Fine-tuning between BMP and NF-κB pathways regulates osteoblastic bone formation

Shizu Hirata-Tsuchiya, Hidefumi Fukushima, Shoichiro Kokabu, Chiaki Kitamura, Eijiro Jimi

Research output: Contribution to journalReview articlepeer-review

1 Citation (Scopus)


Background Bone morphogenetic proteins (BMPs) enhance bone formation and osteoblast differentiation in vivo and in vitro via a Smad signaling pathway. Recent findings have revealed that inhibition of nuclear factor-κB (NF-κB) enhances BMP-induced osteoblast differentiation both in vitro and in vivo, suggesting that NF-κB negatively regulates osteoblastic bone formation. However, the molecular mechanism whereby NF-κB inhibits BMP-induced osteoblastic bone formation is still unclear. Highlight A specific NF-κB inhibitor, BAY11-7082, together with BMP2, enhanced BMP2-induced ectopic bone formation in mice. Furthermore, BMP2 increased alkaline phosphatase (ALP) activity, a typical marker of osteoblast differentiation in mouse embryonic fibroblasts (MEFs) from p65-deficient (p65−/−) mice compared with MEFs from wild type (WT) or p50-deficient (p50−/−) mice. The Smad complex activated by BMP2 bound more stably to the target element, without affecting Smad1/5 phosphorylation, in p65−/− MEFs than in WT MEFs, while p65 overexpression inhibited BMP2 activity by decreasing DNA binding to the Smad complex. Moreover, the C-terminal TA2 domain of p65 associated with the MH1 domain of Smad4 but not of Smad1, and inhibited the BMP-Smad pathway. Conclusion p65 inhibits BMP2-induced osteoblastic bone formation by interfering with DNA binding of the Smad complex via an interaction with Smad4. Thus, targeting the association between p65 and Smad4 may help promote bone regeneration in the treatment of bone diseases.

Original languageEnglish
Pages (from-to)73-77
Number of pages5
Journaljournal of oral biosciences
Issue number3
Publication statusPublished - Aug 1 2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Medicine (miscellaneous)
  • General Biochemistry,Genetics and Molecular Biology
  • General Dentistry


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