Forkhead proteins are critical for bone morphogenetic protein-2 regulation and anti-tumor activity of resveratrol

J Biol Chem. 2007 Jul 6;282(27):19385-98. doi: 10.1074/jbc.M702452200. Epub 2007 May 18.


Osteoporosis is a major public health problem and the most obvious preventive strategy, hormone replacement therapy, has lost favor due to recent findings of the Women's Health Initiative regarding increased risks of breast cancer and cardiovascular disease. Resveratrol, a naturally occurring compound possessing estrogenic activity, is thought to have considerable potential for therapy of osteoporosis. In the present study, resveratrol was found to exhibit bone-protective effects equivalent to those exerted by hormone replacement therapy and decrease the risk of breast cancer in the in vivo and in vitro models. Forkhead proteins were found to be essential for both effects of resveratrol. The bone-protective effect was attributable to induction of bone morphogenetic protein-2 through Src kinase-dependent estrogen receptor activation and FOXA1 is required for resveratrol-induced estrogen receptor-dependent bone morphogenetic protein-2 expression. The tumor-suppressive effects of resveratrol were the consequence of Akt inactivation-mediated FOXO3a nuclear accumulation and activation. Resveratrol is therefore anticipated to be highly effective in management of postmenopausal osteoporosis without an increased risk of breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins / biosynthesis*
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Estrogen Replacement Therapy
  • Estrogens / pharmacology*
  • Estrogens / therapeutic use
  • Female
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Humans
  • Mice
  • Osteoporosis, Postmenopausal / drug therapy
  • Osteoporosis, Postmenopausal / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Estrogen / agonists
  • Receptors, Estrogen / metabolism
  • Resveratrol
  • Risk Factors
  • Stilbenes / pharmacology*
  • Stilbenes / therapeutic use
  • Transforming Growth Factor beta / biosynthesis*
  • src-Family Kinases / metabolism


  • Antineoplastic Agents, Phytogenic
  • BMP2 protein, human
  • Bmp2 protein, mouse
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Proteins
  • Estrogens
  • Forkhead Transcription Factors
  • Receptors, Estrogen
  • Stilbenes
  • Transforming Growth Factor beta
  • src-Family Kinases
  • Proto-Oncogene Proteins c-akt
  • Resveratrol