Bisphosphonates induce the osteogenic gene expression in co‐cultured human endothelial and mesenchymal stem cells

Journal of Cellular and Molecular Medicine

Viviana Ribeiro¹  Mónica Garcia²  Raquel Oliveira¹  Pedro S. Gomes²  Bruno Colaço¹ 

[1] CECAV, Departamento de Zootecnia, Universidade de Trás-os-Montes e Alto Douro, Vila Real, Portugal;FMDUP, Laboratory for Bone Metabolism and Regeneration, Faculty of Dental Medicine, University of Porto, Porto, Portugal

关键词: Alendronate;    Zoledronate;    osteogenic gene expression;    endothelial gene expression;    human dermal microvascular endothelial cells (HDMEC);    human mesenchymal stem cells (HMSC);    co‐cultured cells;   

DOI  :  10.1111/jcmm.12154

来源: Wiley

【 摘 要 】

Abstract

Bisphosphonates (BPs) are known to affect bone homeostasis and also to have anti-angiogenic properties. Because of the intimate relationship between angiogenesis and osteogenesis, this study analysed the effects of Alendronate (AL) and Zoledronate (ZL) in the expression of endothelial and osteogenic genes on interacting endothelial and mesenchymal stem cells, an issue that was not previously addressed. Alendronate and ZL, 10⁻¹²–10⁻⁶ M, were evaluated in a direct co-culture system of human dermal microvascular endothelial cells (HDMEC) and human bone marrow mesenchymal stem cells (HMSC), over a period of 14 days. Experiments with the respective monocultures were run in parallel. Alendronate and ZL caused an initial dose-dependent stimulation in the cell proliferation in the monocultures and co-cultures, and did not interfere with their cellular organization. In HDMEC monocultures, the expression of the endothelial genes CD31, VE-cadherin and VEGFR2 was down-regulated by AL and ZL. In HMSC monocultures, the BPs inhibited VEGF expression, but up-regulated the expression of the osteogenic genes alkaline phosphatase (ALP), bone morphogenic protein-2 (BMP-2) and osteocalcin (OC) and, to a greater extent, osteoprotegerin (OPG), a negative regulator of the osteoclastic differentiation, and increased ALP activity. In co-cultured HDMEC/HMSC, AL and ZL decreased the expression of endothelial genes but elicited an earlier and sustained overexpression of ALP, BMP-2, OC and OPG, compared with the monocultured cells; they also induced ALP activity. This study showed for the first time that AL and ZL greatly induced the osteogenic gene expression on interacting endothelial and mesenchymal stem cells.

【 授权许可】

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© 2013 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

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