix elasticity directs stem cell lineage specification. Cell 126(4):677–689

    Article  CAS  PubMed  Google Scholar 

  • Fierro F et al (2007) Inhibition of platelet-derived growth factor receptorβ by imatinib mesylate suppresses proliferation and alters differentiation of human mesenchymal stem cells in vitro. Cell Prolif 40(3):355–366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fitter S et al (2008) Long-term imatinib therapy promotes bone formation in CML patients. Blood J Am Soc Hematol 111(5):2538–2547

    CAS  Google Scholar 

  • Fitter S et al (2012) Suppression of PDGF-induced PI3 kinase activity by imatinib promotes adipogenesis and adiponectin secretion. J Mol Endocrinol 48(3):229–240

    Article  CAS  PubMed  Google Scholar 

  • Fu J et al (2019) Photoelectric-responsive extracellular matrix for bone engineering. ACS Nano 13(11):13581–13594

    Article  CAS  PubMed  Google Scholar 

  • Garg P et al (2017) Prospective review of mesenchymal stem cells differentiation into osteoblasts. Orthop Surg 9(1):13–19

    Article  PubMed  PubMed Central  Google Scholar 

  • Grigoriadis AE, Heersche J, Aubin JE (1988) Differentiation of muscle, fat, cartilage, and bone from progenitor cells present in a bone-derived clonal cell population: effect of dexamethasone. J Cell Biol 106(6):2139–2151

    Article  CAS  PubMed  Google Scholar 

  • Hosseini S et al (2019) Contribution of osteocalcin-mimetic peptide enhances osteogenic activity and extracellular matrix mineralization of human osteoblast-like cells. Colloids Surf, B 173:662–671

    Article  CAS  Google Scholar 

  • Joiner DM et al (2012) Bone marrow stromal cells from aged male rats have delayed mineralization and reduced response to mechanical stimulation through nitric oxide and ERK1/2 signaling during osteogenic differentiation. Biogerontology 13:467–478

    Article  CAS  PubMed  Google Scholar 

  • Jönsson S et al (2012) Imatinib inhibits proliferation of human mesenchymal stem cells and promotes early but not late osteoblast differentiation in vitro. J Bone Miner Metab 30:119–123

    Article  PubMed  Google Scholar 

  • Kadonaga JT et al (1987) Isolation of cDNA encoding transcription factor Sp1 and functional analysis of the DNA binding domain. Cell 51(6):1079–1090

    Article  CAS  PubMed  Google Scholar 

  • Kimura H, Fujimori K (2014) Activation of early phase of adipogenesis through Krüppel-like factor KLF9-mediated, enhanced expression of CCAAT/enhancer-binding protein β in 3T3-L1 cells. Gene 534(2):169–176

    Article  CAS  PubMed  Google Scholar 

  • Li N et al (2012) Suppression of type I collagen expression by miR-29b via PI3K, Akt, and Sp1 pathway in human Tenon’s fibroblasts. Invest Ophthalmol vis Sci 53(3):1670–1678

    Article  CAS  PubMed  Google Scholar 

  • Li J et al (2013) Dexamethasone shifts bone marrow stromal cells from osteoblasts to adipocytes by C/EBPalpha promoter methylation. Cell Death Dis 4(10):e832–e832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lien CY et al (2009) Restoration of bone mass and strength in glucocorticoid-treated mice by systemic transplantation of CXCR4 and cbfa-1 co-expressing mesenchymal stem cells. J Bone Miner Res 24(5):837–848

    Article  CAS  PubMed  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods 25(4):402–408

    Article  CAS  PubMed  Google Scholar 

  • Martin KE et al (2011) Analysis of the comparative effectiveness of 3 oral bisphosphonates in a large managed care organization: adherence, fracture rates, and all-cause cost. J Manag Care Pharm 17(8):596–609

    PubMed  Google Scholar 

  • Nandan MO, Yang VW (2009) The role of Krüppel-like factors in the reprogramming of somatic cells to induced pluripotent stem cells. Histol Histopathol 24(10):1343

    CAS  PubMed  PubMed Central  Google Scholar 

  • Osyczka AM, Leboy PS (2005) Bone morphogenetic protein regulation of early osteoblast genes in human marrow stromal cells is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling. Endocrinology 146(8):3428–3437

    Article  CAS  PubMed  Google Scholar 

  • Payne KA et al (2010) Effect of phosphatidyl inositol 3-kinase, extracellular signal-regulated kinases 1/2, and p38 mitogen-activated protein kinase inhibition on osteogenic differentiation of muscle-derived stem cells. Tissue Eng Part A 16(12):3647–3655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pei H et al (2011) Krüppel-like factor KLF9 regulates PPARγ transactivation at the middle stage of adipogenesis. Cell Death Differ 18(2):315–327

    Article  CAS  PubMed  Google Scholar 

  • Saito M, Marumo K (2015) Effects of collagen crosslinking on bone material properties in health and disease. Calcif Tissue Int 97:242–261

    Article  CAS  PubMed  Google Scholar 

  • Sandhu SK, Hampson G (2011) The pathogenesis, diagnosis, investigation and management of osteoporosis. J Clin Pathol 64(12):1042–1050

    Article  CAS  PubMed  Google Scholar 

  • Shockley KR et al (2009) PPARγ2 nuclear receptor controls multiple regulatory pathways of osteoblast differentiation from marrow mesenchymal stem cells. J Cell Biochem 106(2):232–246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steinert AF et al (2012) Concise review: the clinical application of mesenchymal stem cells for musculoskeletal regeneration: current status and perspectives. Stem Cells Transl Med 1(3):237–247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676

    Article  CAS  PubMed  Google Scholar 

  • Takahashi K et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872

    Article  CAS  PubMed  Google Scholar 

  • Wang Y et al (2012) Effects of hypoxia on osteogenic differentiation of rat bone marrow mesenchymal stem cells. Mol Cell Biochem 362:25–33

    Article  CAS  PubMed  Google Scholar 

  • Yu W et al (2008) Critical role of phosphoinositide 3-kinase cascade in adipogenesis of human mesenchymal stem cells. Mol Cell Biochem 310:11–18

    Article  CAS  PubMed  Google Scholar 

  • Yu J et al (2015) Suppression of type I collagen expression by miR-29b via PI3K, Akt, and Sp1 pathway, part II: an in vivo investigation. Invest Ophthalmol vis Sci 56(10):6019–6028

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Science and Technology Development Fund (FDCT Macau) (0072/2019/A2 and SKL-QRCM (MUST)-2023–2025).

Author information

Authors and Affiliations

Authors

Contributions

Conceptualization, Q.W.; methodology, X.X., M.Z., Y. Q., and X. W.; software, X.X. and M.Z.; validation, X.X., M.Z., and Q.W.; formal analysis, X.X.; investigation, X.X. and Q.W.; resources, Q.W.; data curation, X.X., M.Z. and Y.Q.; writing—original draft preparation, M.Z. and Q.W.; writing—review and editing, X.X. and Q.W.; visualization, X.X. and Q.W.; supervision, Q.W.; project administration, Q.W.; funding acquisition, Q.W. All authors have read and agreed to the manuscript.

Corresponding author

Correspondence to Qiang Wu.

Ethics declarations

Institutional review board statement

Not applicable.

Informed consent

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 13 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

**ao, X., Zhang, M., Qian, Y. et al. KLF9 regulates osteogenic differentiation of mesenchymal stem cells. J Mol Histol (2024). https://doi.org/10.1007/s10735-024-10204-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10735-024-10204-6

Keywords

Navigation