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Using the Connectivity Map to discover compounds influencing human osteoblast differentiation
Author(s) -
Brum Andrea M.,
van de Peppel Jeroen,
Nguyen Linh,
Aliev Abidin,
SchreudersKoedam Marijke,
Gajadien Tarini,
van der Leije Cindy S.,
van Kerkwijk Anke,
Eijken Marco,
van Leeuwen Johannes P.T.M.,
van der Eerden B C. J.
Publication year - 2018
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.26298
Subject(s) - osteoblast , hmox1 , chemistry , gene expression profiling , microbiology and biotechnology , toxicogenomics , runx2 , gene expression , biology , gene , biochemistry , heme , heme oxygenase , in vitro , enzyme
Osteoporosis is a common skeletal disorder characterized by low bone mass leading to increased bone fragility and fracture susceptibility. Identification of factors influencing osteoblast differentiation and bone formation is very important. Previously, we identified parbendazole to be a novel compound that stimulates osteogenic differentiation of human mesenchymal stromal cells (hMSCs), using gene expression profiling and bioinformatic analyzes, including the Connectivity Map (CMap), as an in‐silico approach. The aim for this paper is to identify additional compounds affecting osteoblast differentiation using the CMap. Gene expression profiling was performed on hMSCs differentiated to osteoblasts using Illumina microarrays. Our osteoblast gene signature, the top regulated genes 6 hr after induction by dexamethasone, was uploaded into CMap ( www.broadinstitute.org/cmap /). Through this approach we identified compounds with gene signatures positively correlating (withaferin‐A, calcium folinate, amylocaine) or negatively correlating (salbutamol, metaraminol, diprophylline) to our osteoblast gene signature. All positively correlating compounds stimulated osteogenic differentiation, as indicated by increased mineralization compared to control treated cells. One of three negatively correlating compounds, salbutamol, inhibited dexamethasone‐induced osteoblastic differentiation, while the other two had no effect. Based on gene expression data of withaferin‐A and salbutamol, we identified HMOX1 and STC1 as being strongly differentially expressed . shRNA knockdown of HMOX1 or STC1 in hMSCs inhibited osteoblast differentiation. These results confirm that the CMap is a powerful approach to identify positively compounds that stimulate osteogenesis of hMSCs, and through this approach we can identify genes that play an important role in osteoblast differentiation and could be targets for novel bone anabolic therapies.