Skullcapflavone II inhibits osteoclastogenesis by regulating reactive oxygen species and attenuates the survival and resorption function of osteoclasts by modulating integrin signaling

Lee, Jiae; Son, Han Saem; Lee, Hyein; Lee, Gong-Rak; Jo, You-Jin; Hong, Seong-Eun; Kim, Na-Rae; Kwon, Minjeong; Kim, Nam Young; Kim, Hyun Jin; Lee, Yoo Jin; Seo, Eun Kyoung; Jeong, Woojin

doi:10.1096/fj.201800866rr

Cited by 25 publications

(24 citation statements)

References 56 publications

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“…The cDNA was amplified in a reaction mixture containing SYBR Green PCR Master Mix (Bioline, Taunton, MA, USA) and 1 M genespecific primer using a StepOnePlus real-time PCR (Applied Biosystems, Foster City, CA, USA) as previously described (28). The primers used in the current study that were not used in the previous report (25,29) were as follows: Il1b (5'-CTGGTGTG TGACGTTCCCATTA-3' and 5'-CCGACAGCGAGGCTTT-3'), Ccl3 (5'-ACCATTGCTCAGGATTATGGA-3' and 5'-GGGGTTCCTC GCTGCCTCCA-3') and Prdx1 (5'-ACCATTGCTCAGGATTATG GA-3' and 5'-CAACGGGAAGATCGTTTATTG-3'). Each mRNA level was normalized to the actin level.…”

Section: Quantification Of Gene Expressionmentioning

confidence: 99%

Dehydrocostus lactone inhibits NFATc1 via regulation of IKK, JNK, and Nrf2, thereby attenuating osteoclastogenesis

Lee

et al. 2020

BMB Rep.

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Excessive and hyperactive osteoclast activity causes bone diseases such as osteoporosis and periodontitis. Thus, the regulation of osteoclast differentiation has clinical implications. We recently reported that dehydrocostus lactone (DL) inhibits osteoclast differentiation by regulating a nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), but the underlying mechanism remains to be elucidated. Here we demonstrated that DL inhibits NFATc1 by regulating nuclear factor-B (NF-B), activator protein-1 (AP-1), and nuclear factor-erythroid 2related factor 2 (Nrf2). DL attenuated IB phosphorylation and p65 nuclear translocation as well as decreased the expression of NF-B target genes and c-Fos. It also inhibited c-Jun N-terminal kinase (JNK) but not p38 or extracellular signalregulated kinase. The reporter assay revealed that DL inhibits NF-B and AP-1 activation. In addition, DL reduced reactive oxygen species either by scavenging them or by activating Nrf2. The DL inhibition of NFATc1 expression and osteoclast differentiation was less effective in Nrf2-deficient cells. Collectively, these results suggest that DL regulates NFATc1 by inhibiting NF-B and AP-1 via down-regulation of IB kinase and JNK as well as by activating Nrf2, and thereby attenuates osteoclast differentiation. [

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Section: Quantification Of Gene Expressionmentioning

confidence: 99%

Dehydrocostus lactone inhibits NFATc1 via regulation of IKK, JNK, and Nrf2, thereby attenuating osteoclastogenesis

Lee

et al. 2020

BMB Rep.

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“…Each mRNA level was normalized to the actin level. The unique primers used in the current study that were not used in the previous report (34,36)…”

Section: Quantification Of Gene Expressionmentioning

confidence: 99%

Dehydrocostus lactone suppresses osteoclast differentiation by regulating NFATc1 and inhibits osteoclast activation through modulating migration and lysosome function

Lee

Hwang

et al. 2019

FASEB j.

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Excessive osteoclast activity can lead to an imbalance between the synthesis and breakdown of bone, with pathologic consequences that include osteoporosis and periodontitis. Thus, controlling osteoclast differentiation and function has significant therapeutic implications. In this study, we investigated the effects of dehydrocostus lactone (DL) on osteoclast differentiation and activation and elucidated the possible mechanisms underlying these processes. DL suppressed osteoclast differentiation by reducing the expression of the nuclear factor of activated T‐cells, cytoplasmic 1. When used to challenge differentiated osteoclasts, DL also effectively inhibited their enlargement and resorption activity, and biochemical approaches revealed that DL attenuates osteoclast activation by inhibiting the migration and lysosome biogenesis and secretion via the down‐regulation of integrin β3, PKC‐β, and autophagy related 5 expression. Furthermore, DL prevented bone destruction in inflammation‐ and ovariectomy‐induced osteolytic mouse models. These results indicate that DL has therapeutic potential to treat bone diseases caused by excessive or hyperactive osteoclasts.—Lee, H. I., Lee, J., Hwang, D., Lee, G.‐R., Kim, N., Kwon, M., Lee, H., Piao, D., Kim, H. J., Kim, N. Y., Kim, H. S., Seo, E. K., Kang, D., Jeong, W. Dehydrocostus lactone suppresses osteoclast differentiation by regulating NFATc1 and inhibits osteoclast activation through modulating migration and lysosome function. FASEB J. 33, 9685–9694 (2019). http://www.fasebj.org

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“…Furthermore, the role of Nrf2 in osteoclastogenesis has been investigated, and its deficiency was found to induce osteoclastogenesis (9). Chemicals that activate Nrf2 have also been investigated for their effects on the suppression of osteoclastogenesis (16).…”

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Octyl itaconate inhibits osteoclastogenesis by suppressing Hrd1 and activating Nrf2 signaling

Sun

Zhang²,

Pan

et al. 2019

The FASEB Journal

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The endogenous metabolite itaconate has emerged as a regulator of macrophage function that limits inflammation. However, its effect on cell differentiation and osteoclast‐related diseases is unclear. Here, for the first time, we explored the effect of itaconate and its cell‐permeable itaconate derivative, 4‐octyl itaconate (OI) on osteoclast differentiation in vitro and in vivo. Firstly, we demonstrated that itaconate concentration was lower in estrogen‐deficient mice. OI released itaconate and induced the expression of nuclear factor–erythroid 2–related factor 2 (Nrf2) in bone marrow–derived macrophages during osteoclastogenesis. Furthermore, OI significantly suppressed the early, middle, and late stages of osteoclastogenesis induced by receptor activator of NF‐αB ligand in vitro, as confirmed by tartrate‐resistant acid phosphatase staining. Moreover, it significantly inhibited fibrous actin ring formation and bone resorption in vitro. Mechanistically, we observed that OI enhanced Nrf2 expression by suppressing its association with ubiquitin via inhibition of the E3 ubiquitin ligase (Hrd1). OI also inhibited LPS‐induced the reactive oxygen species and inflammatory responses via Hrd1. An estrogen deficiency (via ovariectomy)–induced osteoporosis model was also established. Here, on micro‐computed tomography and histologic analysis showed that OI effectively suppressed ovariectomy‐induced bone loss. In summary, OI, an itaconate derivative, can inhibit osteoclastogenesis in vitro and in vivo, indicating that OI could be a potential drug to treat osteoclast‐related diseases; our results also link itaconate to the development of osteoporosis.—Sun, X., Zhang, B., Pan, X., Huang, H., Xie, Z., Ma, Y., Hu, B., Wang, J., Chen, Z., Shi, P. Octyl itaconate inhibits osteoclastogenesis by suppressing Hrd1 and activating Nrf2 signaling. FASEB J. 33, 12929–12940 (2019). http://www.fasebj.org

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Skullcapflavone II inhibits osteoclastogenesis by regulating reactive oxygen species and attenuates the survival and resorption function of osteoclasts by modulating integrin signaling

Cited by 25 publications

References 56 publications

Dehydrocostus lactone inhibits NFATc1 via regulation of IKK, JNK, and Nrf2, thereby attenuating osteoclastogenesis

Dehydrocostus lactone inhibits NFATc1 via regulation of IKK, JNK, and Nrf2, thereby attenuating osteoclastogenesis

Dehydrocostus lactone suppresses osteoclast differentiation by regulating NFATc1 and inhibits osteoclast activation through modulating migration and lysosome function

Octyl itaconate inhibits osteoclastogenesis by suppressing Hrd1 and activating Nrf2 signaling

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