Estrogen and glucocorticoid regulate osteoblast differentiation through the interaction of bone morphogenetic protein-2 and tumor necrosis factor-α in C2C12 cells

Yoshinori Matsumoto, Fumio Otsuka, Mariko Narazaki, Tomoyuki Mukai, Ryutaro Yamanaka, Masaya Takeda, Tomoko Miyoshi, Kenichi Inagaki, Kenei Sada, Hirofumi Makino

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)


Imbalanced functions between osteoclasts and osteoblasts are involved in inflammatory bone damage. The clinical effectiveness of blocking TNF-α in treatment of active rheumatoid arthritis established the significance of TNF-α in the pathogenesis. In the present study, we investigated the cellular mechanism by which estrogen and glucocorticoid interact in osteoblastic differentiation regulated by BMP and TNF-α using mouse myoblastic C2C12 cells. The expression of estrogen receptors, (ER)α and ERβ, and glucocorticoid receptor (GCR) was significantly increased by BMP-2 treatment regardless of the presence of estradiol and dexamethasone. Estradiol, but not dexamethasone, enhanced BMP-induced Runx2 and osteocalcin expression in C2C12 cells. In addition, TNF-α suppressed BMP-2-induced Runx2 and osteocalcin expression, and estradiol and dexamethasone reversed the TNF-α effects on BMP-2-induced Runx2 expression. Dexamethasone also abolished osteocalcin expression induced by BMP-2. Interestingly, BMP-2-induced Smad1/5/8 phosphorylation and Id-1 promoter activity were enhanced by estradiol pretreatment. On the other hand, dexamethasone suppressed BMP-2-induced Smad1/5/8 activation. TNF-α-induced SAPK/JNK activity was suppressed by estradiol, while NFκB phosphorylation was inhibited by dexamethasone. Of note, the inhibitory effects of TNF-α on BMP-2-induced Runx2 and osteocalcin expression were reversed by SAPK/JNK inhibition regardless of the presence of estradiol. The estradiol effects that enhance BMP-2-induced Runx2 and osteocalcin mRNA expression were restored by antagonizing ER, and moreover, membrane-impermeable estradiol-BSA failed to enhance the BMP-2-induced osteoblastic differentiation. Thus, estrogen and glucocorticoid are functionally involved in the process of osteoblast differentiation regulated by BMPs and TNF-α. BMP-2 increases the sensitivities of ERs and GCR, whereas estrogen and glucocorticoid differentially regulate BMP-Smad and TNF-α signaling.

Original languageEnglish
Pages (from-to)118-127
Number of pages10
JournalMolecular and cellular endocrinology
Issue number1-2
Publication statusPublished - Aug 2010


  • Bone morphogenetic protein (BMP)
  • Estrogen
  • Estrogen receptor (ER)
  • Glucocorticoid
  • Nuclear factor-κB (NFκB)
  • Tumor necrosis factor-α (TNF-α)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology


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