Pyrroloquinoline Quinine Inhibits RANKL-Mediated Expression of NFATc1 in Part via Suppression of c-Fos in Mouse Bone Marrow Cells and Inhibits Wear Particle-Induced Osteolysis in Mice

Kong, Lingbo; Yang, Ching Fen; Yu, Lifeng; Smith, Wanli W.; Zhu, Shu; Jun, Zhu; Zhu, Qing

doi:10.1371/journal.pone.0061013

Cited by 25 publications

(19 citation statements)

References 35 publications

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“…Besides, BMMs were prepared as described previously [16]. Briefly, RAW264.7 cells were cultured in DMEM, BMMs and MC-3T3-E1 cells were cultured in α-MEM.…”

Section: Methodsmentioning

confidence: 99%

Picrasidine I from Picrasma Quassioides Suppresses Osteoclastogenesis via Inhibition of RANKL Induced Signaling Pathways and Attenuation of ROS Production

Kong¹,

Wang²,

Yang³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Osteoporosis is a metabolic bone disorder that tortures about millions of people worldwide. Recent study demonstrated agents derived from picrasma quassioides is a promising drug for targets multiple signaling pathways. However its potential in treatment of bone loss has not been fully understood. Methods: The bone marrow macrophages (BMMs) were cultured and induced with M-CSF and RANKL followed by picrasidine I (PI) treatment. Then the effects of PI on osteoclast formation were evaluated by counting tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells. Moreover, effects of PI on bone resorption activity of mature osteoclast were studied through bone resorption pit counting and actin ring structure analysis. Further, the involved potential signaling pathways cross-talking were investigated by performed Western blotting and quantitative real-time PCR examination. Results: Results demonstrated PI strongly inhibited RANKL induced osteoclast formation from its precursors. Mechanistically, the inhibitory effect of PI on osteoclast differentiation was due to the suppression of osteoclastogenic transcription factors, c-Fos and NFATc1. Moreover, PI markedly blocked the RANKL-induced osteoclastogenesis by attenuating MAPKs and NF-κB signaling pathways. In addition, PI decreased the ROS generation in osteoclast and osteoblast. Conclusion: Taken together our data demonstrate that PI has antiosteoclastogenic effect by inhibiting inflammation induced activation of MAPKs, NF-κB and ROS generation followed by suppressing the gene expression of c-Fos and NFATc1 in osteoclast precursors.

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“…Besides, BMMs were prepared as described previously [16]. Briefly, RAW264.7 cells were cultured in DMEM, BMMs and MC-3T3-E1 cells were cultured in α-MEM.…”

Section: Methodsmentioning

confidence: 99%

Picrasidine I from Picrasma Quassioides Suppresses Osteoclastogenesis via Inhibition of RANKL Induced Signaling Pathways and Attenuation of ROS Production

Kong¹,

Wang²,

Yang³

et al. 2017

Cell Physiol Biochem

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“…Bone marrow cells (BMMs) were obtained as described previously [Kong et al, ]. Non‐adherent cells were collected and cultured for 3 days in the presence of M‐CSF (20 ng/mL).…”

Section: Methodsmentioning

confidence: 99%

Picroside II Inhibits RANKL‐Mediated Osteoclastogenesis by Attenuating the NF‐κB and MAPKs Signaling Pathway In Vitro and Prevents Bone Loss in Lipopolysaccharide Treatment Mice

Yang

Gao

Wang

et al. 2017

J of Cellular Biochemistry

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Picroside II, one of the major components isolated from the seed of natural plant picrorhiza, is widely used in traditional Chinese medicine. The present study was performed to define effects of picroside II on nuclear factor-kappaB ligand (RANKL)-stimulated osteoclast differentiation in vitro and on lipopolysaccharide (LPS)-induced bone loss in vivo. The bone marrow cells (BMMs) were harvested and induced with RANKL followed by treatment with picroside II at several doses, and the differentiation of osteoclasts from these cells was evaluated by tartrate-resistant acid phosphatase (TRAP) staining and resorption pit formation assay. The effects of picroside II on osteoclastogenesis were studied by examining RANKL-induced osteoclast F-actin ring formation and osteoclast bone resorption. Moreover, we explored the mechanisms of these downregulation effects by performed Western blotting and quantitative RT-PCR examination. Results demonstrated picroside II strongly inhibited RANKL-induced osteoclast formation when added during the early stage of BMMs cultures, suggesting that it acts on osteoclast precursors to inhibit RANKL/RANK signaling. Moreover, picroside II markedly decreased the phosphorylation of p38, ERK, JNK, p65, and I-κB degradation, and significantly suppressed c-Fos and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), both the key transcription factors during osteoclastogenesis. Furthermore, in vivo studies verified the bone protection effects of picroside II. These results collectively suggested that picroside II acted as an anti-resorption agent by blocking osteoclast activation. J. Cell. Biochem. 118: 4479-4486, 2017. © 2017 Wiley Periodicals, Inc.

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“…Simultaneously, the current methods of preventing and treating osteolysis are far from satisfactory. These drugs have so far remained at animal experiment stage and have not been approved for clinical use (13,14,18,51,(65)(66)(67)(68)(69)(70)(71)(72)(73). Therefore, understanding the failure mechanisms of primary joint replacements, especially the potential for prevention, is critical to reduce the expected joint replacement revision burden.…”

Section: Discussionmentioning

confidence: 99%

“…Considerable progress has been made in understanding the signaling pathways that integrate ER stress, apoptosis, inflammation, osteoclastogenesis, and the physiological significance of this connection. Recently, studies (13,14,18,51,(65)(66)(67)(68)(69)(70)(71)(72)(73) have been focused on designing effective therapy for inflammatory osteolysis by modulating the apoptotic, inflammatory, and osteoclastogenic responses. However, manipulating the interface between these fundamental biological responses for therapeutic purposes, without causing severe untoward effects, is a considerable challenge.…”

Section: Therapeutic Potential and Future Directionsmentioning

confidence: 99%

Apoptotic pathways of macrophages within osteolytic interface membrane in periprosthestic osteolysis after total hip replacement

Liu

Guo

Zhang

et al. 2017

APMIS

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Macrophage apoptosis in interface membrane, which occurs through either death receptor, mitochondrion, or endoplasmic reticulum (ER) stress pathways, has been suggested to play an important role in promoting osteolysis. However, how and why macrophage apoptosis originates and the correlation among these apoptotic pathways is not yet clear. The objective of this study was to identify the apoptotic mechanism of macrophages, and to explore the relationship between the apoptotic pathways and progression of osteolysis. Transmission electron microscopy (TEM) was utilized to analyze the tissue ultrastructure of wear particles, and in situ apoptotic macrophage identification was performed by TUNEL staining. We analyzed the expression of the key biomarkers of apoptotic pathways via immunohistochemistry and Western blotting. Our results demonstrated that the majority of wear particles within osteolytic interface membrane was in the 30-60 nm range, and that macrophage apoptotic ratio increased along with osteolysis progression. Normal hip dysplasia and mechanical loosening of tissues showed low expression levels of biomarkers for ER stress (Ca , JNK, cleaved Caspase-4, IRE1-α, Grp78/Bip, and CHOP), mitochondrion (Bcl-2, Bax, and Cytochrome c), and death receptor (Fas and cleaved Caspase-8) pathways, while osteolytic interface membrane tissues expressed high levels of these biomarkers. In addition, we found that the ER stress intensity was in complete conformity with mitochondrial dysfunction and was consistent with the results of death receptor activation. Thus, our findings suggested that wear particles generated at implant interface can accelerate macrophage apoptosis through changes in apoptotic pathways and ultimately aggravate the symptom of osteolysis. These data represent a preferential apoptotic signaling pathway of macrophages as specific target points for the prevention and therapeutic modulation of periprosthetic osteolysis.

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Pyrroloquinoline Quinine Inhibits RANKL-Mediated Expression of NFATc1 in Part via Suppression of c-Fos in Mouse Bone Marrow Cells and Inhibits Wear Particle-Induced Osteolysis in Mice

Cited by 25 publications

References 35 publications

Picrasidine I from Picrasma Quassioides Suppresses Osteoclastogenesis via Inhibition of RANKL Induced Signaling Pathways and Attenuation of ROS Production

Picrasidine I from Picrasma Quassioides Suppresses Osteoclastogenesis via Inhibition of RANKL Induced Signaling Pathways and Attenuation of ROS Production

Picroside II Inhibits RANKL‐Mediated Osteoclastogenesis by Attenuating the NF‐κB and MAPKs Signaling Pathway In Vitro and Prevents Bone Loss in Lipopolysaccharide Treatment Mice

Apoptotic pathways of macrophages within osteolytic interface membrane in periprosthestic osteolysis after total hip replacement

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