The small molecule harmine regulates NFATc1 and Id2 expression in osteoclast progenitor cells

Egusa, Hiroshi; Doi, Miwako; Saeki, Makio; Fukuyasu, Sho; Akashi, Yoshihiro; Yokota, Yoshifumi; Yatani, Hirofumi; Kamisaki, Yoshínori

doi:10.1016/j.bone.2011.04.003

Cited by 41 publications

(35 citation statements)

References 40 publications

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“…5B) in þ/R740S versus þ/þ osteoclasts at day 6 of culture. Protein expression of dual-specificity tyrosine-phosphorylationregulated kinase 1A (DYRK1A), one of the kinases responsible for phosphorylation of NFATc1, (22,23) was also not affected in þ/R740S osteoclasts (Fig. 5B).…”

Section: Resultsmentioning

confidence: 98%

The R740S mutation in the V-ATPase a3 subunit increases lysosomal pH, impairs NFATc1 translocation, and decreases in vitro osteoclastogenesis

Voronov

Ochotny

Jaumouillé

et al. 2012

Journal of Bone and Mineral Research

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Vacuolar Hþ -ATPase (V-ATPase), a multisubunit enzyme located at the ruffled border and in lysosomes of osteoclasts, is necessary for bone resorption. We previously showed that heterozygous mice with an R740S mutation in the a3 subunit of V-ATPase (þ/R740S) have mild osteopetrosis resulting from an $90% reduction in proton translocation across osteoclast membranes. Here we show that lysosomal pH is also higher in þ/R740S compared with wild-type (þ/þ) osteoclasts. Both osteoclast number and size were decreased in cultures of þ/R740S compared with þ/þ bone marrow cells, with concomitant decreased expression of key osteoclast markers (TRAP, cathepsin K, OSCAR, DC-STAMP, and NFATc1), suggesting that low lysosomal pH plays an important role in osteoclastogenesis. To elucidate the molecular mechanism of this inhibition, NFATc1 activation was assessed. NFATc1 nuclear translocation was significantly reduced in þ/R740S compared with þ/þ cells; however, this was not because of impaired enzymatic activity of calcineurin, the phosphatase responsible for NFATc1 dephosphorylation. Protein and RNA expression levels of regulator of calcineurin 1 (RCAN1), an endogenous inhibitor of NFATc1 activation and a protein degraded in lysosomes, were not significantly different between þ/R740S and þ/þ osteoclasts, but the RCAN1/NFATc1 ratio was significantly higher in þ/R740S versus þ/þ cells. The lysosomal inhibitor chloroquine significantly increased RCAN1 accumulation in þ/þ cells, consistent with the hypothesis that higher lysosomal pH impairs RCAN1 degradation, leading to a higher RCAN1/NFATc1 ratio and consequently NFATc1 inhibition. Our data indicate that increased lysosomal pH in osteoclasts leads to decreased NFATc1 signaling and nuclear translocation, resulting in a cell autonomous impairment of osteoclastogenesis in vitro. ß

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Section: Resultsmentioning

confidence: 98%

The R740S mutation in the V-ATPase a3 subunit increases lysosomal pH, impairs NFATc1 translocation, and decreases in vitro osteoclastogenesis

Voronov

Ochotny

Jaumouillé

et al. 2012

Journal of Bone and Mineral Research

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“…Several genes up-regulated by DYRK1A depletion were targets of transcription factors negatively regulated by DYRK1A-mediated phosphorylation [14][15][16], including the nuclear factor of activated T cells (NFAT) targets EGR2 [17] and ID2 [18], and the p53 target BTG2 [19]. Genes down-regulated by DYRK1A depletion were largely inducible genes involved in cellular responses to stimuli and immune system processes ( Supplementary Fig S2B).…”

Section: Dyrk1a Shares Target Genes With Hp1 Proteinsmentioning

confidence: 99%

DYRK1A phoshorylates histone H3 to differentially regulate the binding of HP1 isoforms and antagonize HP1‐mediated transcriptional repression

et al. 2014

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Heterochromatin protein 1 (HP1) proteins are chromatin-bound transcriptional regulators. While their chromodomain binds histone H3 methylated on lysine 9, their chromoshadow domain associates with the H3 histone fold in a region involved in chromatin remodeling. Here, we show that phosphorylation at histone H3 threonine 45 and serine 57 within this latter region differentially affects binding of the three mammalian HP1 isoforms HP1a, HP1b and HP1c. Both phosphorylation events are dependent on the activity of the DYRK1A kinase that antagonizes HP1-mediated transcriptional repression and participates in abnormal activation of cytokine genes in Downs syndrome-associated megakaryoblastic leukemia.

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“…Harmine is a highly potent inhibitor of dual-specificity tyrosine-phosphorylation regulated kinase (DYRK) [1] . Harmine has been reported to have antidepressantlike actions in rodents [2] .…”

Section: Pharmacological Evidence Of Harminementioning

confidence: 99%

“…Harmine is widely distributed in nature, such as in various plants, marine creatures, insects, mammalians, human tissues and body fluids. Harmine have antimicrobial, antiplasmodial, antifungal, antioxidative, antitumor, antimutagenic, cytotoxic and hallucinogenic properties [1][2][3][4][5][6][7] . Beta-carboline compounds act as inverse agonists at the benzodiazepine site of the gammaaminobutyric acid type A receptors and have actions entirely opposite to those of the anxiolytic benzodiazepines.…”

Section: Introductionmentioning

confidence: 99%

A review on medicinal importance, pharmacological activity and bioanalytical aspects of beta-carboline alkaloid “Harmine”

Patel

Gadewar

Tripathi

et al. 2012

Asian Pacific Journal of Tropical Biomedicine

218

120

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The small molecule harmine regulates NFATc1 and Id2 expression in osteoclast progenitor cells

Cited by 41 publications

References 40 publications

The R740S mutation in the V-ATPase a3 subunit increases lysosomal pH, impairs NFATc1 translocation, and decreases in vitro osteoclastogenesis

The R740S mutation in the V-ATPase a3 subunit increases lysosomal pH, impairs NFATc1 translocation, and decreases in vitro osteoclastogenesis

DYRK1A phoshorylates histone H3 to differentially regulate the binding of HP1 isoforms and antagonize HP1‐mediated transcriptional repression

A review on medicinal importance, pharmacological activity and bioanalytical aspects of beta-carboline alkaloid “Harmine”

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