Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids

J Clin Invest. 2003 Jun;111(11):1651-64. doi: 10.1172/JCI17261.


It has been found that 4-estren-3alpha,17beta-diol, a synthetic ligand for the estrogen receptor (ER) or androgen receptor (AR), which does not affect classical transcription, reverses bone loss in ovariectomized females or orchidectomized males without affecting the uterus or seminal vesicles, demonstrating that the classical genotropic actions of sex steroid receptors are dispensable for their bone-protective effects, but indispensable for their effects on reproductive organs. We have now investigated the mechanism of action of this compound. We report that, identically to 17beta-estradiol or dihydrotestosterone, but differently from raloxifene, estren alters the activity of Elk-1, CCAAT enhancer binding protein-beta (C/EBPbeta), and cyclic adenosine monophosphate-response element binding protein (CREB), or c-Jun/c-Fos by an extranuclear action of the ER or AR, resulting in activation of the Src/Shc/ERK pathway or downregulation of JNK, respectively. All of these effects are non-sex specific, require only the ligand-binding domain of the receptor, and are indispensable for the antiapoptotic action of these ligands on osteoblastic and HeLa cells. Moreover, administration of 17beta-estradiol or 4-estren-3alpha,17beta-diol to ovariectomized mice induces phosphorylation of ERKs, Elk-1, and C/EBPbeta, downregulates c-Jun, and upregulates the expression of egr-1, an ERK/SRE target gene. Kinase-initiated regulation of commonly used transcription factors offers a molecular explanation for the profound skeletal effects of sex steroid receptor ligands, including synthetic ones that are devoid of classical transcriptional activity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • Bone and Bones / drug effects
  • Bone and Bones / metabolism*
  • CCAAT-Enhancer-Binding Protein-alpha / metabolism
  • Cell Line
  • Cytoplasm / metabolism
  • DNA-Binding Proteins*
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Enzyme Activation
  • Estrenes / pharmacology*
  • Estrogen Antagonists / pharmacology
  • Genes, Reporter
  • HeLa Cells
  • Humans
  • Ligands
  • Mice
  • Models, Biological
  • Osteoblasts / metabolism
  • Phosphotransferases / metabolism
  • Plasmids / metabolism
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins c-jun / metabolism
  • Raloxifene Hydrochloride / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Selective Estrogen Receptor Modulators / pharmacology
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Transfection
  • Up-Regulation
  • ets-Domain Protein Elk-1


  • 4-estren-3,17-diol
  • CCAAT-Enhancer-Binding Protein-alpha
  • DNA-Binding Proteins
  • ELK1 protein, human
  • Elk1 protein, mouse
  • Estrenes
  • Estrogen Antagonists
  • Ligands
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Selective Estrogen Receptor Modulators
  • Transcription Factors
  • ets-Domain Protein Elk-1
  • Raloxifene Hydrochloride
  • Phosphotransferases