Connectivity Map-based discovery of parbendazole reveals targetable human osteogenic pathway

被引:76
作者
Brum, Andrea M. [1 ]
van de Peppel, Jeroen [1 ]
van der Leije, Cindy S. [1 ]
Schreuders-Koedam, Marijke [1 ]
Eijken, Marco [2 ]
van der Eerden, Bram C. J. [1 ]
van Leeuwen, Johannes P. T. M. [1 ]
机构
[1] Erasmus MC, Dept Internal Med, NL-3015 CN Rotterdam, Netherlands
[2] Arcarios BV, NL-3015 CN Rotterdam, Netherlands
关键词
Connectivity Map; osteoblast; mesenchymal stem cell; cytoskeleton; osteoporosis; BONE MORPHOGENETIC PROTEIN-2; METHYL BENZIMIDAZOL-2-YL CARBAMATE; GENE-EXPRESSION; CELL-SHAPE; DIFFERENTIATION; OSTEOBLAST; CYTOSKELETAL; INDUCTION; TUBULIN; IDENTIFICATION;
D O I
10.1073/pnas.1501597112
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Osteoporosis is a common skeletal disorder characterized by low bone mass leading to increased bone fragility and fracture susceptibility. In this study, we have identified pathways that stimulate differentiation of bone forming osteoblasts from human mesenchymal stromal cells (hMSCs). Gene expression profiling was performed in hMSCs differentiated toward osteoblasts (at 6 h). Significantly regulated genes were analyzed in silico, and the Connectivity Map (CMap) was used to identify candidate bone stimulatory compounds. The signature of parbendazole matches the expression changes observed for osteogenic hMSCs. Parbendazole stimulates osteoblast differentiation as indicated by increased alkaline phosphatase activity, mineralization, and up-regulation of bone marker genes (alkaline phosphatase/ALPL, osteopontin/SPP1, and bone sialoprotein II/IBSP) in a subset of the hMSC population resistant to the apoptotic effects of parbendazole. These osteogenic effects are independent of glucocorticoids because parbendazole does not up-regulate glucocorticoid receptor (GR) target genes and is not inhibited by the GR antagonist mifepristone. Parbendazole causes profound cytoskeletal changes including degradation of microtubules and increased focal adhesions. Stabilization of microtubules by pretreatment with Taxol inhibits osteoblast differentiation. Parbendazole up-regulates bone morphogenetic protein 2 (BMP-2) gene expression and activity. Cotreatment with the BMP-2 antagonist DMH1 limits, but does not block, parbendazole-induced mineralization. Using the CMap we have identified a previously unidentified lineage-specific, bone anabolic compound, parbendazole, which induces osteogenic differentiation through a combination of cytoskeletal changes and increased BMP-2 activity.
引用
收藏
页码:12711 / 12716
页数:6
相关论文
共 57 条
[1]   Nanotopographical modification: a regulator of cellular function through focal adhesions [J].
Biggs, Manus Jonathan Paul ;
Richards, R. Geoff ;
Dalby, Matthew J. .
NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE, 2010, 6 (05) :619-633
[2]  
Born AK, 2009, EUR CELLS MATER, V18, P49
[3]  
Bruedigam C, 2011, CURR PROTOC STEM CEL, DOI [DOI 10.1002/9780470151808.SC01H03S17, 10.1002/9780470151808.sc01h03s17]
[4]   Addition of bone morphogenetic protein type 2 to ascorbate and β-glycerophosphate supplementation did not enhance osteogenic differentiation of human adipose-derived stem cells [J].
Cabral Cruz, Ariadne Cristiane ;
Silva, Mariana Lucia ;
Caon, Thiago ;
Oliveira Simoes, Claudia Maria .
JOURNAL OF APPLIED ORAL SCIENCE, 2012, 20 (06) :628-635
[5]   Evaluation of phenoxybenzamine in the CFA model of pain following gene expression studies and connectivity mapping [J].
Chang, Meiping ;
Smith, Sarah ;
Thorpe, Andrew ;
Barratt, Michael J. ;
Karim, Farzana .
MOLECULAR PAIN, 2010, 6
[6]   GEF-H1 couples nocodazole-induced microtubule disassembly to cell contractility via RhoA [J].
Chang, Yuan-Chen ;
Nalbant, Perihan ;
Birkenfeld, Joerg ;
Chang, Zee-Fen ;
Bokoch, Gary M. .
MOLECULAR BIOLOGY OF THE CELL, 2008, 19 (05) :2147-2153
[7]   An Osteopontin-Integrin Interaction Plays a Critical Role in Directing Adipogenesis and Osteogenesis by Mesenchymal Stem Cells [J].
Chen, Qing ;
Shou, Peishun ;
Zhang, Liying ;
Xu, Chunliang ;
Zheng, Chunxing ;
Han, Yanyan ;
Li, Wenzhao ;
Huang, Yin ;
Zhang, Xiaoren ;
Shao, Changshun ;
Roberts, Arthur I. ;
Rabson, Arnold B. ;
Ren, Guangwen ;
Zhang, Yanyun ;
Wang, Ying ;
Denhardt, David T. ;
Shi, Yufang .
STEM CELLS, 2014, 32 (02) :327-337
[8]   ESTABLISHMENT AND CHARACTERIZATION OF A SIMIAN-VIRUS 40-IMMORTALIZED OSTEOBLASTIC CELL-LINE FROM NORMAL HUMAN BONE [J].
CHIBA, H ;
SAWADA, N ;
ONO, T ;
ISHII, S ;
MORI, M .
JAPANESE JOURNAL OF CANCER RESEARCH, 1993, 84 (03) :290-297
[9]   ANTIMITOTIC ACTIVITY OF METHYL BENZIMIDAZOL-2-YL CARBAMATE (MBC) IN ASPERGILLUS-NIDULANS [J].
DAVIDSE, LC .
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY, 1973, 3 (03) :317-325
[10]   DIFFERENTIAL BINDING OF METHYL BENZIMIDAZOL-2-YL CARBAMATE TO FUNGAL TUBULIN AS A MECHANISM OF RESISTANCE TO THIS ANTIMITOTIC AGENT IN MUTANT STRAINS OF ASPERGILLUS-NIDULANS [J].
DAVIDSE, LC ;
FLACH, W .
JOURNAL OF CELL BIOLOGY, 1977, 72 (01) :174-193