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Nanotopography Directs Mesenchymal Stem Cells to Osteoblast Lineage Through Regulation of microRNA‐SMAD‐BMP‐2 Circuit
Author(s) -
Kato Rogerio B.,
Roy Bhaskar,
De Oliveira Fabiola S.,
Ferraz Emanuela P.,
De Oliveira Paulo T.,
Kemper Austin G.,
Hassan Mohammad Q.,
Rosa Adalberto L.,
Beloti Marcio M.
Publication year - 2014
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.24614
Subject(s) - nanotopography , osteoblast , microbiology and biotechnology , chemistry , downregulation and upregulation , smad , mesenchymal stem cell , microrna , signal transduction , biology , gene , biochemistry , in vitro
The aim of this study was to investigate if chemically produced nanotopography on titanium (Ti) surface induces osteoblast differentiation of cultured human bone marrow mesenchymal stem cells (hMSCs) by regulating the expression of microRNAs (miRs). It was demonstrated that Ti with nanotopography induces osteoblast differentiation of hMSCs as evidenced by upregulation of osteoblast specific markers compared with untreated (control) Ti at day 4. At this time‐point, miR‐sequencing analysis revealed that 20 miRs were upregulated (>twofold) while 20 miRs were downregulated (>threefold) in hMSCs grown on Ti with nanotopography compared with control Ti. Three miRs, namely miR‐4448, ‐4708, and ‐4773, which were significantly downregulated (>fivefold) by Ti with nanotopography affect osteoblast differentiation of hMSCs. These miRs directly target SMAD1 and SMAD4, both key transducers of the bone morphogenetic protein 2 (BMP‐2) osteogenic signal, which were upregulated by Ti with nanotopography. Overexpression of miR‐4448, ‐4708, and 4773 in MC3T3‐E1 pre‐osteoblasts noticeably inhibited gene and protein expression of SMAD1 and SMAD4 and therefore repressed the gene expression of key bone markers. Additionally, it was observed that the treatment with BMP‐2 displayed a higher osteogenic effect on MC3T3‐E1 cells grown on Ti with nanotopography compared with control Ti, suggesting that the BMP‐2 signaling pathway was more effective on this surface. Taken together, these results indicate that a complex regulatory network involving a miR‐SMAD‐BMP‐2 circuit governs the osteoblast differentiation induced by Ti with nanotopography. J. Cell. Physiol. 229: 1690–1696, 2014. © 2014 Wiley Periodicals, Inc.