THE EFFECT OF ZINC AND BMP2 ON CONNEXIN 43 PRODUCTION IN BONE MARROW MESENCHYMAL STEM CELLS (BM-MSCS) INDUCED BY DMBA

Kemal Yuce

doi:10.51477/mejs.1547916

THE EFFECT OF ZINC AND BMP2 ON CONNEXIN 43 PRODUCTION IN BONE MARROW MESENCHYMAL STEM CELLS (BM-MSCS) INDUCED BY DMBA

Abstract

The aim of this study was to examine how zinc and BMP2 affected the amount of connexin 43 produced by BM-MSCs stimulated with DMBA. BM-MSCs were identified after being generated in a cell culture. BM-MSCs were exposed to combinations of 24 nM DMBA, 1 µM zinc, and 10 ng/mL BMP2. Using immunofluorescence methods, the effects of zinc, BMP2, and DMBA on the formation of connexin 43 in BM-MSCs were assessed. In the present study, BM-MSCs were produced and identified. As a result of immunofluorescence, connexin 43 expression was somewhat downregulated in the BMP2, zinc, and DMBA single applications; this downregulation was more pronounced in the double and triple applications. Zinc concentrations in the medium where BM-MSCs are produced may affect the results of preclinical and clinical studies based on transplantation through the adhesion ability of the cells, depending on the toxic effect. When using BM-MSCs in cancer studies, it should be taken into consideration that the cancerization process may affect the production of connexin 43 and the ability of the cells to adhere.

Keywords

Supporting Institution

This study was supported by the Selcuk University Academic Staff Training Program (ÖYP) Coordination Unit (2013-ÖYP-088).

Project Number

2013-ÖYP-088

Ethical Statement

The current study complies with ethical standards, which is a prerequisite. The approval to the research protocol was obtained from the Laboratory Animals Ethics Board of Selçuk University Experimental Medicine Research and Application Center (Ethics Approval Number: 2016-43, Date:21.12.2016).

References

Platt, K. L., Schollmeier, M., Frank, H., & Oesch, F. "Stereoselective metabolism of dibenz(a,h)anthracene to trans-dihydrodiols and their activation to bacterial mutagens." Environmental health perspectives, 88, 37-41, 1990.
Pugalendhi, P., Manoharan, S., Panjamurthy, K., Balakrishnan, S., & Nirmal, M. R. "Antigenotoxic effect of genistein against 7,12-dimethylbenz[a]anthracene induced genotoxicity in bone marrow cells of female Wistar rats." Pharmacol Rep, 61(2), 296-303, 2009.
Hogan, B. L. "Bone morphogenetic proteins: multifunctional regulators of vertebrate development." Genes Dev, 10(13), 1580-1594, 1996.
Yan, K., Wu, Q., Yan, D. H., Lee, C. H., Rahim, N., Tritschler, I., DeVecchio, J., Kalady, M. F., Hjelmeland, A. B., & Rich, J. N. "Glioma cancer stem cells secrete Gremlin1 to promote their maintenance within the tumor hierarchy." Genes & Development, 28(10), 1085-1100, 2014.
Clement, J. H., Raida, M., Sanger, J., Bicknell, R., Liu, J., Naumann, A., Geyer, A., Waldau, A., Hortschansky, P., Schmidt, A., Hoffken, K., Wolft, S., & Harris, A. L. "Bone morphogenetic protein 2 (BMP-2) induces in vitro invasion and in vivo hormone independent growth of breast carcinoma cells." Int J Oncol, 27(2), 401-407, 2005.
Bafaro, E., Liu, Y., Xu, Y., & Dempski, R. E. "The emerging role of zinc transporters in cellular homeostasis and cancer." Signal Transduction and Targeted Therapy, 2(1), 17029, 2017.
Fukada, T., Civic, N., Furuichi, T., Shimoda, S., Mishima, K., Higashiyama, H., Idaira, Y., Asada, Y., Kitamura, H., Yamasaki, S., Hojyo, S., Nakayama, M., Ohara, O., Koseki, H., dos Santos, H. G., Bonafe, L., Ha-Vinh, R., Zankl, A., Unger, S., Kraenzlin, M. E., Beckmann, J. S., Saito, I., Rivolta, C., Ikegawa, S., Superti-Furga, A., & Hirano, T. "The Zinc Transporter SLC39A13/ZIP13 Is Required for Connective Tissue Development; Its Involvement in BMP/TGF-β Signaling Pathways." PLOS ONE, 3(11), e3642, 2008.
Plotkin, L. I., & Bellido, T. "Beyond gap junctions: Connexin43 and bone cell signaling." Bone, 52(1), 157-166, 2013.

Liu, Y., Zhang, X., Li, Z.-j., & Chen, X.-h. "Up-regulation of Cx43 expression and GJIC function in acute leukemia bone marrow stromal cells post-chemotherapy." Leukemia Research, 34(5), 631-640, 2010.
Defamie, N., Chepied, A., & Mesnil, M. "Connexins, gap junctions and tissue invasion." FEBS Letters, 588(8), 1331-1338, 2014.
Cronier, L., Crespin, S., Strale, P.-O., Defamie, N., & Mesnil, M. "Gap Junctions and Cancer: New Functions for an Old Story." Antioxidants & Redox Signaling, 11(2), 323-338, 2009.
Chen, S. C., Pelletier, D. B., Ao, P., & Boynton, A. L. "Connexin43 reverses the phenotype of transformed cells and alters their expression of cyclin/cyclin-dependent kinases." Cell Growth Differ, 6(6), 681-690, 1995.
Su, V., & Lau, A. F. "Connexins: mechanisms regulating protein levels and intercellular communication." FEBS Lett, 588(8), 1212-1220, 2014.
Fukada, T., Civic, N., Furuichi, T., Shimoda, S., Mishima, K., Higashiyama, H., Idaira, Y., Asada, Y., Kitamura, H., Yamasaki, S., Hojyo, S., Nakayama, M., Ohara, O., Koseki, H., Dos Santos, H. G., Bonafe, L., Ha-Vinh, R., Zankl, A., Unger, S., Kraenzlin, M. E., Beckmann, J. S., Saito, I., Rivolta, C., Ikegawa, S., Superti-Furga, A., & Hirano, T. "The zinc transporter SLC39A13/ZIP13 is required for connective tissue development; its involvement in BMP/TGF-beta signaling pathways." PLoS One, 3(11), e3642, 2008.
Huang, S., Xu, L., Sun, Y., Wu, T., Wang, K., & Li, G. "An improved protocol for isolation and culture of mesenchymal stem cells from mouse bone marrow." Journal of Orthopaedic Translation, 3(1), 26-33, 2015.
Neuhaus, J., Heinrich, M., Schwalenberg, T., & Stolzenburg, J.-U. "TGF-β1 Inhibits Cx43 Expression and Formation of Functional Syncytia in Cultured Smooth Muscle Cells from Human Detrusor." European Urology, 55(2), 491-498, 2009.
Jin, E.-J., Lee, S.-Y., Jung, J.-C., Bang, O.-S., & Kang, S.-S. "TGF-β3 inhibits chondrogenesis of cultured chick leg bud mesenchymal cells via downregulation of connexin 43 and integrin β4." Journal of Cellular Physiology, 214(2), 345-353, 2008.
Chang, H.-M., Cheng, J.-C., & Leung, P. C. K. "Theca-Derived BMP4 and BMP7 Down-Regulate Connexin43 Expression and Decrease Gap Junction Intercellular Communication Activity in Immortalized Human Granulosa Cells." The Journal of Clinical Endocrinology & Metabolism, 98(3), E437-E445, 2013.
Wu, Y.-T., Chang, H.-M., Huang, H.-F., Sheng, J.-Z., & Leung, P. C. K. "Bone morphogenetic protein 2 regulates cell–cell communication by down-regulating connexin43 expression in luteinized human granulosa cells." Molecular Human Reproduction, 2016.
Hou, J., Lü, A.-L., Liu, B.-W., Xing, Y.-J., Da, J., Hou, Z.-L., & Ai, S.-Y. "Combination of BMP-2 and 5-AZA is advantageous in rat bone marrow-derived mesenchymal stem cells differentiation into cardiomyocytes." Cell Biology International, 37(12), 1291-1299, 2013.
Lee, J., Yim, Y. S., Ko, S. J., Kim, D. G., & Kim, C. H. "Gap junctions contribute to astrocytic resistance against zinc toxicity." Brain Research Bulletin, 86(5-6), 314-318, 2011.
Alirezaei, M., Mordelet, E., Rouach, N., Nairn, A. C., Glowinski, J., & Premont, J. "Zinc-induced inhibition of protein synthesis and reduction of connexin-43 expression and intercellular communication in mouse cortical astrocytes." Eur J Neurosci, 16(6), 1037-1044, 2002.
Sun, Z., Zhang, D.-Q., & McMahon, D. G. "Zinc Modulation of Hemi-Gap-Junction Channel Currents in Retinal Horizontal Cells." Journal of Neurophysiology, 101(4), 1774-1780, 2009.
Hernandez, M., Shao, Q., Yang, X.-J., Luh, S.-P., Kandouz, M., Batist, G., Laird, D. W., & Alaoui-Jamali, M. A. "A histone deacetylation-dependent mechanism for transcriptional repression of the gap junction gene cx43 in prostate cancer cells." The Prostate, 66(11), 1151-1161, 2006.
Naus, C. C., Hearn, S., Zhu, D., Nicholson, B. J., & Shivers, R. R. "Ultrastructural analysis of gap junctions in C6 glioma cells transfected with connexin43 cDNA." Exp Cell Res, 206(1), 72-84, 1993.
Zhang, Y. W., Morita, I., Ikeda, M., Ma, K. W., & Murota, S. "Connexin43 suppresses proliferation of osteosarcoma U2OS cells through post-transcriptional regulation of p27." Oncogene, 20(31), 4138-4149, 2001.
J. Marie, P., Fromigué, O., & Modrowski, D.. Deregulation of osteoblast differentiation in primary bone cancers. In (pp. 39-54). 2015. https://doi.org/10.1016/B978-0-12-416721-6.00004-2
Koffler, L., Roshong, S., Kyu Park, I., Cesen-Cummings, K., Thompson, D. C., Dwyer-Nield, L. D., Rice, P., Mamay, C., Malkinson, A. M., & Ruch, R. J. "Growth inhibition in G(1) and altered expression of cyclin D1 and p27(kip-1 )after forced connexin expression in lung and liver carcinoma cells." J Cell Biochem, 79(3), 347-354, 2000

Details

Primary Language

English

Subjects

Animal Physiology - Cell

Journal Section

Research Article

Authors

Kemal Yuce ^*
0000-0001-8915-4900
Türkiye

Publication Date

December 30, 2025

Submission Date

September 10, 2024

Acceptance Date

December 16, 2025

Published in Issue

Year 2025 Volume: 11 Number: 2

DOI

https://doi.org/10.51477/mejs.1547916

IZ

https://izlik.org/JA96TZ54ZK

Cite

RIS / Bibtex

APA

Yuce, K. (2025). THE EFFECT OF ZINC AND BMP2 ON CONNEXIN 43 PRODUCTION IN BONE MARROW MESENCHYMAL STEM CELLS (BM-MSCS) INDUCED BY DMBA. Middle East Journal of Science, 11(2), 127-134. https://doi.org/10.51477/mejs.1547916

AMA

1.Yuce K. THE EFFECT OF ZINC AND BMP2 ON CONNEXIN 43 PRODUCTION IN BONE MARROW MESENCHYMAL STEM CELLS (BM-MSCS) INDUCED BY DMBA. MEJS. 2025;11(2):127-134. doi:10.51477/mejs.1547916

Chicago

Yuce, Kemal. 2025. “THE EFFECT OF ZINC AND BMP2 ON CONNEXIN 43 PRODUCTION IN BONE MARROW MESENCHYMAL STEM CELLS (BM-MSCS) INDUCED BY DMBA”. Middle East Journal of Science 11 (2): 127-34. https://doi.org/10.51477/mejs.1547916.

EndNote

Yuce K (December 1, 2025) THE EFFECT OF ZINC AND BMP2 ON CONNEXIN 43 PRODUCTION IN BONE MARROW MESENCHYMAL STEM CELLS (BM-MSCS) INDUCED BY DMBA. Middle East Journal of Science 11 2 127–134.

IEEE

[1]K. Yuce, “THE EFFECT OF ZINC AND BMP2 ON CONNEXIN 43 PRODUCTION IN BONE MARROW MESENCHYMAL STEM CELLS (BM-MSCS) INDUCED BY DMBA”, MEJS, vol. 11, no. 2, pp. 127–134, Dec. 2025, doi: 10.51477/mejs.1547916.

ISNAD

Yuce, Kemal. “THE EFFECT OF ZINC AND BMP2 ON CONNEXIN 43 PRODUCTION IN BONE MARROW MESENCHYMAL STEM CELLS (BM-MSCS) INDUCED BY DMBA”. Middle East Journal of Science 11/2 (December 1, 2025): 127-134. https://doi.org/10.51477/mejs.1547916.

JAMA

1.Yuce K. THE EFFECT OF ZINC AND BMP2 ON CONNEXIN 43 PRODUCTION IN BONE MARROW MESENCHYMAL STEM CELLS (BM-MSCS) INDUCED BY DMBA. MEJS. 2025;11:127–134.

MLA

Yuce, Kemal. “THE EFFECT OF ZINC AND BMP2 ON CONNEXIN 43 PRODUCTION IN BONE MARROW MESENCHYMAL STEM CELLS (BM-MSCS) INDUCED BY DMBA”. Middle East Journal of Science, vol. 11, no. 2, Dec. 2025, pp. 127-34, doi:10.51477/mejs.1547916.

Vancouver

1.Kemal Yuce. THE EFFECT OF ZINC AND BMP2 ON CONNEXIN 43 PRODUCTION IN BONE MARROW MESENCHYMAL STEM CELLS (BM-MSCS) INDUCED BY DMBA. MEJS. 2025 Dec. 1;11(2):127-34. doi:10.51477/mejs.1547916