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http://dx.doi.org/10.14348/molcells.2018.2359

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)
Publication Information
Molecules and Cells / v.41, no.6, 2018 , pp. 575-581 More about this Journal
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
human mesenchymal stem cells; KLF4; osteogenic differentiation; postmenopausal osteoporosis; SOX5;
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1 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.   DOI
2 Ding, D.C., Shyu, W.C., and Lin, S.Z. (2011). Mesenchymal stem cells. Cell Transplant 20, 5-14.   DOI
3 Dy, P., Han, Y., and Lefebvre, V. (2008). Generation of mice harboring a Sox5 conditional null allele. Genesis 46, 294-299.   DOI
4 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.   DOI
5 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.   DOI
6 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.   DOI
7 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.
8 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.   DOI
9 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.   DOI
10 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.   DOI
11 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.   DOI
12 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.   DOI
13 Pacifici, R. (1996). Estrogen, cytokines, and pathogenesis of postmenopausal osteoporosis. J. Bone Miner Res. 11, 1043-1051.
14 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.   DOI
15 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.   DOI
16 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.   DOI
17 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.   DOI
18 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.   DOI
19 Sapir-Koren, R., and Livshits, G. (2017). Postmenopausal osteoporosis in rheumatoid arthritis: The estrogen deficiency-immune mechanisms link. Bone 103, 102-115.   DOI
20 Silva, I., and Branco, J.C. (2012). Denosumab: recent update in postmenopausal osteoporosis. Acta Reumatol. Port. 37, 302-313.
21 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.   DOI
22 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.   DOI
23 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.   DOI
24 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.   DOI
25 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.   DOI
26 Abdallah, B.M., and Kassem, M. (2008). Human mesenchymal stem cells: from basic biology to clinical applications. Gene Ther. 15, 109-116.   DOI
27 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.   DOI
28 Black, D.M., and Rosen, C.J. (2016). Clinical Practice. Postmenopausal Osteoporosis. N. Engl. J. Med. 374, 254-262.   DOI
29 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.   DOI
30 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.
31 Wegner, M. (1999). From head to toes: the multiple facets of Sox proteins. Nucleic Acids Res. 27, 1409-1420.   DOI
32 Wegner, M. (2010). All purpose Sox: The many roles of Sox proteins in gene expression. Int. J. Biochem. Cell Biol. 42, 381-390.   DOI
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.   DOI
34 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.   DOI
35 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.   DOI
36 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.   DOI