Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts.

By Hiroshi Takayanagi, Sunhwa Kim, T. Koga, H. Nishina, M. Isshiki, H. Yoshida, A. Saiura, M. Isobe, T. Yokochi, J. Inoue and 4 more. Developmental Cell, 2002

2,488 citations recorded by the source corpus.

Signaling by RANKL is essential for terminal differentiation of monocytes/macrophages into osteoclasts. The TRAF6 and c-Fos signaling pathways both play important roles downstream of RANKL. We show here that RANKL selectively induces NFATc1 expression via these two pathways. RANKL also evokes Ca(2+) oscillations that lead to calcineurin-mediated activation of NFATc1, and therefore triggers a sustained NFATc1-dependent transcriptional program during osteoclast differentiation. We also show that NFATc1-deficient embryonic stem cells fail to differentiate into osteoclasts in response to RANKL stimulation, and that ectopic expression of NFATc1 causes precursor cells to undergo efficient differentiation without RANKL signaling. Thus, NFATc1 may represent a master switch for regulating terminal differentiation of osteoclasts, functioning downstream of RANKL.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7d31125e981664377d2b62dd2a08b956b5541cde

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. S. Teitelbaum
2. Hiroshi Takayanagi
3. T. Suda
4. Tadatsugu Taniguchi
5. P. ten Dijke

In Molecular Biology

1. S. Teitelbaum
2. Hiroshi Takayanagi
3. J. Smolen
4. F. Ross
5. Soo Young Lee
6. K. Redlich
7. P. Hogan
8. N. Lee

Citations in the corpus

• Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. (2006, background): “In addition, c-Fos activates transcription of Ifnb (encoding IFN-b), which mediates a negative feedback loop that suppresses osteoclast differentiation (Takayanagi et al., 2002b).”
• Tissue-specific signals control reversible program of localization and functional polarization of macrophages. (2014, neutral): “…been reported, and the deletion of these transcription factors resulted in the ablation of particular tissue macrophage subsets (Kohyama et al., 2009; A-Gonzalez et al., 2013; Takayanagi et al., 2002), suggesting their involvement in the differentiation of the corresponding macrophage populations.”
• Transcriptional regulation by calcium, calcineurin, and NFAT. (2003, background): “…between calcineurin and osteoclast differentiation has been made in a bone marrow culture model, in which either CsA or FK506 caused a concentration-dependent inhibition of differentiation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (Takayanagi et al. 2002).”
• Current Understanding of RANK Signaling in Osteoclast Differentiation and Maturation (2017, background): “…pumped out through the ruffled border and form HCl with Cl - , which demineralizes the bone matrix, and various hydrolases such as cathepsin K, CLC-7 chloride channel, and TRAP, which are NFATc1 target genes, are activated (Matsumoto et al., 2004; Takayanagi et al., 2002; Vaananen et al., 1990).”
• Inflammatory bone loss: pathogenesis and therapeutic intervention (2012, background): “NFATC1, which is also partly activated by FOS-mediated signalling, is an important transcription factor for osteoclast generatio”
• Osteoclasts: what do they do and how do they do it? (2007, neutral): “The key genomic osteoclastogenic event is activation of an AP-1/NFATc1 transcription complex.(29,30) RANKL generates this complex by inducing expression of the c-Fos family(31) and promoting nuclear translocation of Jun proteins.”
• Osteoclast differentiation and activation (2003, methodology): “Several groups have used gene expression arrays to map these changes in cell culture system”
• Transforming Growth Factor- 1 to the Bone (2005, background): “1 and MITF (107, 108), NFAT-c (109), and the transmembrane adaptor protein DAP12 (110).”