Modulating calcium‐mediated NFATc1 and mitogen‐activated protein kinase deactivation underlies the inhibitory effects of kavain on osteoclastogenesis and bone resorption

Guo, Qiang; Cao, Zhen; Wu, Bo; Chen, Fangxiao; Tickner, Jennifer; Wang, Ziyi; Qiu, Heng; Wang, Chao; Chen, Kai; Tan, Renxiang; Gao, Qile; Xu, Jiake

doi:10.1002/jcp.26893

Cited by 10 publications

(8 citation statements)

References 45 publications

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“…Treatment reduced inflammatory cell infiltration within soft tissues and also decreased osteoclastic activity. These results are consistent with those obtained in a model of ovariectomy-induced bone loss where kavain was suggested as a candidate drug for the pharmacological management of osteolytic diseases 15 . Indeed, it has been demonstrated that kavain is able to inhibit receptor activator of nuclear factor‐κB ligand (RANKL)-induced osteoclast differentiation and associated bone resorption 15 .…”

Section: Discussionsupporting

confidence: 90%

“…The anti-inflammatory properties of kavain and its derivatives in multiple cell types such as macrophages, osteoblasts and even adipocytes are now well described 12,14,15,18 . Interestingly, such effects are mediated by several pathways involved in NFκB activation including ERK/LITAF 13 and peroxisome proliferation–activated receptor γ coactivator α (PGC-1α) 12 leading to the control of other detrimental biological events such as oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

“…Kavain, a compound extracted from the Piper methysticum plant, has recently been described as a promising anti-inflammatory agent and has been evaluated in several in vitro and animal models 12–15 . In macrophages stimulated by Escherichia coli lipopolysaccharide (LPS), treatment with kavain significantly reduced TNF-α secretion, 13 while in another cellular model, kavain was shown to inhibit RANKL-induced osteoclast formation 15 . In an attempt to optimize kavain’s anti-inflammatory effects and to reduce potential side effects, an effort has been made to identify kavain analogs 16 .…”

Section: Introductionmentioning

confidence: 99%

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Identification of a Kavain Analog with Efficient Anti-inflammatory Effects

Huck¹,

Han²,

Mulhall³

et al. 2019

Sci Rep

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Kavain, a compound derived from Piper methysticum, has demonstrated anti-inflammatory properties. To optimize its drug properties, identification and development of new kavain-derived compounds was undertaken. A focused library of analogs was synthesized and their effects on Porphyromonas gingivalis (P. gingivalis) elicited inflammation were evaluated in vitro and in vivo. The library contained cyclohexenones (5,5-dimethyl substituted cyclohexenones) substituted with a benzoate derivative at the 3-position of the cyclohexanone. The most promising analog identifed was a methylated derivative of kavain, Kava-205Me (5,5-dimethyl-3-oxocyclohex-1-en-1-yl 4-methylbenzoate.) In an in vitro assay of anti-inflammatory effects, murine macrophages (BMM) and THP-1 cells were infected with P. gingivalis (MOI = 20:1) and a panel of cytokines were measured. Both cell types treated with Kava-205Me (10 to 200 μg/ml) showed significantly and dose-dependently reduced TNF-α secretion induced by P. gingivalis. In BMM, Kava-205Me also reduced secretion of other cytokines involved in the early phase of inflammation, including IL-12, eotaxin, RANTES, IL-10 and interferon-γ (p < 0.05). In vivo, in an acute model of P. gingivalis-induced calvarial destruction, administration of Kava-205Me significantly improved the rate of healing associated with reduced soft tissue inflammation and osteoclast activation. In an infective arthritis murine model induced by injection of collagen-antibody (ArthriomAb) + P. gingivalis, administration of Kava-205Me was able to reduce efficiently paw swelling and joint destruction. These results highlight the strong anti-inflammatory properties of Kava-205Me and strengthen the interest of testing such compounds in the management of P. gingivalis elicited inflammation, especially in the management of periodontitis.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of a Kavain Analog with Efficient Anti-inflammatory Effects

Huck¹,

Han²,

Mulhall³

et al. 2019

Sci Rep

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“…Bone absorption is an essential function of osteoclasts in the body [34,35]. The maintenance of the healthy bone structure, morphology, and bone volume requires the dynamic balance between osteoblasts and osteoclasts.…”

Section: Discussionmentioning

confidence: 99%

CircRNA_28313/miR-195a/CSF1 axis modulates osteoclast differentiation to affect OVX-induced bone absorption in mice

et al. 2019

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Osteoblastic bone formation and osteoclastic bone resorption dynamically maintain the bone homeostasis; in the present study, we attempt to investigate the mechanism of the excessive activation of osteoclasts inducing the deregulation of bone homeostasis from the perspective of non-coding RNA regulation. Differentially expressed patterns of circRNAs were examined in non-treated and RANKL + CSF1-treated bone marrow monocyte/macrophage (BMM) cells and differentially-expressed miRNAs during osteoclast differentiation were analyzed and identified. We found that circRNA_28313 was significantly induced by RANKL + CSF1 treatment. circRNA_28313 knockdown significantly inhibited RANKL + CSF1-induced differentiation of osteoclasts within BMM cells in vitro, while suppressed ovariectomized (OVX)-induced bone resorption in mice in vivo. Via bioinformatics analyses, it has been demonstrated that miR-195a might bind to circRNA_28313 and CSF1 and together form a circRNA-miRNA-mRNA network. circRNA_28313 relieves miR-195a-mediated suppression on CSF1 via acting as a ceRNA, therefore modulating the osteoclast differentiation in BMM cells. In conclusion, circRNA_28313, miR-195a, and CSF1 form a ceRNA network to function in RANKL + CSF1-induced osteoclast differentiation, thus affecting OVX-induced bone absorption in mice.

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“…Osteoclasts are differentiated from monocyte/macrophage lineage, which undergoes sequential stages including preosteoclast formation and cell‐cell fusion, involving a variety of proteins and kinases 23‐25 . Id2 is a member of Id family, which functioned as inhibitor of cell differentiation 26 .…”

Section: Discussionmentioning

confidence: 99%

Harmine targets inhibitor of DNA binding‐2 and activator protein‐1 to promote preosteoclast PDGF‐BB production

Huang

Xia

et al. 2021

J Cellular Molecular Medi

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Osteoporosis is one of the most common metabolic bone diseases affecting millions of people. We previously found that harmine prevents bone loss in ovariectomized mice via increasing preosteoclast platelet‐derived growth factor‐BB (PDGF‐BB) production and type H vessel formation. However, the molecular mechanisms by which harmine promotes preosteoclast PDGF‐BB generation are still unclear. In this study, we revealed that inhibitor of DNA binding‐2 (Id2) and activator protein‐1 (AP‐1) were important factors implicated in harmine‐enhanced preosteoclast PDGF‐BB production. Exposure of RANKL‐induced Primary bone marrow macrophages (BMMs), isolated from tibiae and femora of mice, to harmine increased the protein levels of Id2 and AP‐1. Knockdown of Id2 by Id2‐siRNA reduced the number of preosteoclasts as well as secretion of PDGF‐BB in RANKL‐stimulated BMMs administrated with harmine. Inhibition of c‐Fos or c‐Jun (components of AP‐1) both reversed the stimulatory effect of harmine on preosteoclast PDGF‐BB production. Dual‐luciferase reporter assay analyses determined that PDGF‐BB was the direct target of AP‐1 which was up‐regulated by harmine treatment. In conclusion, our data demonstrated a novel mechanism involving in the production of PDGF‐BB increased by harmine, which may provide potential therapeutic targets for bone loss diseases.

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Modulating calcium‐mediated NFATc1 and mitogen‐activated protein kinase deactivation underlies the inhibitory effects of kavain on osteoclastogenesis and bone resorption

Cited by 10 publications

References 45 publications

Identification of a Kavain Analog with Efficient Anti-inflammatory Effects

Identification of a Kavain Analog with Efficient Anti-inflammatory Effects

CircRNA_28313/miR-195a/CSF1 axis modulates osteoclast differentiation to affect OVX-induced bone absorption in mice

Harmine targets inhibitor of DNA binding‐2 and activator protein‐1 to promote preosteoclast PDGF‐BB production

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