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Accepted (AM)Open Access (License Unspecified), Open
Journal article
A novel library screen identifies immunosuppressors that promote osteoblast differentiation
Bone (New York, N.Y.), v 50(6), pp 1294-1303
01 Jun 2012
PMID: 22421346
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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► High-throughput screen identifies osteogenic compounds. ► Two immunosuppressors among many selected for secondary analysis. ► Rapamycin and FK-506 promote osteogenesis. ► Pathway analysis supports different roles. ► Novel approach for identifying potential factors mitigating bone loss.
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Details
- Title
- A novel library screen identifies immunosuppressors that promote osteoblast differentiation
- Creators
- Ariana Darcy - Boston UniversityMicah Meltzer - Boston UniversityJoseph Miller - Boston UniversitySteven Lee - Boston UniversityScott Chappell - Boston UniversityKris Ver Donck - Digilab, Inc. Holliston, MA 01746, USAMonty Montano - Boston University
- Publication Details
- Bone (New York, N.Y.), v 50(6), pp 1294-1303
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Health Sciences
- Web of Science ID
- WOS:000304503700012
- Scopus ID
- 2-s2.0-84860835899
- Other Identifier
- 991021866417704721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Endocrinology & Metabolism