TNF‐α promotes osteoclastogenesis through JNK signaling‐dependent induction of Semaphorin3D expression in estrogen‐deficiency induced osteoporosis

Sang, Chenglin; Zhang, Jiefeng; Zhang, Yongxian; Chen, Fangjing; Cao, Xia; Guo, Lei

doi:10.1002/jcp.25784

Cited by 27 publications

(21 citation statements)

References 38 publications

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“…Many published studies have described the role of TNF in the development of osteoporosis. For example, TNF/TNFR1 signaling promoted osteoclastogenesis by JNK signaling-induced expression of semaphorin 3D [24]. Another study showed that TNF/TNFR1 signaling suppressed bone formation in estrogen deficiency-induced osteoporosis by inhibiting semaphorin 3B via Wnt/β-catenin signaling [25].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-218 Negatively Regulates Osteoclastogenic Differentiation by Repressing the Nuclear Factor-κB Signaling Pathway and Targeting Tumor Necrosis Factor Receptor 1

Wang

Yang

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Postmenopausal osteoporosis is a common disease associated with estrogen deficiency leading to bone loss and bone tissue changes. The resultant bone fragility and increased risk of fracture has serious adverse effects on health and quality of life of the elderly, making it an important health issue. MicroRNA-218 (miR-218) is closely related to the development of osteoporosis. In this study, we investigated the regulatory mechanisms of miR-218 in osteoclastogenesis. Methods: We investigated miR-218 levels on differentiation of RAW 264.7 cells into osteoclasts compared with normal cells. Next, RAW 264.7 cells were transfected with miR-218 mimics or inhibitors to study the role of miR-218 in osteoclastogenic differentiation. Tartrate-resistant acid phosphatase (TRAP) staining was performed to determine osteoclastogenic differentiation. Bioinformatics analysis and luciferase reporter assay were used to identify and validate miR-218 target genes. Results: miR-218 was downregulated following RAW 264.7 cell differentiation into osteoclasts. miR-218 overexpression attenuated osteoclast differentiation, whereas low miR-218 expression promoted it as demonstrated by increased expression of osteoclast-specific genes and TRAP staining. Bioinformatics analysis and the luciferase reporter assay showed that tumor necrosis factor receptor 1 (TNFR1), a cell membrane receptor of TNF (TNF is an activator of nuclear factor-κB [NF-κB]), is a direct target of miR-218. Conclusions: Our findings indicate that miR-218 regulates osteoclastogenic differentiation negatively by repressing NF-κB signaling by targeting TNFR1, suggesting that targeting miR-218 may be a therapeutic approach in postmenopausal osteoporosis.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-218 Negatively Regulates Osteoclastogenic Differentiation by Repressing the Nuclear Factor-κB Signaling Pathway and Targeting Tumor Necrosis Factor Receptor 1

Wang

Yang

Zhang

et al. 2018

Cell Physiol Biochem

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“…JNK signaling activated by the inflammatory cytokines TNF-α and IL-1 induces cell-cell fusion to form osteoclasts and enhances osteoclast survival, respectively [ 69 , 70 , 71 ]. IL-17A facilitates autophagic activity of osteoclast precursors and promotes osteoclastogenesis via activating the RANKL-JNK pathway [ 72 ].…”

Section: Jnk Signaling In Osteoclastsmentioning

confidence: 99%

“…JNK signaling also induces the expression of the calcium/calmodulin-dependent protein kinase (CaMK), c-Fos, and NFATc1, which are involved in the maintenance of osteoclast lineage commitment [ 65 , 75 ]. Semaphorin 3D is a downstream target of JNK signaling and is involved in stimulating TNF-α-induced osteoclastogenesis [ 69 ].…”

Section: Jnk Signaling In Osteoclastsmentioning

confidence: 99%

Roles of Mitogen-Activated Protein Kinases in Osteoclast Biology

Lee

Seo

Choi

et al. 2018

IJMS

175

145

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Bone undergoes continuous remodeling, which is homeostatically regulated by concerted communication between bone-forming osteoblasts and bone-degrading osteoclasts. Multinucleated giant osteoclasts are the only specialized cells that degrade or resorb the organic and inorganic bone components. They secrete proteases (e.g., cathepsin K) that degrade the organic collagenous matrix and establish localized acidosis at the bone-resorbing site through proton-pumping to facilitate the dissolution of inorganic mineral. Osteoporosis, the most common bone disease, is caused by excessive bone resorption, highlighting the crucial role of osteoclasts in intact bone remodeling. Signaling mediated by mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38, has been recognized to be critical for normal osteoclast differentiation and activation. Various exogenous (e.g., toll-like receptor agonists) and endogenous (e.g., growth factors and inflammatory cytokines) stimuli contribute to determining whether MAPKs positively or negatively regulate osteoclast adhesion, migration, fusion and survival, and osteoclastic bone resorption. In this review, we delineate the unique roles of MAPKs in osteoclast metabolism and provide an overview of the upstream regulators that activate or inhibit MAPKs and their downstream targets. Furthermore, we discuss the current knowledge about the differential kinetics of ERK, JNK, and p38, and the crosstalk between MAPKs in osteoclast metabolism.

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“…The therapeutic targets are mainly focused on the inhibition of osteoclast activity and the promotion of osteogenesis. Therefore, the repression of osteoclastogenesis and bone resorption activity are of great significance in the prevention and treatment of osteoporosis . We found that ABP can decrease the expression of NFATc1, Integrin β3, TRAcP, and CTSK via suppressing the phosphorylation of MAPK pathways, which inhibited RANKL induced osteoclast differentiation and function (Figure ).…”

Section: Discussionmentioning

confidence: 86%

Achyranthes bidentata polysaccharide suppresses osteoclastogenesis and bone resorption via inhibiting RANKL signaling

Song

Cao

Huang

et al. 2018

J of Cellular Biochemistry

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Osteoclasts are highly differentiated multinucleated giant cells that play fundamental roles in bone resorption and in the pathogenesis of osteolytic conditions, such as osteoporosis and cancer-induced bone loss. Achyranthes bidentata polysaccharide (ABP) is a hydrophilic compound with anti-oxidation and anti-aging characteristics. The impact of ABP on RANKL-induced osteoclast formation and bone resorption has not been assessed, hence, in this study we investigated the effect of ABP on osteoclast formation and resorption in murine bone marrow derived osteoclasts. We found that ABP was able to suppress RANKL-induced osteoclast differentiation and bone resorption activity at concentrations above 6.5 µM, while demonstrating no cytotoxicity at concentrations up to 10 µM. The actions of ABP were mediated through inhibition of RANKL-induced c-Fos and NFATc1 gene and protein expression. Furthermore, we found that ABP suppressed NFATc1 transcriptional activity, and the phosphorylation of MAPK pathways induced by RANKL. Collectively, ABP attenuates RANKL-mediated osteoclast activity and signaling, and might serve as a potential therapeutic candidate for preventing bone loss related diseases.

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TNF‐α promotes osteoclastogenesis through JNK signaling‐dependent induction of Semaphorin3D expression in estrogen‐deficiency induced osteoporosis

Cited by 27 publications

References 38 publications

MicroRNA-218 Negatively Regulates Osteoclastogenic Differentiation by Repressing the Nuclear Factor-κB Signaling Pathway and Targeting Tumor Necrosis Factor Receptor 1

MicroRNA-218 Negatively Regulates Osteoclastogenic Differentiation by Repressing the Nuclear Factor-κB Signaling Pathway and Targeting Tumor Necrosis Factor Receptor 1

Roles of Mitogen-Activated Protein Kinases in Osteoclast Biology

Achyranthes bidentata polysaccharide suppresses osteoclastogenesis and bone resorption via inhibiting RANKL signaling

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