NFAT expression in human osteoclasts

Abstract

Nuclear factor of activated T-cells cytoplasmic (NFATc) is a family of transcription factors originally identified in T-cells. The gene family is currently known to have four members (NFATc1 through NFATc4) which have roles both within and outside the immune system. We show that NFATc1 is the major induced NFAT in human osteoclasts, with expression greatly exceeding that of NFATc2 through NFATc4. In macrophage-like cells in culture, NFATc1 through NFATc4 are expressed at similar low levels. NFATc1 is comprised of five mRNA transcript variants known to encode three different protein isoforms. The mRNA encoding isoform C (mRNA variant 3) was the most expressed with 38 copies per nanogram followed by isoform B (mRNA variant 5) with 17 copies per nanogram of total RNA. Isoform A (mRNA variant 1) and mRNA variants 2 and 4 made up less than 1% of the total NFATc1 expressed. NFATc1 is activated by calcineurin after calcium-calmodulin signalling. The induction of NFATc1 in osteoclasts was not altered in the presence of cyclosporin A, an inhibitor of calcineurin, suggesting that NFATc1 does not participate in autoregulatory activation of its own promoter. The NFATc1 variants expressed by human osteoclasts are not those normally expressed by effector T-cells but are similar to those seen in naïve T-cells.

Retracted: Elevated expression of CaMKIIγ during osteoclastogenesis and its functional implications

“…Other studies have begun to identify which of the 40 different pathways initiated by Ca 2þ /CaM signaling might be responsible for the underlying effects on osteoclastogenesis. Notably, calcineurin, a major downstream target of Ca 2þ /CaM signaling, has been recognized as a key regulator via activating NFAT, a crucial transcription factor in osteoclastogenesis [Takayanagi et al, 2002; also see reviews by Boyle et al, 2003;Hirotani et al, 2004;Ikeda et al, 2004;Koga et al, 2004;Day et al, 2005;Zhang et al, 2005;Zhu et al, 2005]; while the role of calcineurin-NFAT pathway in osteoclastogenesis is now widely accepted, our present data provide yet another mechanism, strongly suggesting a role for CaMdependent kinase II (CaMKII), another major downstream target of Ca 2þ /CaM signaling, in osteoclastogenesis.…”

Induction of Estrogen Receptor α Expression with Decoy Oligonucleotide Targeted to NFATc1 Binding Sites in Osteoblasts

“…These proteins were initially identified as transcription factors that mediate Ca 2ϩ /calmodulin-and calcineurin (Cn)-dependent transcription of many cytokines involved in T-cell activation (Rao et al, 1997). NFATc1 is referred to as the master transcription factor for differentiation of osteoclasts (OCs), the cells responsible for bone resorption (Takayanagi et al, 2002;Day et al, 2005;Kim et al, 2005;Asagiri and Takayanagi, 2007). Nevertheless, recent studies suggest that it also has an important role on the transcriptional program of osteoblasts (OBs), the bone-forming cells that play a central role also in modulating osteoclastogenesis (Koga et al, 2005;Zayzafoon, 2005;Winslow et al, 2006;Yeo et al, 2006).…”

“…Nevertheless, recent studies suggest that it also has an important role on the transcriptional program of osteoblasts (OBs), the bone-forming cells that play a central role also in modulating osteoclastogenesis (Koga et al, 2005;Zayzafoon, 2005;Winslow et al, 2006;Yeo et al, 2006). In fact, several lines of evidence indicate that NFATc1 is not only a transcriptional regulator of a number of osteoclast-specific genes, such as cathepsin K, calcitonin receptor, ␤ 3 integrin, TRAP, and ACP5 (Ikeda et al, 2004;Matsumoto et al, 2004;Matsuo et al, 2004;Day et al, 2005;Kim et al, 2005;Crotti et al, 2006) but also contributes to the transcriptional control of genes expressed in OBs including Osterix (Koga et al, 2005) and Fra-2 (Zayzafoon, 2005) and modulates the activity of ligands for osteoclast-associated receptors such as OSCAR Zayzafoon, 2006) primarily produced by osteoblasts.…”

Early Growth Response-1 (EGR-1) and Nuclear Factor of Activated T Cells (NFAT) Cooperate to Mediate CD40L Expression in Megakaryocytes and Platelets

“…Although each of the four calcium-dependent NFAT family members (NFATc1, -c2, -c3, and -c4) is expressed in T cells and has apparently redundant function, NFATc1 and NFATc2 are considered principle regulators of cytokines in activated T cells (14,15). Outside the lymphoid compartment, NFAT is widely but variably expressed, and it is shown to mediate tissue-specific gene regulation during embryonic development and transduce inflammatory signals in endothelial cells (15)(16)(17)(18)(19)(20). The nearly ubiquitous expression of the NFAT in diverse cell types suggests that NFAT protein is a key modulator of inflammation and adaptive immunity and has impact on human disease (18).…”