Shikonin mitigates ovariectomy-induced bone loss and RANKL-induced osteoclastogenesis via TRAF6-mediated signaling pathways

Chen, Kai; Yan, Zijun; Wang, Yiran; Yang, Yilin; Cai, Mengxi; Chunyou, Huang; Li, Bo; Yang, Mingyuan; Zhou, Xin; Wei, Xianzhao; Yang, Chen; Chen, Ziqiang; Zhai, Xiaofeng; Li, Ming

doi:10.1016/j.biopha.2020.110067

Cited by 20 publications

(10 citation statements)

References 38 publications

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“…At the molecular level, OVX induces RANKL, the total protein level of p65, and the phosphorylation of p65 and IκB-α mainly in the osteoclasts of the mandible, which presumably enhance differentiation of osteoclasts and in turn the loss of bone mass. 50–52 The counteraction of ZOL on OVX-caused bone mass loss may be mechanistically attributed, in part, to its inhibition of the OVX-caused activation of the RANKL-NF-κB signalling pathway that leads to enhanced differentiation of osteoclasts. 24,28,34 It cannot be excluded that the increase in the number of apoptotic osteoblasts in the OVX group and the decrease in the number of apoptotic osteoblasts in the ZOL group also involve the same molecular mechanism.…”

Section: Discussionmentioning

confidence: 99%

Zoledronic acid modulates osteoclast apoptosis through activation of the NF-κB signaling pathway in ovariectomized rats

Cheng

Liao

Zhou

et al. 2021

Exp Biol Med (Maywood)

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Bone mass loss (osteoporosis) seen in postmenopausal women is an adverse factor for implant denture. Using an ovariectomized rat model, we studied the mechanism of estrogen-deficiency-caused bone loss and the therapeutic effect of Zoledronic acid. We observed that ovariectomized-caused resorption of bone tissue in the mandible was evident at four weeks and had not fully recovered by 12 weeks post-ovariectomized compared with the sham-operated controls. Further evaluation with a TUNEL assay showed ovariectomized enhanced apoptosis of osteoblasts but inhibited apoptosis of osteoclasts in the mandible. Zoledronic acid given subcutaneously as a single low dose was shown to counteract both of these ovariectomized effects. Immunohistochemical staining showed that ovariectomized induced the protein levels of RANKL and the 65-kD subunit of the NF-κB complex mainly in osteoclasts, as confirmed by staining for TRAP, a marker for osteoclasts, whereas zoledronic acid inhibited these inductions. Western blotting showed that the levels of RANKL, p65, as well as the phosphorylated form of p65, and IκB-α were all higher in the ovariectomized group than in the sham and ovariectomized + zoledronic acid groups at both the 4th- and 12th-week time points in the mandible. These data collectively suggest that ovariectomized causes bone mass loss by enhancing apoptosis of osteoblasts and inhibiting apoptosis of osteoclasts. In osteoclasts, these cellular effects may be achieved by activating RANKL-NF-κB signalling. Moreover, zoledronic acid elicits its therapeutic effects in the mandible by counteracting these cellular and molecular consequences of ovariectomized.

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Section: Discussionmentioning

confidence: 99%

Zoledronic acid modulates osteoclast apoptosis through activation of the NF-κB signaling pathway in ovariectomized rats

Cheng

Liao

Zhou

et al. 2021

Exp Biol Med (Maywood)

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“…This indicates that both JNK and ERK1/2 can be involved in active FGF23 increase in starved MLO-Y4 cells and suggests that the effect of 17β-E2, in maintaining FGF23 levels at the control values, is due to its ability to inhibit these kinases and/or factors downstream from their signaling pathway. Nuclear factor kappa B (NF-κB) is one of the transcription factors activated by ERK1/2 and involved in bone loss following estrogen withdrawal and in FGF23 regulation [46][47][48][49]. The activation of NF-κB is due to the phosphorylation of the IKK kinase, which phosphorylates and inhibits IKB-α, the endogenous inhibitor of NF-κB, by promoting its degradation.…”

Section: Role Of Map Kinases On Osia-induced Intra-and Extracellular ...mentioning

confidence: 99%

Effect of Oxidative Stress-Induced Apoptosis on Active FGF23 Levels in MLO-Y4 Cells: The Protective Role of 17-β-Estradiol

Domazetovic

Falsetti

Ciuffi

et al. 2022

IJMS

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The discovery that osteocytes secrete phosphaturic fibroblast growth factor 23 (FGF23) has defined bone as an endocrine organ. However, the autocrine and paracrine functions of FGF23 are still unknown. The present study focuses on the cellular and molecular mechanisms involved in the complex control of FGF23 production and local bone remodeling functions. FGF23 was assayed using ELISA kit in the presence or absence of 17β–estradiol in starved MLO-Y4 osteocytes. In these cells, a relationship between oxidative stress-induced apoptosis and up-regulation of active FGF23 levels due to MAP Kinases activation with involvement of the transcriptional factor (NF-kB) has been demonstrated. The active FGF23 increase can be due to up-regulation of its expression and post-transcriptional modifications. 17β–estradiol prevents the increase of FGF23 by inhibiting JNK and NF-kB activation, osteocyte apoptosis and by the down-regulation of osteoclastogenic factors, such as sclerostin. No alteration in the levels of dentin matrix protein 1, a FGF23 negative regulator, has been determined. The results of this study identify biological targets on which drugs and estrogen may act to control active FGF23 levels in oxidative stress-related bone and non-bone inflammatory diseases.

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“…Shikonin is a bioactive constituent of traditional Chinese herbs. Chen et al found that shikonin can prevent the interaction of TRAF6 and RANK [101]. Nodakenin, a coumarin isolated from the roots of Angelica gigas, prevents NF-κB activation by interfering with the activation of TRAF6 in macrophages [102].…”

Section: Targeting Traf6 Antagonist Researchmentioning

confidence: 99%

The relationship between TRAF6 and tumors

Liu

Tang

et al. 2020

Cancer Cell Int

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Tumor necrosis factor receptor (TNFR)-related factors (TRAFs) are important linker molecules in the tumor necrosis factor superfamily (TNFSF) and the Toll-like/interleukin-1 receptor (TLR/ILR) superfamily. There are seven members: TRAF1-TRAF7, among those members, tumor necrosis factor receptor-associated factor 6 (TRAF6) is upregulated in various tumors, which has been related to tumorigenesis and development. With the in-depth study of the relationship between TRAF6 and different types of tumors, TRAF6 has oncogenic characteristics involved in tumorigenesis, tumor development, invasion, and metastasis through various signaling pathways, therefore, targeting TRAF6 has provided a novel strategy for tumor treatment. This review summarizes and analyzes the role of TRAF6 in tumorigenesis and tumor development in combination with the current research on TRAF6 and tumors.

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Shikonin mitigates ovariectomy-induced bone loss and RANKL-induced osteoclastogenesis via TRAF6-mediated signaling pathways

Cited by 20 publications

References 38 publications

Zoledronic acid modulates osteoclast apoptosis through activation of the NF-κB signaling pathway in ovariectomized rats

Zoledronic acid modulates osteoclast apoptosis through activation of the NF-κB signaling pathway in ovariectomized rats

Effect of Oxidative Stress-Induced Apoptosis on Active FGF23 Levels in MLO-Y4 Cells: The Protective Role of 17-β-Estradiol

The relationship between TRAF6 and tumors

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