Journal
JOURNAL OF BONE AND MINERAL METABOLISM
Volume 29, Issue 6, Pages 652-661Publisher
SPRINGER JAPAN KK
DOI: 10.1007/s00774-011-0261-0
Keywords
Retinoic acid; Retinoic acid receptor; Vitamin A; Osteoclast; Nuclear factor of activated T cells
Funding
- Department of Veterans Affairs
- Indian Trail Foundation
- Miami VAHS GRECC and Research Service
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Ingestion of excess vitamin A appears to correlate with an increased fracture risk, an outcome that is likely mediated by retinoic acids (RAs); these are vitamin A metabolites that have dramatic effects on skeletal development. We studied the impacts of RA and isoform-specific RA receptor (RAR) agonists (alpha, beta, and gamma) on osteoclast formation (osteoclastogenesis) in two model systems: RAW264.7 cells and murine bone marrow-derived monocytes. The pan-RAR agonists, all-trans and 9-cis RA, inhibited receptor activator of nuclear factor kappa B ligand (RANKL)-mediated osteoclast differentiation in a concentration-dependent manner. Isoform-specific RAR agonists (alpha, beta, and gamma) also inhibited osteoclastogenesis, with the RAR alpha agonist producing the most consistent reductions in both osteoclast number and size and total area covered. Inhibition of osteoclastogenesis correlated with reductions in expression, DNA binding, and nuclear abundance of nuclear factor of activated T cells c1 (NFATc1), a transcription factor critical for osteoclastogenesis. The upregulation of three NFATc1-responsive genes, cathepsin K, dendritic cell-specific transmembrane protein and osteoclast-associated receptor were similarly reduced following RA or RAR agonist exposure. These results suggest that RA blocks in vitro RANKL-mediated osteoclastogenesis by decreasing NFATc1 function.
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