DOI QR코드

DOI QR Code

TNF-α-Induced SOX5 Upregulation Is Involved in the Osteogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells Through KLF4 Signal Pathway

  • Xu, Lijun (Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University) ;
  • Zheng, Lili (Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University) ;
  • Wang, Zhifang (Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University) ;
  • Li, Chong (Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University) ;
  • Li, Shan (Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University) ;
  • Xia, Xuedi (Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University) ;
  • Zhang, Pengyan (Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University) ;
  • Li, Li (Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University) ;
  • Zhang, Lixia (Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University)
  • Received : 2017.12.07
  • Accepted : 2018.03.21
  • Published : 2018.06.30

Abstract

Postmenopausal osteoporosis (PMOP) is a common systemic skeletal disease characterized by reduced bone mass and microarchitecture deterioration. Although differentially expressed SOX5 has been found in bone marrow from ovariectomized mice, its role in osteogenic differentiation in human mesenchymal stem cells (hMSCs) from bone marrow in PMOP remains unknown. In this study, we investigated the biological function of SOX5 and explore its molecular mechanism in hMSCs from patients with PMOP. Our findings showed that the mRNA and protein expression levels of SOX5 were upregulated in hMSCs isolated from bone marrow samples of PMOP patients. We also found that SOX5 overexpression decreased the alkaline phosphatase (ALP) activity and the gene expression of osteoblast markers including Collagen I, Runx2 and Osterix, which were increased by SOX5 knockdown using RNA interference. Furthermore, $TNF-{\alpha}$ notably upregulated the SOX5 mRNA expression level, and SOX5 knockdown reversed the effect of $TNF-{\alpha}$ on osteogenic differentiation of hMSCs. In addition, SOX5 overexpression increased Kruppel-like factor 4 (KLF4) gene expression, which was decreased by SOX5 silencing. KLF4 knockdown abrogated the suppressive effect of SOX5 overexpression on osteogenic differentiation of hMSCs. Taken together, our results indicated that $TNF-{\alpha}$-induced SOX5 upregulation inhibited osteogenic differentiation of hMSCs through KLF4 signal pathway, suggesting that SOX5 might be a novel therapeutic target for PMOP treatment.

Keywords

References

  1. Abdallah, B.M., and Kassem, M. (2008). Human mesenchymal stem cells: from basic biology to clinical applications. Gene Ther. 15, 109-116. https://doi.org/10.1038/sj.gt.3303067
  2. Alm, J.J., Heino, T.J., Hentunen, T.A., Vaananen, H.K., and Aro, H.T. (2012). Transient 100 nM dexamethasone treatment reduces interand intraindividual variations in osteoblastic differentiation of bone marrow-derived human mesenchymal stem cells. Tissue Eng. Part C Methods 18, 658-666. https://doi.org/10.1089/ten.tec.2011.0675
  3. Axelsson, A.S., Mahdi, T., Nenonen, H.A., Singh, T., Hanzelmann, S., Wendt, A., Bagge, A., Reinbothe, T.M., Millstein, J., Yang, X., et al. (2017). Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes. Nat. Commun. 8, 15652. https://doi.org/10.1038/ncomms15652
  4. Black, D.M., and Rosen, C.J. (2016). Clinical Practice. Postmenopausal Osteoporosis. N. Engl. J. Med. 374, 254-262. https://doi.org/10.1056/NEJMcp1513724
  5. Chen, H.F., Huang, C.H., Liu, C.J., Hung, J.J., Hsu, C.C., Teng, S.C., and Wu, K.J. (2014). Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis. Nat. Commun. 5, 4697. https://doi.org/10.1038/ncomms5697
  6. Ding, D.C., Shyu, W.C., and Lin, S.Z. (2011). Mesenchymal stem cells. Cell Transplant 20, 5-14. https://doi.org/10.3727/096368910X
  7. Dy, P., Han, Y., and Lefebvre, V. (2008). Generation of mice harboring a Sox5 conditional null allele. Genesis 46, 294-299. https://doi.org/10.1002/dvg.20392
  8. Feng, X., Shi, Y., Xu, L., Peng, Q., Wang, F., Wang, X., Sun, W., Lu, Y., Tsao, B.P., Zhang, M., et al. (2016). Modulation of IL-6 induced RANKL expression in arthritic synovium by a transcription factor SOX5. Sci. Rep. 6, 32001. https://doi.org/10.1038/srep32001
  9. Kameda, Y., Takahata, M., Mikuni, S., Shimizu, T., Hamano, H., Angata, T., Hatakeyama, S., Kinjo, M., and Iwasaki, N. (2015). Siglec-15 is a potential therapeutic target for postmenopausal osteoporosis. Bone 71, 217-226. https://doi.org/10.1016/j.bone.2014.10.027
  10. Kim, J.H., Kim, K., Youn, B.U., Lee, J., Kim, I., Shin, H.I., Akiyama, H., Choi, Y., and Kim, N. (2014). Kruppel-like factor 4 attenuates osteoblast formation, function, and cross talk with osteoclasts. J. Cell Biol. 204, 1063-1074. https://doi.org/10.1083/jcb.201308102
  11. Li, W., Liu, M., Su, Y., Zhou, X., Liu, Y., and Zhang, X. (2015). The Janus-faced roles of Kruppel-like factor 4 in oral squamous cell carcinoma cells. Oncotarget 6, 44480-44494.
  12. Lotters, F.J., van den Bergh, J.P., de Vries, F., and Rutten-van Molken, M.P. (2016). Current and Future Incidence and Costs of Osteoporosis-Related Fractures in The Netherlands: Combining Claims Data with BMD Measurements. Calcif. Tissue Int. 98, 235-243. https://doi.org/10.1007/s00223-015-0089-z
  13. Lv, H., Sun, Y., and Zhang, Y. (2015). MiR-133 is involved in estrogen deficiency-induced osteoporosis through modulating osteogenic differentiation of mesenchymal stem cells. Med. Sci. Monit. 21, 1527-1534. https://doi.org/10.12659/MSM.894323
  14. Mariner, P.D., Johannesen, E., and Anseth, K.S. (2012). Manipulation of miRNA activity accelerates osteogenic differentiation of hMSCs in engineered 3D scaffolds. J. Tissue Eng. Regen. Med. 6, 314-324. https://doi.org/10.1002/term.435
  15. Nosho, K., Yamamoto, H., Takahashi, T., Mikami, M., Taniguchi, H., Miyamoto, N., Adachi, Y., Arimura, Y., Itoh, F., Imai, K., et al. (2007). Genetic and epigenetic profiling in early colorectal tumors and prediction of invasive potential in pT1 (early invasive) colorectal cancers. Carcinogenesis 28, 1364-1370. https://doi.org/10.1093/carcin/bgl246
  16. Ohnishi, S., Ohnami, S., Laub, F., Aoki, K., Suzuki, K., Kanai, Y., Haga, K., Asaka, M., Ramirez, F., and Yoshida, T. (2003). Downregulation and growth inhibitory effect of epithelial-type Kruppel-like transcription factor KLF4, but not KLF5, in bladder cancer. Biochem. Biophys. Res. Commun. 308, 251-256. https://doi.org/10.1016/S0006-291X(03)01356-1
  17. Pacifici, R. (1996). Estrogen, cytokines, and pathogenesis of postmenopausal osteoporosis. J. Bone Miner Res. 11, 1043-1051.
  18. Pineda, B., Serna, E., Laguna-Fernandez, A., Noguera, I., Panach, L., Hermenegildo, C., Tarin, J.J., Cano, A., and Garcia-Perez, M.A. (2014). Gene expression profile induced by ovariectomy in bone marrow of mice: a functional approach to identify new candidate genes associated to osteoporosis risk in women. Bone 65, 33-41. https://doi.org/10.1016/j.bone.2014.05.001
  19. Raehtz, S., Bierhalter, H., Schoenherr, D., Parameswaran, N., and McCabe, L.R. (2017). Estrogen deficiency exacerbates type 1 diabetes-induced bone TNF-alpha expression and osteoporosis in female mice. Endocrinology 158, 2086-2101. https://doi.org/10.1210/en.2016-1821
  20. Rodriguez, J.P., Montecinos, L., Rios, S., Reyes, P., and Martinez, J. (2000). Mesenchymal stem cells from osteoporotic patients produce a type I collagen-deficient extracellular matrix favoring adipogenic differentiation. J. Cell Biochem. 79, 557-565. https://doi.org/10.1002/1097-4644(20001215)79:4<557::AID-JCB40>3.0.CO;2-H
  21. Sang, C., Zhang, Y., Chen, F., Huang, P., Qi, J., Wang, P., Zhou, Q., Kang, H., Cao, X., and Guo, L. (2016). Tumor necrosis factor alpha suppresses osteogenic differentiation of MSCs by inhibiting semaphorin 3B via Wnt/beta-catenin signaling in estrogen-deficiency induced osteoporosis. Bone 84, 78-87. https://doi.org/10.1016/j.bone.2015.12.012
  22. Sapir-Koren, R., and Livshits, G. (2017). Postmenopausal osteoporosis in rheumatoid arthritis: The estrogen deficiency-immune mechanisms link. Bone 103, 102-115. https://doi.org/10.1016/j.bone.2017.06.020
  23. Silva, I., and Branco, J.C. (2012). Denosumab: recent update in postmenopausal osteoporosis. Acta Reumatol. Port. 37, 302-313.
  24. Song, I., Choi, Y.J., Jin, Y., Kim, J.W., Koh, J.T., Ji, H.M., Jeong, S.Y., Won, Y.Y., Kim, W., and Chung, Y.S. (2017). STRA6 as a possible candidate gene for pathogenesis of osteoporosis from RNAseq analysis of human mesenchymal stem cells. Mol. Med. Rep. 16, 4075-4081. https://doi.org/10.3892/mmr.2017.7072
  25. Tai, S.K., Yang, M.H., Chang, S.Y., Chang, Y.C., Li, W.Y., Tsai, T.L., Wang, Y.F., Chu, P.Y., and Hsieh, S.L. (2011). Persistent Kruppel-like factor 4 expression predicts progression and poor prognosis of head and neck squamous cell carcinoma. Cancer Sci. 102, 895-902. https://doi.org/10.1111/j.1349-7006.2011.01859.x
  26. Tiwari, A., Loughner, C.L., Swamynathan, S., and Swamynathan, S.K. (2017). KLF4 plays an essential role in corneal epithelial homeostasis by promoting epithelial cell fate and suppressing epithelialmesenchymal transition. Invest Ophthalmol. Vis. Sci. 58, 2785-2795. https://doi.org/10.1167/iovs.17-21826
  27. Udalamaththa, V.L., Jayasinghe, C.D., and Udagama, P.V. (2016). Potential role of herbal remedies in stem cell therapy: proliferation and differentiation of human mesenchymal stromal cells. Stem Cell Res. Ther. 7, 110. https://doi.org/10.1186/s13287-016-0366-4
  28. Wang, J., and Zhao, Q. (2017). Expression of CCR3, SOX5 and LC3 in patients with elderly onset rheumatoid arthritis and the clinical significance. Exp. Ther. Med. 14, 3573-3576. https://doi.org/10.3892/etm.2017.4961
  29. Wang, D., Han, S., Wang, X., Peng, R., and Li, X. (2015). SOX5 promotes epithelial-mesenchymal transition and cell invasion via regulation of Twist1 in hepatocellular carcinoma. Med. Oncol. 32, 461.
  30. Wang, C., Meng, H., Wang, X., Zhao, C., Peng, J., and Wang, Y. (2016). Differentiation of bone marrow mesenchymal stem cells in osteoblasts and adipocytes and its role in treatment of osteoporosis. Med. Sci. Monit. 22, 226-233. https://doi.org/10.12659/MSM.897044
  31. Wegner, M. (1999). From head to toes: the multiple facets of Sox proteins. Nucleic Acids Res. 27, 1409-1420. https://doi.org/10.1093/nar/27.6.1409
  32. Wegner, M. (2010). All purpose Sox: The many roles of Sox proteins in gene expression. Int. J. Biochem. Cell Biol. 42, 381-390. https://doi.org/10.1016/j.biocel.2009.07.006
  33. Xu, X., Jia, X., Mo, L., Liu, C., Zheng, L., Yuan, Q., and Zhou, X. (2017). Intestinal microbiota: a potential target for the treatment of postmenopausal osteoporosis. Bone Res. 5, 17046. https://doi.org/10.1038/boneres.2017.46
  34. Yang, N., Wang, G., Hu, C., Shi, Y., Liao, L., Shi, S., Cai, Y., Cheng, S., Wang, X., Liu, Y., et al. (2013). Tumor necrosis factor alpha suppresses the mesenchymal stem cell osteogenesis promoter miR-21 in estrogen deficiency-induced osteoporosis. J. Bone Miner Res. 28, 559-573. https://doi.org/10.1002/jbmr.1798
  35. Yao, W., Guan, M., Jia, J., Dai, W., Lay, Y.A., Amugongo, S., Liu, R., Olivos, D., Saunders, M., Lam, K.S., et al. (2013). Reversing bone loss by directing mesenchymal stem cells to bone. Stem Cells 31, 2003-2014. https://doi.org/10.1002/stem.1461
  36. Zhao, J.W., Gao, Z.L., Mei, H., Li, Y.L., and Wang, Y. (2011). Differentiation of human mesenchymal stem cells: the potential mechanism for estrogen-induced preferential osteoblast versus adipocyte differentiation. Am. J. Med. Sci. 341, 460-468. https://doi.org/10.1097/MAJ.0b013e31820865d5

Cited by

  1. Enhancement of MicroRNA-200c on Osteogenic Differentiation and Bone Regeneration by Targeting Sox2-Mediated Wnt Signaling and Klf4 vol.30, pp.11, 2018, https://doi.org/10.1089/hum.2019.019
  2. Restoration of primary cilia in obese adipose-derived mesenchymal stem cells by inhibiting Aurora A or extracellular signal-regulated kinase vol.10, pp.1, 2018, https://doi.org/10.1186/s13287-019-1373-z
  3. Shu-Di-Huang and Gan-Cao Herb Pair Restored the Differentiation Potentials of Mesenchymal Stem Progenitors in Treating Osteoporosis via Downregulation of NF-κB Signaling Pathway vol.2021, pp.None, 2018, https://doi.org/10.1155/2021/7795527