Estrogen facilitates osteoblast differentiation by upregulating bone morphogenetic protein-4 signaling

Yoshinori Matsumoto, Fumio Otsuka, Mariko Narazaki, Takayuki Katsuyama, Eri Nakamura, Naoko Yamauchi, Kenichi Inagaki, Kenei Sada, Hirofumi Makino

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)


Imbalanced functions of osteoclasts and osteoblasts are involved in various types of bone damage including postmenopausal osteoporosis. In the present study, we investigated the cellular mechanism by which estrogen interacts in the process of osteoblastic differentiation regulated by BMP-4 using mouse MC3T3-E1 cells that express estrogen receptors (ER) and BMP-4. Estradiol enhanced BMP-4-induced Runx2, osterix, ALP and osteocalcin expression in MC3T3-E1 cells. BMP-4-induced mineralization shown by Alizarin red staining was also facilitated by estrogen treatment. It was revealed that estrogen upregulated BMP-4-induced Smad1/5/8 phosphorylation, BRE-Luc activity and Id-1 mRNA expression. The expression of BMPRII was increased by estrogen in MC3T3-E1 cells, and inhibition of BMPRII or ALK-2/3 signaling impaired the effect of estrogen on BMP-4 signaling. Of note, the enhanced expression of osterix, ALP and osteocalcin mRNAs induced by BMP-4 and estrogen was reversed in the presence of an ER antagonist. Given that membrane-impermeable estrogen also upregulated BMP-4-induced expression of osteoblastic markers and Id-1 mRNA, non-genomic ER activity is involved in the mechanism by which estrogen enhances BMP-4-induced osteoblast differentiation in MC3T3-E1 cells. On the other hand, the expression of ERα and endogenous BMP-4 was suppressed by BMP-4 treatment regardless of the presence of estrogen, implying the presence of a negative feedback loop for osteoblast differentiation. Thus, estrogen is functionally involved in the process of osteoblast differentiation regulated by BMP-4 through upregulating BMP sensitivity of MC3T3-E1 cells.

Original languageEnglish
Pages (from-to)513-520
Number of pages8
Issue number5
Publication statusPublished - May 2013


  • Bone morphogenetic protein (BMP)
  • Estradiol
  • Estrogen
  • Estrogen receptor (ER)
  • Mineralization
  • Osteoblast differentiation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology
  • Pharmacology
  • Clinical Biochemistry
  • Organic Chemistry


Dive into the research topics of 'Estrogen facilitates osteoblast differentiation by upregulating bone morphogenetic protein-4 signaling'. Together they form a unique fingerprint.

Cite this