Regulatory mechanism of NFATc1 in RANKL‐induced osteoclast activation

Song, In-Sun; Kim, Jung Ha; Kim, Kabsun; Jin, Hye-Mi; Youn, Bang Ung; Kim, Nacksung

doi:10.1016/j.febslet.2009.06.047

Cited by 138 publications

(128 citation statements)

References 31 publications

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“…It is possible that downregulation of cFos gene expression by AAT leads to a reduction of RANK expression on the cell surface. It has also been reported that RANKL-induced expression of NFATc1, a master regulator of osteoclast differentiation, is tightly regulated by cFos (42). In the present study, we observed a reduction of NFATc1 gene expression.…”

Section: Disclosuresupporting

confidence: 64%

α-1 Antitrypsin Inhibits RANKL-induced Osteoclast Formation and Functions

Akbar

Nardo

Chen

et al. 2017

Mol Med

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Osteoporosis is a global public health problem affecting more than 200 million people worldwide. We previously showed that treatment with α-1 antitrypsin (AAT), a multifunctional protein with antiinflammatory properties, mitigated bone loss in an ovariectomized mouse model. However, the underlying mechanisms of the protective effect of AAT on bone tissue are largely unknown. In this study, we investigated the effect of AAT on osteoclast formation and function in vitro. Our results showed that AAT dose-dependently inhibited the formation of receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclasts derived from mouse bone marrow macrophage/monocyte (BMM) lineage cells and the RAW 264.7 murine macrophage cell line. To elucidate the possible mechanisms underlying this inhibition, we tested the effect of AAT on the gene expression of cell surface molecules, transcription factors and cytokines associated with osteoclast formation. We showed that AAT inhibited macrophage colony-stimulating factor (M-CSF)-induced cell surface RANK expression in osteoclast precursor cells. In addition, AAT inhibited RANKL-induced TNF-α production, cell surface CD9 expression and dendritic cell-specific transmembrane protein (DC-STAMP) gene expression. Importantly, AAT treatment significantly inhibited osteoclast-associated mineral resorption. Together, these results uncover new mechanisms for the protective effects of AAT and strongly support the notion that AAT has therapeutic potential for the treatment of osteoporosis.

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Section: Disclosuresupporting

confidence: 64%

α-1 Antitrypsin Inhibits RANKL-induced Osteoclast Formation and Functions

Akbar

Nardo

Chen

et al. 2017

Mol Med

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“…The stimulatory effects of S100A8 cannot be explained by the induction of genes known to be important for the differentiation and function of osteoclasts, such as NF-ATc1 (29,30), DC-STAMP (31), TRAP (32), and cathepsin K (33), because their expression was not regulated by S100A8 stimulation. However, we did notice a marked change in the shape of the osteoclasts.…”

Section: Discussionmentioning

confidence: 99%

S100A8 enhances osteoclastic bone resorption in vitro through activation of Toll‐like receptor 4: Implications for bone destruction in murine antigen‐induced arthritis

Grevers¹,

Vries²,

Vogl³

et al. 2011

Arthritis & Rheumatism

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Objective. Rheumatoid arthritis, which is associated with elevated levels of S100A8 and S100A9, is characterized by severe bone erosions caused by enhanced osteoclast formation and activity. The aim of the present study was to investigate the role of S100A8 and S100A9 in osteoclastic bone destruction in murine antigen-induced arthritis (AIA).Methods. Bone destruction was analyzed in the arthritic knee joints of S100A9-deficient mice in which S100A8 protein expression was also lacking, and in wild-type (WT) controls. Osteoclast precursors from S100A9-deficient and WT mice were differentiated into osteoclasts in vitro. Additionally, precursors were stimulated with S100A8, S100A9, or S100A8/A9 during osteoclastogenesis. Receptor involvement was investigated using an anti-receptor for advanced glycation end products (anti-RAGE)-blocking antibody, soluble RAGE, or Toll-like receptor 4 (TLR-4)-deficient osteoclast precursors. The formation of osteoclasts and actin rings, the regulation of osteoclast markers, and bone resorption were analyzed.Results. Bone erosions and cathepsin K staining were significantly suppressed in S100A9-deficient mice after AIA induction. However, osteoclast precursors from S100A9-deficient mice developed normally into functional osteoclasts, which excludes a role for intrinsic S100A8/A9. In contrast to the results observed with S100A9 and S100A8/A9, the addition of S100A8 during osteoclastogenesis resulted in stimulation of osteoclast formation in conjunction with enhanced actin ring formation and increased bone resorption. Analysis of the putative receptor for S100A8 in osteoclastogenesis revealed that osteoclast differentiation and function could not be inhibited by blocking RAGE, whereas the increase in osteoclast numbers and enhanced bone resorption were completely abrogated using TLR-4-deficient osteoclast precursors.Conclusion. These results demonstrate that S100A8 stimulated osteoclast formation and activity and suggest that both S100A8 and TLR-4 are important factors in mediating osteoclastic bone destruction in experimental arthritis.Bone erosions are an important hallmark of rheumatoid arthritis (RA) and typically result from enhanced formation and activity of osteoclasts in affected joints. Osteoclasts originate from hematopoietic precursors of the monocyte/macrophage lineage that differentiate into multinucleated osteoclasts under the

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“…However, upon kahweol treatment, the protein levels of c-fms, NFATc1, and Src were decreased at 10 μM of kahweol. It is known that NFATc1 binds directly to the promoter regions of its target genes such as Src and cathepsin K and induces expression (22). To confirm the inhibition effects of kahweol on the expression of NFATc1, we further examined the expression levels of Src and cathepsin K in BMM-derived OCLs.…”

Section: Effects Of Kahweol On Intracellular Signaling and Expressionmentioning

confidence: 99%

The Coffee Diterpene Kahweol Prevents Osteoclastogenesis via Impairment of NFATc1 Expression and Blocking of Erk Phosphorylation

et al. 2012

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Abstract. Osteoclasts (OCLs) are multinucleated bone resorbing cells whose differentiation is regulated by receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colonystimulating factor (M-CSF). It is known that inflammatory cytokines and oxidative stress stimulate differentiation of OCLs. Here we evaluated the effects of kahweol, a coffee-specific diterpene, which has been reported to possess anti-oxidant and anti-inflammatory properties, on the differentiation of bone marrow-derived macrophages (BMMs) or murine monocytic cell line RAW-D cells into OCLs. Kahweol dose-dependently inhibited the formation of tartrate-resistant acid phosphatase staining-positive OCLs from both BMMs and RAW-D cells. In addition, kahweol prevented the bone resorbing activity of OCLs. Kahweol completely abolished RANKL-stimulated phosphorylation of extracellular signal-regulated kinase and impaired phosphorylation of Akt. Moreover, the protein levels of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), a master regulator for OCL differentiation; and OCL markers transcriptionally regulated by NFATc1 such as Src and cathepsin K were down-regulated by kahweol treatment. As one of the molecular mechanisms for the inhibitory effects of kahweol, we also showed that kahweol up-regulated heme oxygenase-1 and inhibited high mobility group box 1 release. Thus, kahweol in coffee is a useful constituent for inhibition of OCL differentiation.

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Regulatory mechanism of NFATc1 in RANKL‐induced osteoclast activation

Cited by 138 publications

References 31 publications

α-1 Antitrypsin Inhibits RANKL-induced Osteoclast Formation and Functions

α-1 Antitrypsin Inhibits RANKL-induced Osteoclast Formation and Functions

S100A8 enhances osteoclastic bone resorption in vitro through activation of Toll‐like receptor 4: Implications for bone destruction in murine antigen‐induced arthritis

The Coffee Diterpene Kahweol Prevents Osteoclastogenesis via Impairment of NFATc1 Expression and Blocking of Erk Phosphorylation

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