Vol 59, No 3 (2021)
Original paper
Published online: 2021-09-27

open access

Page views 7316
Article views/downloads 826
Get Citation

Connect on Social Media

Connect on Social Media

SDF-1/CXCR4 axis promotes osteogenic differentiation of BMSCs through the JAK2/STAT3 pathway

Wen Xiong1, Xin Guo1, Xianhua Cai1
Pubmed: 34580847
Folia Histochem Cytobiol 2021;59(3):187-194.


Introduction. This study aimed to investigate the effects of stromal cell-derived factor-1 (SDF-1) and activation of its receptor, chemokine receptor 4 (CXCR4), on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), and the key signaling mechanisms involved in these effects.

Material and methods. BMSCs were treated with 100 μg/L SDF-1 and cultured in osteogenic medium for 7 days. RT-qPCR and western blotting were used to detect the protein and mRNA levels of Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), Runt-related transcription factor 2 (Runx2), and osteocalcin (OCN). Alizarin-red staining was used to detect the mineralization-inducing ability of the cells.

Results. After BMSCs were treated with SDF-1, the levels of JAK2 mRNA, STAT3 mRNA, and protein phosphorylation increased, the number of mineralized nodules of BMSCs increased, and the osteogenic-differentiation ability was enhanced. In addition, after BMSCs were treated with an inhibitor of JAK2 phosphorylation, the levels of JAK2, STAT3, Runx2, and OCN decreased significantly, the number of mineralized nodules of BMSCs also decreased, and the osteogenic-differentiation ability decreased. The inhibition of CXCR4-treated BMSCs further confirmed that SDF-1/CXCR4 activated JAK2/STAT3 to regulate the osteogenic differentiation of BMSCs.

Conclusions. SDF-1/CXCR4 promoted the osteogenic differentiation of BMSCs through JAK2/STAT3 activation.

Article available in PDF format

View PDF Download PDF file


  1. Nishigaki A, Tsuzuki-Nakao T, Kido T, et al. Concentration of stromal cell-derived factor-1 (SDF-1/CXCL12) in the follicular fluid is associated with blastocyst development. Reprod Med Biol. 2019; 18(2): 161–166.
  2. Kawaguchi N, Zhang TT, Nakanishi T. Involvement of CXCR4 in Normal and Abnormal Development. Cells. 2019; 8(2).
  3. Li G, An J, Han X, et al. Hypermethylation of microRNA-149 activates SDF-1/CXCR4 to promote osteogenic differentiation of mesenchymal stem cells. J Cell Physiol. 2019; 234(12): 23485–23494.
  4. Chen Q, Zheng C, Li Y, et al. Bone Targeted Delivery of SDF-1 via Alendronate Functionalized Nanoparticles in Guiding Stem Cell Migration. ACS Appl Mater Interfaces. 2018; 10(28): 23700–23710.
  5. Li G, Yun X, Ye K, et al. Long non-coding RNA-H19 stimulates osteogenic differentiation of bone marrow mesenchymal stem cells via the microRNA-149/SDF-1 axis. J Cell Mol Med. 2020; 24(9): 4944–4955.
  6. Zhuang XM, Zhou B, Yuan KF. Role of p53 mediated miR-23a/CXCL12 pathway in osteogenic differentiation of bone mesenchymal stem cells on nanostructured titanium surfaces. Biomed Pharmacother. 2019; 112: 108649.
  7. Barzelay A, Weisthal Algor S, Niztan A, et al. Adipose-Derived Mesenchymal Stem Cells Migrate and Rescue RPE in the Setting of Oxidative Stress. Stem Cells Int. 2018; 2018: 9682856.
  8. Herberg S, Fulzele S, Yang N, et al. Stromal cell-derived factor-1β potentiates bone morphogenetic protein-2-stimulated osteoinduction of genetically engineered bone marrow-derived mesenchymal stem cells in vitro. Tissue Eng Part A. 2013; 19(1-2): 1–13.
  9. Periyasamy-Thandavan S, Burke J, Mendhe B, et al. MicroRNA-141-3p Negatively Modulates SDF-1 Expression in Age-Dependent Pathophysiology of Human and Murine Bone Marrow Stromal Cells. J Gerontol A Biol Sci Med Sci. 2019; 74(9): 1368–1374.
  10. Itoh S, Udagawa N, Takahashi N, et al. A critical role for interleukin-6 family-mediated Stat3 activation in osteoblast differentiation and bone formation. Bone. 2006; 39(3): 505–512.
  11. Yue R, Zhou BoO, Shimada IS, et al. Leptin Receptor Promotes Adipogenesis and Reduces Osteogenesis by Regulating Mesenchymal Stromal Cells in Adult Bone Marrow. Cell Stem Cell. 2016; 18(6): 782–796.
  12. Pajarinen J, Lin T, Gibon E, et al. Mesenchymal stem cell-macrophage crosstalk and bone healing. Biomaterials. 2019; 196: 80–89.
  13. Yu X, Li Z, Wan Q, et al. Inhibition of JAK2/STAT3 signaling suppresses bone marrow stromal cells proliferation and osteogenic differentiation, and impairs bone defect healing. Biol Chem. 2018; 399(11): 1313–1323.
  14. Han J, Feng Z, Xie Yu, et al. Oncostatin M-induced upregulation of SDF-1 improves Bone marrow stromal cell migration in a rat middle cerebral artery occlusion stroke model. Exp Neurol. 2019; 313: 49–59.
  15. Zhang P, Zhang H, Lin J, et al. Insulin impedes osteogenesis of BMSCs by inhibiting autophagy and promoting premature senescence via the TGF-β1 pathway. Aging (Albany NY). 2020; 12(3): 2084–2100.
  16. Li X, Zheng Y, Hou L, et al. Exosomes derived from maxillary BMSCs enhanced the osteogenesis in iliac BMSCs. Oral Dis. 2020; 26(1): 131–144.
  17. Onodera K, Sakurada A, Notsuda H, et al. Growth inhibition of KRAS‑ and EGFR‑mutant lung adenocarcinoma by cosuppression of STAT3 and the SRC/ARHGAP35 axis. Oncol Rep. 2018; 40(3): 1761–1768.
  18. Park SY, Lee CJ, Choi JH, et al. The JAK2/STAT3/CCND2 Axis promotes colorectal Cancer stem cell persistence and radioresistance. J Exp Clin Cancer Res. 2019; 38(1): 399.
  19. Hubbard SR. Mechanistic Insights into Regulation of JAK2 Tyrosine Kinase. Front Endocrinol (Lausanne). 2017; 8: 361.
  20. Liu H, Du T, Li C, et al. STAT3 phosphorylation in central leptin resistance. Nutr Metab (Lond). 2021; 18(1): 39.
  21. Chen XM, Yu YH, Wang L, et al. Effect of the JAK2/STAT3 signaling pathway on nerve cell apoptosis in rats with white matter injury. Eur Rev Med Pharmacol Sci. 2019; 23(1): 321–327.
  22. Yu X, Wan QL, Li Z, et al. [(*)AG490 could suppress bone marrow mesenchymal stem cells migration, mineralization and bone defect healing via inhibiting Jak2-STAT3 pathway]. Zhonghua Kou Qiang Yi Xue Za Zhi. 2018; 53(5): 293–300.
  23. Teicher BA, Fricker SP. CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res. 2010; 16(11): 2927–2931.
  24. Mousavi A. CXCL12/CXCR4 signal transduction in diseases and its molecular approaches in targeted-therapy. Immunol Lett. 2020; 217: 91–115.
  25. Ding Qi, Sun J, Xie W, et al. Stemona alkaloids suppress the positive feedback loop between M2 polarization and fibroblast differentiation by inhibiting JAK2/STAT3 pathway in fibroblasts and CXCR4/PIK/AKT1 pathway in macrophages. Int Immunopharmacol. 2019; 72: 385–394.
  26. Dimova I, Karthik S, Makanya A, et al. SDF-1/CXCR4 signalling is involved in blood vessel growth and remodelling by intussusception. J Cell Mol Med. 2019; 23(6): 3916–3926.
  27. Ge G, Zhang H, Li R, et al. The Function of SDF-1-CXCR4 Axis in SP Cells-Mediated Protective Role for Renal Ischemia/Reperfusion Injury by SHH/GLI1-ABCG2 Pathway. Shock. 2017; 47(2): 251–259.
  28. Wang G, Zhuo Z, Zhang Q, et al. Transfection of CXCR-4 using microbubble-mediated ultrasound irradiation and liposomes improves the migratory ability of bone marrow stromal cells. Curr Gene Ther. 2015; 15(1): 21–31.
  29. Jaerve A, Schira J, Müller HW. Concise review: the potential of stromal cell-derived factor 1 and its receptors to promote stem cell functions in spinal cord repair. Stem Cells Transl Med. 2012; 1(10): 732–739.
  30. Azab AK, Runnels JM, Pitsillides C, et al. CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy. Blood. 2009; 113(18): 4341–4351.
  31. Xiu G, Li X, Yin Y, et al. SDF-1/CXCR4 Augments the Therapeutic Effect of Bone Marrow Mesenchymal Stem Cells in the Treatment of Lipopolysaccharide-Induced Liver Injury by Promoting Their Migration Through PI3K/Akt Signaling Pathway. Cell Transplant. 2020; 29: 963689720929992.
  32. Liu Y, Liang HM, Lv YQ, et al. Blockade of SDF-1/CXCR4 reduces adhesion-mediated chemoresistance of multiple myeloma cells via interacting with interleukin-6. J Cell Physiol. 2019; 234(11): 19702–19714.