Dried Plum Polyphenols Inhibit Osteoclastogenesis by Downregulating NFATc1 and Inflammatory Mediators
- 700 Downloads
Dried plums and their polyphenols have been shown to suppress bone resorption by downregulating receptor activator NF-κB 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 μg/mL) downregulated osteoclast precursor cyclooxygenase expression and nitric oxide (NO) by inhibiting inducible NO synthase. NO and tumor necrosis factor (TNF)-α were also suppressed in the presence of RANKL during osteoclastogenesis by the polyphenols. Increased TNF-α 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 (NFATc1). 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.
KeywordsBone Osteoclast Antioxidant Osteoporosis Macrophage
This material is based upon work supported by Cooperative State Research, Education and Extension Service, U.S. Department of Agriculture, under award 2006-35200-17383. Additionally, this study was supported by the California Dried Plum Board and the Oklahoma Center for the Advancement of Science and Technology (HR06-109).
- 3.Park EK, Kim MS, Lee SH, Kim KH, Park JY, Kim TH, Lee IS, Woo JT, Jung JC, Shin HI, Choi JY, Kim SY (2004) Furosin, an ellagitannin, suppresses RANKL-induced osteoclast differentiation and function through inhibition of MAP kinase activation and actin ring formation. Biochem Biophys Res Commun 325:1472–1480PubMedCrossRefGoogle Scholar
- 9.Arjmandi BH, Lucas EA, Juma S, Soliman A, Stoecker BJ, Khalil DA, Smith BJ, Wang C (2001) Dried plums prevent ovariectomy-induced bone loss in rats. J Am Nutraceut Assoc 4:50–56Google Scholar
- 11.Bu SY, Hunt TS, Smith BJ (2008) Dried plum polyphenols attenuate the detrimental effects of TNF-alpha on osteoblast function coincident with upregulation of Runx2, Osterix and IGF-I. J Nutr Biochem (in press)Google Scholar
- 13.Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E, Tan HL, Elliott G, Kelley MJ, Sarosi I, Wang L, Xia XZ, Elliott R, Chiu L, Black T, Scully S, Capparelli C, Morony S, Shimamoto G, Bass MB, Boyle WJ (1999) Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA 96:3540–3545PubMedCrossRefGoogle Scholar
- 15.Sakuma Y, Tanaka K, Suda M, Yasoda A, Natsui K, Tanaka I, Ushikubi F, Narumiya S, Segi E, Sugimoto Y, Ichikawa A, Nakao K (2000) Crucial involvement of the EP4 subtype of prostaglandin E receptor in osteoclast formation by proinflammatory cytokines and lipopolysaccharide. J Bone Miner Res 14:218–227CrossRefGoogle Scholar
- 23.Tang QY, Kukita T, Ushijima Y, Kukita A, Nagata K, Sandra F, Watanabe T, Toh K, Okuma Y, Kawasaki S, Rasubala L, Teramachi J, Miyamoto I, Wu Z, Iijima T (2006) Regulation of osteoclastogenesis by Simon extracts composed of caffeic acid and related compounds: successful suppression of bone destruction accompanied with adjuvant-induced arthritis in rats. Histochem Cell Biol 125:215–225PubMedCrossRefGoogle Scholar
- 25.Chen Y, Shen S, Lee W, Hou W, Yang L, Lee TJF (2001) Inhibition of nitric oxide synthase inhibitors and lipopolysaccharide induced inducible NOS and cyclooxygenase-2 gene expression by rutin, quercetin, and quercetin pentaacetate in RAW 264.7 macrophages. J Cell Biochem 82:537–548PubMedCrossRefGoogle Scholar
- 47.Pacifici R (2007) Estrogen deficiency, T cells and bone loss. Cell Immunol. September 19 [Epub ahead of print]Google Scholar