Regulation of NFATc1 in Osteoclast Differentiation

“The multinucleated osteoclasts reorganize the actin cytoskeleton to attach to the bone surface and to resorb the bone.[4] Osteoclast differentiation is regulated by two essential cytokines, macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL).”

“[47,48] Yasui et al.”

“Bone is a highly dynamic tissue that undergoes continuous remodeling, which is regulated by various factors, including cytokines/chemokines, hormones, and mechanical stimuli.[1,2] Under normal conditions, bone homeostasis is controlled by the balance between bone formation and bone resorption, processes regulated by o…”

“[32,33] In the alternative pathway, NF-κB-inducing kinase (NIK) and IKKα phosphorylate and process p100 to generate p52 by proteasomes, resulting in the activation of the p52/RelB complex.”

“[32,33] In the alternative pathway, NF-κB-inducing kinase (NIK) and IKKα phosphorylate and process p100 to generate p52 by proteasomes, resulting in the activation of the p52/RelB complex.”

“[5-8] RANKL mediates biological effects in bone through its sole receptor, RANK.”

“Epigenetics is defined as heritable change in the function of genetic elements without changes in the DNA sequence.[46] There are three classes of epigenetic markers, DNA methylation, histone modification, and noncoding RNAs.”

“Targeted deletion of PLC-γ2 in mice results in an osteopetrotic phenotype, and the osteoclast precursor cells lacking PLC-γ2 do not sufficiently induce NFATc1 expression even in the presence of RANKL.”

“Bone is a highly dynamic tissue that undergoes continuous remodeling, which is regulated by various factors, including cytokines/chemokines, hormones, and mechanical stimuli.[1,2] Under normal conditions, bone homeostasis is controlled by the balance between bone formation and bone resorption, processes regulated by o…”

“[31] The NF-κB family, a group of dimeric transcription fac-”

“Since the discovery of the first NFAT protein, NFATs have been discovered to be involved in immune cell activation, heart valve formation, cardiac hypertrophy, and osteoclast development.[16-19] However, the function and regulation of NFAT proteins is best understood in T cells.”

“[5-8] RANKL mediates biological effects in bone through its sole receptor, RANK.”

“[5-8] RANKL mediates biological effects in bone through its sole receptor, RANK.”

“[53,54] The miRNA biogenesis pathway has multiple steps: transcription, pri-miRNA processing, transport to the cytoplasm, precursor miRNA processing, strand selection, target transcription, and fate transcription.[55,56] Very little is known about the role of miRNAs during osteoclast differentiation.”

“[5-8] RANKL mediates biological effects in bone through its sole receptor, RANK.”

“Since the discovery of the first NFAT protein, NFATs have been discovered to be involved in immune cell activation, heart valve formation, cardiac hypertrophy, and osteoclast development.[16-19] However, the function and regulation of NFAT proteins is best understood in T cells.”

“[5-8] RANKL mediates biological effects in bone through its sole receptor, RANK.”

“[36,37] Recently, it has been reported that dehydroxymethylepoxyquinomicin (DHMEQ), an NF-κB inhibitor, attenuates RANKL-induced osteoclastogenesis through down-regulation of NFATc1.”

“c-Fos-knockout mice develop osteopetrosis owing to defects in osteoclast lineage commitment.[27,28] In addition to osteoclast differentiation, the induction of NFATc1 mRNA by RANKL is also abrogated in c-Fos-deficient cells.”

“[65] As expected, Ca2+ oscillation and the induction of NFATc1 were also suppressed in DAP12-/- FcRγ-/cells, recovered by the overexpression of NFATc1, but not cFos or TRAF6.”

“Several kinases such as glycogen synthase kinase 3 (GSK3), casein kinase 1 (CK1), p38, and JNK phosphorylate the various serine-rich motifs in NFAT proteins, thereby preventing translocation into the nucleus or promoting nuclear export of NFAT proteins.[59-63] A recent study has reported that the ectopic expression of…”

“[1,2] Under normal conditions, bone homeostasis is controlled by the balance between bone formation and bone resorption, processes regulated by osteoblasts and osteoclasts, respectively.[3] However, excessive bone resorption by osteoclasts compared to bone formation by osteoblasts, results in osteopenic disorders such…”

“c-Fos-knockout mice develop osteopetrosis owing to defects in osteoclast lineage commitment.[27,28] In addition to osteoclast differentiation, the induction of NFATc1 mRNA by RANKL is also abrogated in c-Fos-deficient cells.”

“[10,29] Studies have also reported that c-Fos is recruited to the NFATc1 promoter at an early stage of osteoclast differentiation.”

“However, NFATc1-deficient mice exhibit a severe osteopetrotic phenotype, while NFATc2-deficient mice show normal skeletal development.[15,30,39] To investigate the unexpected non-redundant role played by NFATc1 in the skeletal system, Asagiri et al.”

“[65-67] Interestingly, the defect in osteoclast differentiation in DAP12 FcRγ cells is fixed by the overexpression of DAP12, but not DAP12Y65F, which has a mutation in ITAM, suggesting that the ITAMmediated signaling pathway is indispensable for osteo-”

“[23-26] These results indicate some degree of redundancy among NFAT proteins in T cells.”

“This leads to their translocation from the cytosol to the nucleus, where they regulate the target genes.[21,22] There is a high degree of structural similarity among the different members of the NFAT family, which allows for redundancy in some NFAT functions in T cells.”

“In particular, NFATc1, a master regulator of osteoclast differentiation, regulates a number of osteoclast specific genes such as TRAP, cathepsin K, calcitonin receptor, and osteoclast-associated receptor (OSCAR) through cooperation with MITF and c-Fos.[10-13] The essential role of NFATc1 in osteoclast differentiation…”

“Knockout mice deficient in individual NFAT proteins show only mild changes in immune function; however, elimination of more than one NFAT protein in mice results in severe alterations in the immune system.[23-26] These results indicate some degree of redundancy among NFAT proteins in T cells.”

“Several kinases such as glycogen synthase kinase 3 (GSK3), casein kinase 1 (CK1), p38, and JNK phosphorylate the various serine-rich motifs in NFAT proteins, thereby preventing translocation into the nucleus or promoting nuclear export of NFAT proteins.[59-63] A recent study has reported that the ectopic expression of…”

“These transgenic mice are viable and exhibit an osteopetrotic bone phenotype owing to a severe defect in the osteoclastogenesis process.[14] Another report states that osteoclast-specific conditional NFATc1-deficient mice develop osteopetrosis owing to impaired osteoclastogenesis.”

“[15] NFATc1-deficient embryonic stem cells cannot differentiate into osteoclasts in response to RANKL.”

“Knockout mice deficient in individual NFAT proteins show only mild changes in immune function; however, elimination of more than one NFAT protein in mice results in severe alterations in the immune system.[23-26] These results indicate some degree of redundancy among NFAT proteins in T cells.”

“This leads to their translocation from the cytosol to the nucleus, where they regulate the target genes.[21,22] There is a high degree of structural similarity among the different members of the NFAT family, which allows for redundancy in some NFAT functions in T cells.”

“In addition, the Ca2+ chelator BAPTA-AM suppresses osteoclast differentiation mediated by RANKL through the inhibition of nuclear localization of NFATc1.”

“Several kinases such as glycogen synthase kinase 3 (GSK3), casein kinase 1 (CK1), p38, and JNK phosphorylate the various serine-rich motifs in NFAT proteins, thereby preventing translocation into the nucleus or promoting nuclear export of NFAT proteins.[59-63] A recent study has reported that the ectopic expression of…”

“Knockout mice deficient in individual NFAT proteins show only mild changes in immune function; however, elimination of more than one NFAT protein in mice results in severe alterations in the immune system.[23-26] These results indicate some degree of redundancy among NFAT proteins in T cells.”

“[32,33] In the alternative pathway, NF-κB-inducing kinase (NIK) and IKKα phosphorylate and process p100 to generate p52 by proteasomes, resulting in the activation of the p52/RelB complex.[32-35] The important role played by NF-κB proteins in osteoclastogenesis has been verified by the severe osteopetrotic phenotype o…”

“In particular, NFATc1, a master regulator of osteoclast differentiation, regulates a number of osteoclast specific genes such as TRAP, cathepsin K, calcitonin receptor, and osteoclast-associated receptor (OSCAR) through cooperation with MITF and c-Fos.[10-13] The essential role of NFATc1 in osteoclast differentiation…”

“Since the discovery of the first NFAT protein, NFATs have been discovered to be involved in immune cell activation, heart valve formation, cardiac hypertrophy, and osteoclast development.[16-19] However, the function and regulation of NFAT proteins is best understood in T cells.”

“[58] Well known inhibitors of calcineurin, such as FK506 and cyclosporine A, strongly inhibit RANKL-induced osteoclast differentiation by blocking NFATc1 translocation into the nucleus in vitro and in vivo.”

“In particular, NFATc1, a master regulator of osteoclast differentiation, regulates a number of osteoclast specific genes such as TRAP, cathepsin K, calcitonin receptor, and osteoclast-associated receptor (OSCAR) through cooperation with MITF and c-Fos.[10-13] The essential role of NFATc1 in osteoclast differentiation…”

“In addition, the Ca2+ chelator BAPTA-AM suppresses osteoclast differentiation mediated by RANKL through the inhibition of nuclear localization of NFATc1.”

“[53,54] The miRNA biogenesis pathway has multiple steps: transcription, pri-miRNA processing, transport to the cytoplasm, precursor miRNA processing, strand selection, target transcription, and fate transcription.[55,56] Very little is known about the role of miRNAs during osteoclast differentiation.”

“Several kinases such as glycogen synthase kinase 3 (GSK3), casein kinase 1 (CK1), p38, and JNK phosphorylate the various serine-rich motifs in NFAT proteins, thereby preventing translocation into the nucleus or promoting nuclear export of NFAT proteins.[59-63] A recent study has reported that the ectopic expression of…”

“Lee et al.[57] have shown that miRNA-124 regulates osteoclastogenesis by suppressing NFATc1 expression (Fig.”

“Post-translational modification such as ubiquitination and acetylation are important mechanisms of gene regulation.[50] Our previous studies have indicated that the stability of NFATc1 proteins is controlled by ubiquitination and”

“[47,48] Yasui et al.[49] recently used ChIP sequencing technology to demonstrate that histone H3 lysine 4 (H3K4me3) is present in the NFATc1 gene in osteoclast precursor cells, but is markedly reduced in mature osteoclasts.”

“1).[40-42] We have also found that protein inhibitor of activated STAT3 (PIAS3) inhibits RANKL-mediated transcription of NFATc1 (Fig.”

“In addition, the Ca2+ chelator BAPTA-AM suppresses osteoclast differentiation mediated by RANKL through the inhibition of nuclear localization of NFATc1.”

“1).[43] Interferon regulatory factor-8 (IRF-8) and B-cell CLL/lymphoma 6 (Bcl-6) have also been identified as negative regulators of NFATc1.”

“These play an important role in the determination of cell fate.[47] Among the epigenetic modification methods, DNA methylation is understood the best.”

“Since the discovery of the first NFAT protein, NFATs have been discovered to be involved in immune cell activation, heart valve formation, cardiac hypertrophy, and osteoclast development.[16-19] However, the function and regulation of NFAT proteins is best understood in T cells.”

“1).[40-42] We have also found that protein inhibitor of activated STAT3 (PIAS3) inhibits RANKL-mediated transcription of NFATc1 (Fig.”

“Nfatc1, a master regulator of osteoclast differentiation (20), was present within the osteoclast lineage differentiation, supporting the reliability of our computational analysis.”

“Indeed, in osteoclasts, most studies show that RANK-mediated signalling pathways and/or transcription factors converge towards NFATc1 as the ultimate master regulator of osteoclast multinucleation (Kim and Kim, 2014).”

“Among them, NFATc1 is considered to be the master transcription factor that drives terminal differentiation of osteclasts via regulating numerous osteoclast-specific genes such as tartrate-resistant acid phosphatase (TRAP), cathepsin K and calcitonin receptor [12,13].”