Molecules in focus
NFATc1: Functions in osteoclasts

https://doi.org/10.1016/j.biocel.2009.12.018Get rights and content

Abstract

NFATc1 is an important transcription factor which is critical for lineage selection in T-cell differentiation, cardiac valve morphogenesis, lymphatic endothelial development, osteoblast differentiation and osteoclastogenesis. Especially, it is a master regulator of RANKL-induced osteoclast differentiation and plays a pivotal role in osteoclast fusion and osteoclast activation via up-regulation of various genes responsible for osteoclast adhesion, migration, acidification, degradation of inorganic and organic bone matrix. In the present review, some of the known features of NFATc1 such as structure, function and its roles in physiological or pathophysiological processes are highlighted.

Introduction

Nuclear factor of activated T-cells cytoplasmic (NFATc) is a family of transcription factors originally identified in T-cells. The gene family has five members (NFATc1 through NFATc5), which play roles both within and outside the immune system. NFATc1 is a broadly expressed member of the NFAT family and resides in endocardial cushion (ECC) endothelial cells, skeletal muscle fibres, T lymphocytes, osteoblasts, osteoclasts, etc. (Combs and Yutzey, 2009, Mutungi, 2008, Penolazzi et al., 2007, Rao et al., 1997). The autoregulation of NFATc1 is a crucial step for cell-fate determination.

Section snippets

Structure

The human and murine NFATc1 genes span approximately 150 kb of chromosomal DNA (Serfling et al., 2006). NFATc1 is the major induced NFATc in human osteoclasts, which has a significant homology with the protein sequences of NFAT family members. The N-terminal domain that binds calcineurin is dephosphorylated when calcineurin is activated, and controls the calcineurin-regulated nuclear translocation of NFAT (Zhou et al., 1998). The C-terminal domain binds DNA sequence specifically and cooperates

NF-κB, c-Jun, c-Fos signals with NFATc1

The binding of RANKL to RANK results in the recruitment of TRAF6, and leads to the activation of downstream molecules, such as NF-κB, c-Jun, and c-Fos. Cooperation of NFATc2 and NF-κB activates the initial induction of NFATc1. C-Jun signaling in cooperation with NFAT is also crucial for RANKL-regulated osteoclast (OC) differentiation. The osteoclastogenic activities of NFAT are abrogated by overexpression of dominant-negative c-Jun. Overexpression of NFAT in transgenic mice expressing

Biological function in osteoclasts

Takayanagi et al. (2002) demonstrate that NFATc1-deficient embryonic stem cells fail to differentiate into osteoclasts and ectopic expression of NFATc1 causes precursor cells to undergo efficient differentiation without RANKL signaling. These experiments reveal the essential and sufficient role of NFATc1 in in vitro osteoclastogenesis. NFATc1-deficient mice have a defect in cardiac valve formation, which leads to embryonic death at around E14.5. Therefore, the function of NFATc1 in vivo cannot

Possible medical applications

Until now, a series of molecules have been shown to inhibit osteoclast differentiation through NFATc1 suppression, such as 1-alpha,25-dihydroxy vitamin D(3) (Sakai et al., 2009), VIVIT peptide (Liu et al., 2009), IL-10 (Evans and Fox, 2007), diphenylhydantoin (Koide et al., 2009), caffeic acid phenethyl ester (Ha et al., 2009), IL-4, (−)-DHMEQ, tanshinone IIA, PIAS3, dehydroxymethylepoxyquinomicin, adiponectin, bavachalcone, and dried plum polyphenols (Bu et al., 2008). Therefore, NFATc1 may be

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