Stimuli and Relevant Signaling Cascades for NFATc1 in Bone Cell Homeostasis: Friend or Foe?

Author(s): Zhen Zhang, Hao Wen, Xiaobin Yang, Ke Zhang, Baorong He, Xinliang Zhang*, Lingbo Kong*.

Journal Name: Current Stem Cell Research & Therapy

Volume 14 , Issue 3 , 2019

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Bone homeostasis is strictly regulated by balanced activity of bone-forming osteoblasts and bone-resorbing osteoclasts.Disruption of the balance of activity between osteoblasts and osteoclasts leads to various metabolic bone diseases. Osteoclasts are cells of hematopoietic origin that they are large, multinucleated cells formed by the fusion of precursor cells of monocyte/macrophage lineage, they are unique cells that degrade the bone matrix, activation of transcription factors nuclear factoractivated T cells c1 (NFATc1) is required for sufficient osteoclast differentiation and it plays the role of a master transcription regulator of osteoclast differentiation, meanwhile, NFATc1 could be employed to elicit anabolic effects on bone. In this review, we have summarized the various mechanisms that control NFATc1 regulation during osteoclast and osteoblast differentiation as well as a new strategy for promoting bone regeneration in osteopenic disease.

Keywords: Nuclear factor of activated T-cells cytoplasmic 1, PU.1, CCAAT/enhancer binding protein α CaMK, calcineurin, bone cell homeostasis, in-vivo.

Xu S, Shu P, Zou S, et al. NFATc1 is a tumor suppressor in hepatocellular carcinoma and induces tumor cell apoptosis by activating the FasL-mediated extrinsic signaling pathway. Cancer Med 2018; 7(9): 4701-17.
Takayanagi H. The role of NFAT in osteoclast formation. Ann N Y Acad Sci 2007; 1116: 227-37.
Asagiri M, Sato K, Usami T, et al. Autoamplification of NFATc1 expression determines its essential role in bone homeostasis. J Exp Med 2005; 202(9): 1261-9.
Winslow MM, Pan M, Starbuck M, et al. Calcineurin/NFAT signaling in osteoblasts regulates bone mass. Dev Cell 2006; 10(6): 771-82.
Kim JH, Kim N. Regulation of NFATc1 in Osteoclast Differentiation. J Bone Metab 2014; 21(4): 233-41.
Klemsz MJ, McKercher SR, Celada A, et al. The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene. Cell 1990; 61(1): 113-24.
Kwon OH, Lee CK, Lee YI, et al. The hematopoietic transcription factor PU.1 regulates RANK gene expression in myeloid progenitors. Biochem Biophys Res Commun 2005; 335(2): 437-46.
Carey JO, Posekany KJ, deVente JE, et al. Phorbol ester-stimulated phosphorylation of PU.1: Association with leukemic cell growth inhibition. Blood 1996; 87(10): 4316-24.
Nutt SL, Metcalf D, D’Amico A, et al. Dynamic regulation of PU.1 expression in multipotent hematopoietic progenitors. J Exp Med 2005; 201(2): 221-31.
Carey HA, Hildreth BE III, Geisler JA, et al. Enhancer variants reveal a conserved transcription factor network governed by PU.1 during osteoclast differentiation. Bone Res 2018; 6: 8.
Ishiyama K, Yashiro T, Nakano N, et al. Involvement of PU.1 in NFATc1 promoter function in osteoclast development. Allergol Int 2015; 64(3): 241-7.
Matsumoto M, Kogawa M, Wada S, et al. Essential role of p38 mitogen-activated protein kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATc1 and PU.1. J Biol Chem 2004; 279(44): 45969-79.
Sharma SM, Bronisz A, Hu R, et al. MITF and PU.1 recruit p38 MAPK and NFATc1 to target genes during osteoclast differentiation. J Biol Chem 2007; 282(21): 15921-9.
Ishii J, Kitazawa R, Mori K, et al. Lipopolysaccharide suppresses RANK gene expression in macrophages by down-regulating PU.1 and MITF. J Cell Biochem 2008; 105(3): 896-904.
Ramji DP, Foka P. CCAAT/enhancer-binding proteins: structure, function and regulation. Biochem J 2002; 365(Pt 3): 561-75.
Landschulz WH, Johnson PF, Adashi EY, et al. Isolation of a recombinant copy of the gene encoding C/EBP. Genes Dev 1988; 2(7): 786-800.
Nerlov C. The C/EBP family of transcription factors: A paradigm for interaction between gene expression and proliferation control. Trends Cell Biol 2007; 17(7): 318-24.
Ye M, Zhang H, Amabile G, et al. C/EBPa controls acquisition and maintenance of adult haematopoietic stem cell quiescence. Nat Cell Biol 2013; 15(4): 385-94.
Ohlsson E, Schuster MB, Hasemann M, Porse BT. The multifaceted functions of C/EBPalpha in normal and malignant haematopoiesis. Leukemia 2016; 30(4): 767-75.
Jules J, Chen W, Feng X, Li YP. CCAAT/Enhancer-binding Protein alpha (C/EBPalpha) Is Important for Osteoclast Differentiation and Activity. J Biol Chem 2016; 291(31): 16390-403.
Grigoriadis AE, Wang ZQ, Cecchini MG, et al. c-Fos: A key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science 1994; 266(5184): 443-8.
Chen W, Zhu G, Tang J, et al. C/ebpalpha controls osteoclast terminal differentiation, activation, function, and postnatal bone homeostasis through direct regulation of Nfatc1. J Pathol 2018; 244(3): 271-82.
Chen W, Zhu G, Jules J, et al. Monocyte-Specific Knockout of C/ebpalpha Results in Osteopetrosis Phenotype, Blocks Bone Loss in Ovariectomized Mice, and Reveals an Important Function of C/ebpalpha in Osteoclast Differentiation and Function. J Bone Miner Res 2018; 33(4): 691-703.
Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003; 423(6937): 337-42.
Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet 2003; 4(8): 638-49.
Berridge MJ, Lipp P, Bootman MD. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 2000; 1(1): 11-21.
Soderling TR, Stull JT. Structure and regulation of calcium/calmodulin-dependent protein kinases. Chem Rev 2001; 101(8): 2341-52.
Sato K, Suematsu A, Nakashima T, et al. Regulation of osteoclast differentiation and function by the CaMK-CREB pathway. Nat Med 2006; 12(12): 1410-6.
Shinohara M, Takayanagi H. Novel osteoclast signaling mechanisms. Curr Osteoporos Rep 2007; 5(2): 67-72.
Kawamura H, Arai M, Togari A. Inhibitory effect of chlorpromazine on RANKL-induced osteoclastogenesis in mouse bone marrow cells. J Pharmacol Sci 2011; 117(1): 54-62.
Ho N, Liauw JA, Blaeser F, et al. Impaired synaptic plasticity and cAMP response element-binding protein activation in Ca2+/calmodulin-dependent protein kinase type IV/Gr-deficient mice. J Neurosci 2000; 20(17): 6459-72.
Negishi-Koga T, Takayanagi H. Ca2+-NFATc1 signaling is an essential axis of osteoclast differentiation. Immunol Rev 2009; 231(1): 241-56.
Seales EC, Micoli KJ, McDonald JM. Calmodulin is a critical regulator of osteoclastic differentiation, function, and survival. J Cell Biochem 2006; 97(1): 45-55.
Hogan PG, Chen L, Nardone J, Rao A. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev 2003; 17(18): 2205-32.
Chang EJ, Ha J, Huang H, et al. The JNK-dependent CaMK pathway restrains the reversion of committed cells during osteoclast differentiation. J Cell Sci 2008; 121(Pt 15): 2555-64.
Kim SD, Kim HN, Lee JH, et al. Trapidil, a platelet-derived growth factor antagonist, inhibits osteoclastogenesis by down-regulating NFATc1 and suppresses bone loss in mice. Biochem Pharmacol 2013; 86(6): 782-90.
Turnbull IR, Gilfillan S, Cella M, et al. Cutting edge: TREM-2 attenuates macrophage activation. J Immunol 2006; 177(6): 3520-4.
Hamerman JA, Jarjoura JR, Humphrey MB, et al. Cutting edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12. J Immunol 2006; 177(4): 2051-5.
Mocsai A, Humphrey MB, Van Ziffle JA, et al. The immunomodulatory adapter proteins DAP12 and Fc receptor gamma-chain (FcRgamma) regulate development of functional osteoclasts through the Syk tyrosine kinase. Proc Natl Acad Sci USA 2004; 101(16): 6158-63.
Mao D, Epple H, Uthgenannt B, et al. PLCgamma2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2. J Clin Invest 2006; 116(11): 2869-79.
Koga T, Inui M, Inoue K, et al. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 2004; 428(6984): 758-63.
Park-Min KH, Ji JD, Antoniv T, et al. IL-10 suppresses calcium-mediated costimulation of receptor activator NF-kappa B signaling during human osteoclast differentiation by inhibiting TREM-2 expression. J Immunol 2009; 183(4): 2444-55.
Awumey EM, Moonga BS, Sodam BR, et al. Molecular and functional evidence for calcineurin-A alpha and beta isoforms in the osteoclast: Novel insights into cyclosporin A action on bone resorption. Biochem Biophys Res Commun 1999; 254(1): 248-52.
Sun L, Moonga BS, Lu M, et al. Molecular cloning, expression, and function of osteoclastic calcineurin Aalpha. Am J Physiol Renal Physiol 2003; 284(3): F575-83.
Hirotani H, Tuohy NA, Woo JT, et al. The calcineurin/nuclear factor of activated T cells signaling pathway regulates osteoclastogenesis in RAW264.7 cells. J Biol Chem 2004; 279(14): 13984-92.
Song R, Li J, Zhang J, et al. Peptides derived from transcription factor EB bind to calcineurin at a similar region as the NFAT-type motif. Biochimie 2017; 142158-67.
Kuroda Y, Hisatsune C, Nakamura T, et al. Osteoblasts induce Ca2+ oscillation-independent NFATc1 activation during osteoclastogenesis. Proc Natl Acad Sci USA 2008; 105(25): 8643-8.
Takayanagi H, Kim S, Koga T, et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 2002; 3(6): 889-901.
Tomida T, Hirose K, Takizawa A, et al. NFAT functions as a working memory of Ca2+ signals in decoding Ca2+ oscillation. EMBO J 2003; 22(15): 3825-32.
Stern PH. The calcineurin-NFAT pathway and bone: intriguing new findings. Mol Interv 2006; 6(4): 193-6.

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Year: 2019
Page: [239 - 243]
Pages: 5
DOI: 10.2174/1574888X14666181205122729
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