Gene Set: PARK_OSTEOBLAST_DIFFERENTIATION_BY_PHENYLAMIL_DN

Standard name PARK_OSTEOBLAST_DIFFERENTIATION_BY_PHENYLAMIL_DN
Systematic name M2423
Brief description Genes down-regulated in M2-10B4 cells (osteoblast) in response to phenylamil [PubChem=4755].
Full description or abstract Stimulation of osteoblast differentiation from mesenchymal stem cells is a potential strategy for bone repair. Bone morphogenetic proteins (BMPs) that induce osteoblastic differentiation have been successfully used in humans to treat fractures. Here we outline a new approach to the stimulation of osteoblast differentiation using small molecules that stimulate BMP activity. We have identified the amiloride derivative phenamil as a stimulator of osteoblast differentiation and mineralization. Remarkably, phenamil acts cooperatively with BMPs to induce the expression of BMP target genes, osteogenic markers, and matrix mineralization in both mesenchymal stem cell lines and calvarial organ cultures. Transcriptional profiling of cells treated with phenamil led to the identification of tribbles homolog 3 (Trb3) as a mediator of its effects. Trb3 is induced by phenamil selectively in cells with osteoblastic potential. Both Trb3 and phenamil stabilize the expression of SMAD, the critical transcription factor in BMP signaling, by promoting the degradation of SMAD ubiquitin regulatory factor 1. Small interfering RNA-mediated knockdown of Trb3 blunts the effects of phenamil on BMP signaling and osteogenesis. Thus, phenamil induces osteogenic differentiation, at least in part, through Trb3-dependent promotion of BMP action. The synergistic use of small molecules such as phenamil along with BMPs may provide new strategies for the promotion of bone healing.
Collection C2: curated gene sets
      CGP: chemical and genetic perturbations
Source publication Pubmed 19433444   Authors: Park KW,Waki H,Kim WK,Davies BS,Young SG,Parhami F,Tontonoz P
Exact source Fig. 2S: Change folds < 1
Related gene sets (show 1 additional gene sets from the source publication)

(show 1 gene sets from the same authors)
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Organism Mus musculus
Contributed by Arthur Liberzon (Broad Institute)
Source platform SEQ_ACCESSION
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Compendia expression profiles Human tissue compendium (Novartis)
NCI-60 cell lines (National Cancer Institute)
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Version history 3.1: First introduced

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