Neratinib exerts dual effects on cartilage degradation and osteoclast production in Osteoarthritis by inhibiting the activation of the MAPK/NF-κB signaling pathways

Qiu, Jianxin; Jiang, Ting; Yang, Guangtao; Gong, Yuhang; Zhang, Weikang; Zheng, Xiaohang; Chen, Haixiao; Hong, Zhenghua

doi:10.1016/j.bcp.2022.115155

Cited by 12 publications

(11 citation statements)

References 26 publications

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“…The formation and differentiation of osteoclasts are strictly controlled under physiological conditions. At the same time, various pathological factors could stimulate osteoclasts' formation and lead to osteolytic bone disease (7,41,51). According to our research, MRL did not affect BMMs cell proliferation and apoptosis but inhibited RANKL-induced osteoclast formation in a dose-dependent and time-dependent manner in the rst place.…”

Section: Discussionmentioning

confidence: 54%

“…Bone health is strictly regulated, while osteoporosis occurs mainly due to the disruption of bone homeostasis, which depends on the balance between osteoclastic bone resorption and osteoblastic bone formation (2,5). As the only specialized multinucleated cells derived from the mononuclear macrophage lineage in vivo (6), osteoclasts could be activated under the stimulation of various pathological factors (7) (chronic use of drugs, immobilization, malnutrition, and chronic in ammation) to accelerate bone resorption (8, 9), leading to osteoporosis and osteoporosis-related diseases, including Alzheimer's disease, diabetes and cancers and so on (10,11). Therefore, inhibiting the formation and activity of osteoclasts is a crucial strategy for treating osteoporosis.…”

Section: Introductionmentioning

confidence: 99%

“…The binding of c-Fms and macrophage colony-stimulating factor (M-CSF) bene ts preosteoclasts and osteoclasts' subsequent survival and proliferation (6, 8). The induction of osteoclast differentiation is in connection with the binding of RANK to RANKL (7,10). And then, RANKL/RANK signaling gives rise to the collection of TNF receptor-associated factor 6 (TRAF6) (9), inducing the mobilization of several subsequent pathways, such as mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways (11,21), which are classical pathways related to osteoclast differentiation (10).…”

Section: Introductionmentioning

confidence: 99%

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Myrislignan Targets Extracellular Signal-regulated Kinase (ERK) and Modulates Mitochondrial Function to Dampen Osteoclastogenesis and Ovariectomy-i nduced Osteoporosis

Chen

Gan

Wang

et al. 2023

Preprint

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Background Numerous studies have confirmed that activated osteoclasts cause excessive bone resorption, disrupting bone homeostasis and leading to osteoporosis. Moreover, ERK signaling is the classical pathway related to osteoclast differentiation. Besides, reactive oxygen species (ROS) is mainly from mitochondria, which is closely associated with the differentiation of osteoclasts. Myrislignan (MRL), a natural product derived from nutmeg, has various pharmacological activities. However, its effect on the treatment of osteoporosis is unclear. Therefore, this study mainly investigated whether MRL could inhibit osteoclastogenesis and bone mass loss in ovariectomy (OVX) mice via suppressing mitochondrial function and ERK signaling.Methods Tartrate-resistant and phosphatase (TRAP) assay and bone resorption assay were used to observe the effect of MRL on osteoclastogenesis. Furthermore, we added MitoSOX RED and tetramethyl rhodamine methyl ester (TMRM) staining to test the inhibitory effect of MRL on mitochondria. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay detected whether MRL suppressed the expression of specific genes in osteoclasts. The impact of MRL on mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) related proteins was evaluated by western blotting. Besides, a specific ERK agonist LM22B-10 (LM), was added to revalidate the inhibitory effect of MRL on ERK. Moreover, we established an OVX mouse model to assess the therapeutic effect of MRL on osteoporosis in vivo.Results MRL was proven to press osteoclast differentiation and bone resorption function, significantly reducing osteoclastic gene expression. Mechanistically, MRL inhibited the phosphorylation of ERK by suppressing the role of mitochondria, causing the downregulation of nuclear factor of activated T cells 1 (NFATc1) signaling. The experiment result of adding LM further clarified the targeted inhibition effect of MRL on ERK. The results of microscopic computed tomography (Micro-CT) and histology sections of the tibia in vivo indicated that OVX mice had lower bone mass and higher expression of ERK. However, after the MRL application, these results were significantly reversed, suggesting that MRL had a decent anti-osteoporosis effect.Conclusion We saw for the first time that MRL could inhibit ERK signaling by suppressing mitochondrial function, thus reducing OVX-induced osteoporosis. This novel finding could provide a broad prospect for the treatment of osteoporosis.

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Section: Discussionmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Myrislignan Targets Extracellular Signal-regulated Kinase (ERK) and Modulates Mitochondrial Function to Dampen Osteoclastogenesis and Ovariectomy-i nduced Osteoporosis

Chen

Gan

Wang

et al. 2023

Preprint

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“…RANK signaling is activated by RANKL via TRAF6, which, in turn, induces MAPK or NF-κB activation. Hence, the MAPK and NF-κB axes are crucial for modulating osteoclast differentiation in skeletal development and homeostasis (23)(24)(25)(26)(27)(28)(29)(30)(31).…”

Section: Discussionmentioning

confidence: 99%

“…The advancement of the inflammatory response and the differentiation of osteoblastic and osteoclastic cells depend on the mitogen-activated protein kinase (MAPK) and nuclear factor κappa B (NF-κB) axis [23][24][25][26][27][28]. A prior investigation revealed that AS-IV strongly inhibits osteoclastogenesis and suppresses osteolysis via downregulation of ERK signaling [22].…”

Section: Introductionmentioning

confidence: 99%

Astragaloside IV attenuates glucocorticoid-induced osteoclastogenesis and bone loss via the MAPK/NF-κB pathway

Guo,

Li,

Yang

et al. 2023

Preprint

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Background Astragaloside IV (AS-IV) is a bioactive saponin extracted from astragalus membranaceus, and it is reported to promote osteoblast differentiation while inhibiting osteoclastogenesis. However, the mechanism of AS-IV in glucocorticoid-induced osteoclastogenesis (GIO) remains undetermined. Herein, we examined the influence of AS-IV on GIO and bone loss. Methods RAW264.7 cells were incubated with dexamethasone (Dex) alone or Dex and receptor activator of nuclear factor-B ligand (RANKL) (Dex and RANKL) for 2 days, and then treated with Dex or Dex and RANKL through AS-IV for the timeframes indicated. Following, mice were intraperitoneally administered with an intermediate-acting glucocorticoid, methylprednisolone (MP), or MP and AS-IV for 6 weeks. Results AS-IV significantly decreased Dex-induced osteoclast nucleus and area, however, it did not impact the number of Dex-induced osteoclasts in RAW264.7 cells. AS-IV also significantly decreased the osteoclastic marker protein expressions in Dex-induced RAW264.7 cells with concentration of dose dependent fashion. Additionally, AS-IV promoted p38 phosphorylation (p-) and p-p65 translocation to the nucleus, while inhibiting phosphorylation of extracellular signal-regulated kinase (ERK) (p-ERK) and inhibitor of Nuclear factor κB (NF-κB) (p-IκB) levels. However, the AS-IV-mediated action on p-MAPK, p-NF-κB, and osteoclastic marker expressions were reversed by MAPK or IκB inhibitor in Dex-induced RAW264.7 cells. Furthermore, our in vivo evaluation revealed that AS-IV also attenuated the MP-mediated bone loss, and suppressed osteoclastogenesis. Conclusions This study demonstrates that AS-IV inhibits GIO and attenuates bone loss via the MAPK/NF-κB pathway. This also suggested that AS-IV could be a potential promising therapeutic agent for glucocorticoid-triggered bone loss.

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StemRegenin 1 attenuates the RANKL-induced osteoclastogenesis via inhibiting AhR-c-src-NF-κB/p-ERK MAPK-NFATc1 signaling pathway

Zhou,

Li,

Ying

et al. 2024

iScience

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Neratinib exerts dual effects on cartilage degradation and osteoclast production in Osteoarthritis by inhibiting the activation of the MAPK/NF-κB signaling pathways

Cited by 12 publications

References 26 publications

Myrislignan Targets Extracellular Signal-regulated Kinase (ERK) and Modulates Mitochondrial Function to Dampen Osteoclastogenesis and Ovariectomy-i nduced Osteoporosis

Myrislignan Targets Extracellular Signal-regulated Kinase (ERK) and Modulates Mitochondrial Function to Dampen Osteoclastogenesis and Ovariectomy-i nduced Osteoporosis

Astragaloside IV attenuates glucocorticoid-induced osteoclastogenesis and bone loss via the MAPK/NF-κB pathway

StemRegenin 1 attenuates the RANKL-induced osteoclastogenesis via inhibiting AhR-c-src-NF-κB/p-ERK MAPK-NFATc1 signaling pathway

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