Novel antiosteoclastogenic activity of phloretin antagonizing RANKL-induced osteoclast differentiation of murine macrophages
Article first published online: 15 JUN 2012
© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Molecular Nutrition & Food Research
Volume 56, Issue 8, pages 1223–1233, August 2012
How to Cite
Kim, J.-L., Kang, M.-K., Gong, J.-H., Park, S.-H., Han, S.-Y. and Kang, Y.-H. (2012), Novel antiosteoclastogenic activity of phloretin antagonizing RANKL-induced osteoclast differentiation of murine macrophages. Mol. Nutr. Food Res., 56: 1223–1233. doi: 10.1002/mnfr.201100831
- Issue published online: 10 AUG 2012
- Article first published online: 15 JUN 2012
- Manuscript Accepted: 13 APR 2012
- Manuscript Revised: 1 APR 2012
- Manuscript Received: 28 DEC 2011
- National Research Foundation of Korea
- Ministry of Knowledge Economy
- Bone resorption;
- Nuclear factor κB;
- Receptor activator of nuclear factor κB ligand
Bone-remodeling imbalance resulting in more bone resorption than bone formation is known to cause skeletal diseases such as osteoporosis. Phloretin, a natural dihydrochalcone compound largely present in apple peels, possesses antiphotoaging, and antiinflammatory activity.
Methods and results
Phloretin inhibited receptor activator of NF-κB ligand (RANKL)-induced formation of multinucleated osteoclasts and diminished bone resorption area produced during the osteoclast differentiation process. It was also found that ≥10 μM phloretin reduced RANKL-enhanced tartrate-resistance acid phosphatase activity and matrix metalloproteinase-9 secretion in a dose-dependent manner. The phloretin treatment retarded RANKL-induced expression of carbonic anhydrase II, vacuolar-type H+-ATPase D2 and β3 integrin, all involved in the bone resorption. Furthermore, submicromolar phloretin diminished the expression and secretion of cathepsin K elevated by RANKL, being concurrent with inhibition of TRAF6 induction and NF-κB activation. RANKL-induced activation of nuclear factor of activated T cells c1 (NFATc1) and microphthalmia-associated transcription factor was also suppressed by phloretin.
These results demonstrate that the inhibition of osteoclast differentiation and bone resorption by phloretin entail a disturbance of TRAF6-NFATc1-NF-κB pathway triggered by RANKL. Therefore, phloretin may be a potential therapeutic agent targeting osteoclast differentiation and bone resorption in skeletal diseases such as osteoporosis.