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• W2086923306 endingPage "1303" @default.
• W2086923306 startingPage "1294" @default.
• W2086923306 abstract "Bone homeostasis can be compromised by an increase in osteoclast-mediated resorption and/or a decrease in osteoblast-mediated bone deposition. While many efforts have focused on treating osteoclast resorption, there has been less emphasis on identifying strategies for promoting osteoblast function. Herein, we describe a high-throughput screening assay to select for small molecules that augment bone morphogenetic protein-2 (BMP-2)-mediated osteoblast lineage commitment. After an initial screen of 5405 compounds; consisting of FDA-approved drugs, known bioactives, and compounds with novel chemical makeup, we identified 45 small molecules that promoted osteoblast commitment. Of the 45 candidates, there was a broad array of classes that included nine retinoid analogs/derivatives and four immunosuppressants, notably rapamycin and FK-506, which were chosen for further study. Treatment of osteoblast precursor cells with rapamycin or FK-506, either alone, or synergistically with BMP-2, increased levels of phospho-Smad 1/5/8 protein and transcription of Runx-2, Osx and Smad-7, consistent with a role in promoting osteoblast differentiation. Only FK-506 was able to enhance osteocalcin transcripts and Alizarin Red staining, both late markers for differentiation. When osteoblast differentiation was suppressed with exogenous TGF-β1 treatment, rapamycin (but not FK-506) was able to rescue expression of differentiation markers, indicating distinct but overlapping activity of these compounds. Collectively, these data add to an understanding of pathways engaged in osteoblastogenesis, support a role for non-redundant immunosuppressant signaling, and provide a novel approach for the discovery of potentially therapeutic compounds that affect bone remodeling." @default.
• W2086923306 created "2016-06-24" @default.
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• W2086923306 date "2012-06-01" @default.
• W2086923306 modified "2023-10-03" @default.
• W2086923306 title "A novel library screen identifies immunosuppressors that promote osteoblast differentiation" @default.
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• W2086923306 doi "https://doi.org/10.1016/j.bone.2012.03.001" @default.
• W2086923306 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3352976" @default.
• W2086923306 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/22421346" @default.
• W2086923306 hasPublicationYear "2012" @default.
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