NFATc1 regulation of the human β3 integrin promoter in osteoclast differentiation

Crotti, Tania; Flannery, Merrilee R.; Walsh, Nicole C.; Fleming, Joseph D.; Goldring, Steven R.; McHugh, Kevin P.

doi:10.1016/j.gene.2005.12.012

Cited by 146 publications

(120 citation statements)

References 38 publications

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“…S4 A-E). Consistent with inhibition of Cn, CsA treatment significantly decreased induction of the NFATc1-dependent integrin β3 gene (34,35) by TNF (Fig. S4B).…”

Section: Tnf Triggers a Differentiation Program In Human Macrophages Viasupporting

confidence: 62%

TNF activates calcium–nuclear factor of activated T cells (NFAT)c1 signaling pathways in human macrophages

Yarilina

Chen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

116

122

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Acute activation of cells by tumor necrosis factor (TNF) has been well characterized, but little is known about later phases of TNF responses that are relevant for cells exposed to TNF for several days during inflammation. We found that prolonged exposure of human macrophages to TNF resulted in a wave of delayed but sustained activation of c-Jun and nuclear factor κB (NF-κB) proteins and of calcium oscillations that became apparent 1-3 d after TNF stimulation. These signaling events culminated in the induction and activation of the calcium-dependent transcription factor, nuclear factor of activated T cells (NFAT)c1, which mediated a gene expression program leading to cell fusion and osteoclast differentiation. TNF-induced NFATc1 activity primed macrophages for enhanced osteoclastogenesis in response to RANKL. High NFATc1 expression was apparent in synovial macrophages in a subset of patients with TNF-driven inflammatory arthritis. Thus, long-term exposure to TNF activates calcium-dependent signaling and an NFATc1-mediated gene activation program important for cell fusion and osteoclastogenesis. These findings identify a signaling pathway activated by TNF that is important for myeloid cell differentiation and suggest a role for TNF-induced calcium and NFAT signaling in chronic inflammation and associated bone resorption.calcium signaling | polykaryon

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“…S4 A-E). Consistent with inhibition of Cn, CsA treatment significantly decreased induction of the NFATc1-dependent integrin β3 gene (34,35) by TNF (Fig. S4B).…”

Section: Tnf Triggers a Differentiation Program In Human Macrophages Viasupporting

confidence: 62%

TNF activates calcium–nuclear factor of activated T cells (NFAT)c1 signaling pathways in human macrophages

Yarilina

Chen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

116

122

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“…49,50) Our results indicated that, although tetrandrine had little effect on the initial induction of NFATc1 by sRANKL, it did inhibit the subsequent auto-amplification of NFATc1. All NFAT family members, including NFATc1, are mainly regulated by the serine/threonine phosphatase calcineurin, which is activated by intracellular Ca…”

Section: Discussionmentioning

confidence: 69%

Tetrandrine Prevents Bone Loss in Sciatic-Neurectomized Mice and Inhibits Receptor Activator of Nuclear Factor κB Ligand-Induced Osteoclast Differentiation

Takahashi

Tonami

Tachibana

et al. 2012

Biological & Pharmaceutical Bulletin

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One of the mediators of osteoclast differentiation is receptor activator of nuclear factor κB ligand (RANKL), which is produced by osteoblasts. Binding of RANKL to its receptor, RANK, activates several signaling pathways, including those involving mitogen-activated protein kinases (MAPKs), nuclear factor κB (NF-κB), nuclear factor of activated T cells c1 (NFATc1) and Ca 2 -calcineurin. In the present study, we found that tetrandrine, a bisbenzylisoquinoline alkaloid extracted from the root of Stephania tetrandra S. MOORE, significantly ameliorated the decrease of bone mass in sciatic-neurectomized osteoporosis model mice. It appears that tetrandrine acts directly on osteoclast precursors, since tetrandrine inhibited osteoclast differentiation not only in mouse bone marrow cells, but also in monocultures of murine macrophage RAW 264.7 cells without osteoblasts. Tetrandrine suppressed RANKL-induced amplification of NFATc1, a master regulator of osteoclast differentiation. However, it did not affect other signaling molecules such as MAPKs and NF-κB. These results suggest that tetrandrine is a candidate for the treatment of bone-destructive diseases, or at least a suitable lead compound for further development.Key words tetrandrine; osteoporosis; osteoclast; receptor activator of nuclear factor κB ligand; nuclear factor of activated T cell c1Bone remodeling is a physiological process that involves resorption of bone by osteoclasts and synthesis of bone matrix by osteoblasts.1) A relative increase of bone resorption over bone formation can result in osteoporosis, one of the most prevalent diseases in the aged population.2,3) Osteoclasts are known to be formed by the fusion of hematopoietic cells of the monocyte-macrophage lineage during the early stage of the differentiation process.4) Terminal differentiation in this lineage is characterized by acquisition of mature phenotypic markers, such as expression of tartrate-resistant acid phosphatase (TRAP), calcitonin receptor, matrix metalloproteinase 9 (MMP9), and cathepsin K, as well as morphological conversion into large multinucleated cells and formation of resorption lacunae on bone. 5-7)The essential signaling molecules for osteoclast differentiation include receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF), and both of them are produced by osteoblasts. 8)RANKL induces the signaling essential for precursor cells to differentiate into osteoclasts, 9) whereas M-CSF provides the survival signal for these cells.10) RANKL binding to RANK, a receptor of RANKL that is expressed in osteoclast precursors, mediates the biological effects of RANKL and leads to the recruitment of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), which in turn results in the activation of the downstream signaling pathway, including nuclear factor κB (NF-κB), c-Jun N-terminal protein kinase (JNK), p38, extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase/AKT. [11][12][13][14] RANKL activation of JNK ph...

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“…Because NFATc1 as an upstream transcription factor to regulate integrin b3 expression, DICAMmediated inhibition of integrin b3 expression may be due to delayed osteoclast differentiation. (27,28) However, we cannot rule out the possibility of accelerated endocytosis and degradation of integrin b3 by DICAM. More studies are needed to understand the precise molecular mechanism of DICAM's gene expression during osteoclastogenesis.…”

Section: Discussionmentioning

confidence: 94%

DICAM inhibits osteoclast differentiation through attenuation of the integrin αVβ3 pathway

Jung

Han

Kim

et al. 2012

Journal of Bone and Mineral Research

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Dual immunoglobulin (Ig) domain-containing adhesion molecule (DICAM) is involved in cell-cell adhesion through a heterophilic interaction with aVb3 integrin, which suggests that DICAM may participate in osteoclast differentiation. DICAM was localized in the plasma membrane of RAW264.7 and THP-1 cells, and its expression gradually increased during osteoclastogenesis in mouse bone marrow-derived macrophages (BMMs) treated with receptor activator of nuclear factor k-B ligand (RANKL) and macrophage colonystimulating factor (M-CSF). Forced expression of DICAM in BMMs and RAW264.7 cells blocked the generation of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts. Conversely, knockdown of DICAM by small hairpin RNA (shRNA) increased osteoclast formation in RAW264.7 cells. DICAM-mediated suppression of osteoclast differentiation was in part due to the inhibition of the p38 mitogenactivated protein (MAP) kinase pathway, which was corroborated by a decrease in the expression of c-Fos and nuclear factor of activated T cells (NFAT)c1. Mechanistically, DICAM directly interacted with integrin b3, which inhibited heterodimerization between integrin aV and b3. Exogenous expression of integrin b3 or high-dose M-CSF rescued DICAM-mediated inhibition of osteoclastogenesis, suggesting crosstalk between the integrin b3 and c-Fms pathways. Finally, recombinant DICAM ectodomain suppressed the RANKL-and M-CSFinduced osteoclastogenesis of BMMs. Collectively, these results indicate that DICAM acts as a negative regulator of osteoclast differentiation by suppressing the integrin aVb3 pathway. ß

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NFATc1 regulation of the human β3 integrin promoter in osteoclast differentiation

Cited by 146 publications

References 38 publications

TNF activates calcium–nuclear factor of activated T cells (NFAT)c1 signaling pathways in human macrophages

TNF activates calcium–nuclear factor of activated T cells (NFAT)c1 signaling pathways in human macrophages

Tetrandrine Prevents Bone Loss in Sciatic-Neurectomized Mice and Inhibits Receptor Activator of Nuclear Factor κB Ligand-Induced Osteoclast Differentiation

DICAM inhibits osteoclast differentiation through attenuation of the integrin αVβ3 pathway

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