Open AccessBisphosphonates induce the osteogenic gene expression in co‐cultured human endothelial and mesenchymal stem cells
Author(s) -
Ribeiro Viviana,
Garcia Mónica,
Oliveira Raquel,
Gomes Pedro S.,
Colaço Bruno,
Fernandes Maria Helena
Publication year - 2014
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12154
Subject(s) - mesenchymal stem cell , osteocalcin , angiogenesis , stem cell , endothelial stem cell , microbiology and biotechnology , alkaline phosphatase , bone morphogenetic protein 2 , cancer research , osteoprotegerin , biology , chemistry , gene , biochemistry , in vitro , enzyme , activator (genetics)
Bisphosphonates ( BP s) 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 CD 31, VE ‐cadherin and VEGFR 2 was down‐regulated by AL and ZL . In HMSC monocultures, the BP s 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.