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Molecular and Cellular Biology, October 2008, p. 6402-6412, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00299-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Association of Notch2 and NF-{kappa}B Accelerates RANKL-Induced Osteoclastogenesis{triangledown}

Hidefumi Fukushima,1,2* Akihiro Nakao,1 Fujio Okamoto,1 Masashi Shin,2 Hiroshi Kajiya,1 Seiji Sakano,3 Anna Bigas,4 Eijiro Jimi,2,5 and Koji Okabe1

Department of Physiological Science and Molecular Biology, Fukuoka Dental College, Fukuoka 814-0193, Japan,1 Department of Bioscience,2 Center for Oral Biological Research, Kyushu Dental College, Kitakyushu 803-8580, Japan,5 Central R&D Laboratories, Asahi Kasei Corporation, Shizuoka 416-8501, Japan,3 Centre Oncologia Molecular, IDIBELL, Gran Via Km 2.7 Hospitalet, Barcelona, Spain4

Received 22 February 2008/ Returned for modification 9 April 2008/ Accepted 11 August 2008

Notch signaling plays a key role in various cell differentiation processes including bone homeostasis. However, the specific involvement of Notch in regulating osteoclastogenesis is still controversial. In the present study, we show that RANKL induces expression of Jagged1 and Notch2 in bone marrow macrophages during osteoclast differentiation. Suppression of Notch signaling by a selective {gamma}-secretase inhibitor or Notch2 short hairpin RNA suppresses RANKL-induced osteoclastogenesis. In contrast, induction of Notch signaling by Jagged1 or by ectopic expression of intracellular Notch2 enhances NFATc1 promoter activity and expression and promotes osteoclastogenesis. Finally, we found that Notch2 and p65 interact in the nuclei of RANKL-stimulated cells and that both proteins are recruited to the NFATc1 promoter, driving its expression. Taken together, our results show a new molecular cross talk between Notch and NF-{kappa}B pathways that is relevant in osteoclastogenesis.

* Corresponding author. Mailing address: Division of Molecular Signaling and Biochemistry, Department of Bioscience, Kyushu Dental College, 2-6-1 Manazuru, Kokurakita-ku, Kitakyushu 803-8580, Fukuoka, Japan. Phone: 81-93-285-3051. Fax: 81-93-582-6000. E-mail: r07fukushima{at}fa.kyu-dent.ac.jp

{triangledown} Published ahead of print on 18 August 2008.

Molecular and Cellular Biology, October 2008, p. 6402-6412, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00299-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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  • Wang, Z., Li, Y., Kong, D., Banerjee, S., Ahmad, A., Azmi, A. S., Ali, S., Abbruzzese, J. L., Gallick, G. E., Sarkar, F. H. (2009). Acquisition of Epithelial-Mesenchymal Transition Phenotype of Gemcitabine-Resistant Pancreatic Cancer Cells Is Linked with Activation of the Notch Signaling Pathway. Cancer Res. 69: 2400-2407 [Abstract] [Full Text]  


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