Dried plum polyphenols inhibit osteoclastogenesis by downregulating NFATc1 and inflammatory mediators.
Dried plums and their polyphenols have been shown to suppress bone resorption by downregulating receptor activator NF-kappaB ligand (RANKL). Due to the anti-inflammatory and antioxidant properties of these compounds, this study was designed to investigate whether dried plum polyphenols exert additional, more direct effects on osteoclasts and their precursors. RAW 264.7 macrophages were used as a model to study osteoclast precursors and osteoclast differentiation and activity. Under inflammatory conditions induced by lipopolysaccharide (LPS), polyphenols extracted from dried plum (10, 20, and 30 microg/mL) downregulated osteoclast precursor cyclooxygenase expression and nitric oxide (NO) by inhibiting inducible NO synthase. NO and tumor necrosis factor (TNF)-alpha were also suppressed in the presence of RANKL during osteoclastogenesis by the polyphenols. Increased TNF-alpha production in response to oxidative stress, but not LPS, was decreased over time. As expected, LPS and H2O2 significantly increased the number of tartrate-resistant acid phosphatase-positive cells by 127% and 30%, respectively. Dried plum polyphenols decreased osteoclast differentiation under normal as well as inflammatory and oxidative stress conditions, coincident with the suppression of the transcription factor, nuclear factor for activated T cells (NFATcl). These inhibitory effects on osteoclastogenesis were confirmed in primary bone marrow cultures. Resorption pit formation was decreased to a similar extent as osteoclast differentiation, suggesting that dried plum polyphenols primarily affect osteoclast differentiation as opposed to activity. Our data demonstrate that dried plum polyphenols directly inhibit osteoclastogenesis, leading to a decrease in osteoclast activity, by downregulating NFATc1 and inflammatory mediators.
Department of Nutritional Sciences, College of Human Environmental Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
So Young
SY
Bu
Megan
M
Lerner
Barbara J
BJ
Stoecker
Emily
E
Boldrin
Daniel J
DJ
Brackett
Edralin A
EA
Lucas
Brenda J
BJ
Smith
D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology; D059808:Polyphenols; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D027861:Prunus / Q000737:chemistry*; D000071681:Tartrate-Resistant Acid Phosphatase; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D000975:Antioxidants; D004791:Enzyme Inhibitors; D005419:Flavonoids; D018836:Inflammation Mediators; D007527:Isoenzymes; D008070:Lipopolysaccharides; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D010636:Phenols; D010936:Plant Extracts; D059808:Polyphenols; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase