Osteomyelosclerosis, anemia and extramedullary hematopoiesis in mice lacking the transcription factor NFATc2

Bauer, Wolfgang; Rauner, Martina; Haase, Michael; Kujawski, Satu; Arabanian, Laleh S.; Habermann, Ivonne; Hofbauer, Lorenz C.; Ehninger, Gerhard; Kiani, Alexander

doi:10.3324/haematol.2011.042515

Cited by 19 publications

(24 citation statements)

References 40 publications

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“…However, NFATc2 −/− mice have been reported to have an enhanced TH 2 immune response [58], reduced muscle growth [59], dysfunctional chondrogenesis [60], and osteoarthritis [61]. In addition, it appears that aged NFATc2 −/− mice can develop anemia and lymphocytosis as well [62]. Therefore, it is possible that long term complete inhibition of this NFAT isoform may have unwanted adverse effects.…”

Section: Discussionmentioning

confidence: 99%

NFATc2 Modulates Microglial Activation in the AβPP/PS1 Mouse Model of Alzheimer’s Disease

Manocha

Ghatak

Puig

et al. 2017

JAD

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Alzheimer’s disease (AD) brains are characterized by fibrillar amyloid-β (Aβ) peptide containing plaques and associated reactive microglia. The proinflammatory phenotype of the microglia suggests that they may negatively affect disease course and contribute to behavioral decline. This hypothesis predicts that attenuating microglial activation may provide benefit against disease. Prior work from our laboratory and others has characterized a role for the transcription factor, nuclear factor of activated T cells (NFAT), in regulating microglial phenotype in response to different stimuli, including Aβ peptide. We observed that the NFATc2 isoform was the most highly expressed in murine microglia cultures, and inhibition or deletion of NFATc2 was sufficient to attenuate the ability of the microglia to secrete cytokines. In order to determine whether the NFATc2 isoform, in particular, was a valid immunomodulatory target in vivo, we crossed an NFATc2−/− line to a well-known AD mouse model, an AβPP/PS1 mouse line. As expected, the AβPP/PS1 × NFATc2−/− mice had attenuated cytokine levels compared to AβPP/PS1 mice as well as reduced microgliosis and astrogliosis with no effect on plaque load. Although some species differences in relative isoform expression may exist between murine and human microglia, it appears that microglial NFAT activity is a viable target for modulating the proinflammatory changes that occur during AD.

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Section: Discussionmentioning

confidence: 99%

NFATc2 Modulates Microglial Activation in the AβPP/PS1 Mouse Model of Alzheimer’s Disease

Manocha

Ghatak

Puig

et al. 2017

JAD

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“…NFAT is an essential transcription factor for the expression of various genes, but it is relatively unknown how NFAT activation in osteoblasts affects the hematopoietic niche in the bone marrow microenvironment. It has been shown that NFATc2 −/− mice (C57BL/6 background) exhibit increased bone formation and decreased populations of granulocytes, lymphocytes, and megakaryocytes in the bone marrow [30]; however, this NFAT knockout mouse model was not an osteoblast specific model. To determine whether inhibition of NFAT activation specifically in osteoblasts regulates hematopoiesis in the bone marrow microenvironment, we generated a mouse model expressing dominant-negative NFAT driven by a 2.3 kb fragment of the collagen α I promoter to inhibit the transactivation of NFAT 1–4 isoforms in osteoblasts [25].…”

Section: Discussionmentioning

confidence: 99%

“…The role of NFAT in cellular interactions between osteoblasts and hematopoietic lineage cells in the bone microenvironment is relatively unknown. Studies have examined NFAT signaling in the bone microenvironment using animal models that have global NFAT inhibition or by the inhibition of NFAT activity exclusively in hematopoietic cells [30, 33]. It has been shown that adult NFATc2 knockout mice exhibit extramedullary hematopoiesis and suffer from osteomyelosclerosis and hypoplasia in the bone marrow (with significant losses of erythrocytes, lymphocytes, and megakaryocytes) [30].…”

Section: Discussionmentioning

confidence: 99%

“…Studies have examined NFAT signaling in the bone microenvironment using animal models that have global NFAT inhibition or by the inhibition of NFAT activity exclusively in hematopoietic cells [30, 33]. It has been shown that adult NFATc2 knockout mice exhibit extramedullary hematopoiesis and suffer from osteomyelosclerosis and hypoplasia in the bone marrow (with significant losses of erythrocytes, lymphocytes, and megakaryocytes) [30]. Others have reported that repression of NFAT signaling in HSCs negatively regulates the development of myeloid progenitor cells [33].…”

Section: Discussionmentioning

confidence: 99%

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NFAT Signaling in Osteoblasts Regulates the Hematopoietic Niche in the Bone Microenvironment

Sesler

Zayzafoon

2013

Clinical and Developmental Immunology

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Osteoblasts support hematopoietic cell development, including B lymphopoiesis. We have previously shown that the nuclear factor of activated T cells (NFAT) negatively regulates osteoblast differentiation and bone formation. Interestingly, in smooth muscle, NFAT has been shown to regulate the expression of vascular cellular adhesion molecule-1 (VCAM-1), a mediator of cell adhesion and signaling during leukocyte development. To examine whether NFAT signaling in osteoblasts regulates hematopoietic development in vivo, we generated a mouse model expressing dominant-negative NFAT driven by the 2.3 kb fragment of the collagen-αI promoter to disrupt NFAT activity in osteoblasts (dnNFATOB). Bone histomorphometry showed that dnNFATOB mice have significant increases in bone volume (44%) and mineral apposition rate (131%) and decreased trabecular thickness (18%). In the bone microenvironment, dnNFATOB mice displayed a significant increase (87%) in Lineage−cKit+Sca-1+ (LSK) cells and significant decreases in B220+CD19−IgM− pre-pro-B cells (41%) and B220+CD19+IgM+ immature B cells (40%). Concurrent with these findings, LSK cell differentiation into B220+ cells was inhibited when cocultured on differentiated primary osteoblasts harvested from dnNFATOB mice. Gene expression and protein levels of VCAM-1 in osteoblasts decreased in dnNFATOB mice compared to controls. These data suggest that osteoblast-specific NFAT activity mediates early B lymphopoiesis, possibly by regulating VCAM-1 expression on osteoblasts.

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“…The role of NFAT1 in hematopoiesis has been demonstrated only recently. 101 Kiani et al have shown that NFAT is expressed during HSC differentiation toward megakaryocytes, whereas differentiation toward granulocytes and erythroid cells does not require NFAT expression. 10,102 Lack of NFAT leads to erythropenia, reduced numbers of hematopoietic progenitors, and later to reduced bone marrow hematopoiesis.…”

Section: Nfat Signaling Confers Innate Immune Protection and Regulatementioning

confidence: 99%

NFAT control of innate immunity

Frič

Zelante

Wong

et al. 2012

Blood

209

179

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Osteomyelosclerosis, anemia and extramedullary hematopoiesis in mice lacking the transcription factor NFATc2

Cited by 19 publications

References 40 publications

NFATc2 Modulates Microglial Activation in the AβPP/PS1 Mouse Model of Alzheimer’s Disease

NFATc2 Modulates Microglial Activation in the AβPP/PS1 Mouse Model of Alzheimer’s Disease

NFAT Signaling in Osteoblasts Regulates the Hematopoietic Niche in the Bone Microenvironment

NFAT control of innate immunity

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