The forkhead transcription factor Foxc2 promotes osteoblastogenesis via up-regulation of integrin β1 expression

Su Jin Park, Jogeswar Gadi, Kyoung Won Cho, Kwang Joon Kim, Se Hwa Kim, Han Sung Jung, Sung Kil Lim

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

The forkhead box C2 (Foxc2) protein, a member of the forkhead/winged helix transcription factor family, plays an important role in regulation of metabolism, arterial specification, and vascular sprouting. Foxc2-null mutants die prenatally or perinatally, and they exhibit hypoplasia of the vertebrae and insufficient chondrification or ossification of medial structures. However, the role of Foxc2 in osteoblastogenesis is not yet fully understood. According to the degree of differentiation of osteoblasts, we found that Foxc2 expression was gradually increased and dose-dependently up-regulated by well-known bone anabolic agents, such as hPTH(1-34) and BMP2. In ex vivo mouse calvarial organ culture, a significant reduction of the basal expression of Foxc2 induced by siFoxc2 remarkably suppressed cell proliferation and differentiation and induced cell death. Knockdown of Foxc2 expression using siFoxc2 in both MC3T3-E1 and primary mouse calvarial cells also resulted in a significant suppression of proliferation and differentiation, and induced cell death, supporting the ex vivo observations. In addition, the resistance to apoptosis induced by serum deprivation and phosphorylation of both Akt and ERK was significantly reduced after siFoxc2 treatment. Conversely, overexpression of Foxc2 increased the proliferation of MC3T3-E1 and primary mouse calvarial cells. Furthermore, we found that Foxc2 enhanced the expression of integrin β1, an important modulator of osteoblastogenesis, by direct binding to a Forkhead-binding element in its promoter. Taken together, these results indicate that Foxc2 plays an important role in osteoblastogenesis by promoting osteoblast proliferation, survival and differentiation through up-regulation of integrin β1 in response to stimuli which induce bone formation.

Original languageEnglish
Pages (from-to)428-438
Number of pages11
JournalBone
Volume49
Issue number3
DOIs
Publication statusPublished - 2011 Sep

Bibliographical note

Funding Information:
We thank Prof. Eun Jig Lee (Yonsei University, Seoul, Korea) for providing a recombinant adenoviral vector expressing human Foxc2 and a control vector expressing β-galactosidase (β-gal) gene (LacZ). This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 20110001024 ). This work was also supported by the grant 03-PJ10-PG6-GP01-0002 from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea . The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Histology
  • Physiology

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