PD0325901, an ERK inhibitor, attenuates RANKL‐induced osteoclast formation and mitigates cartilage inflammation by inhibiting the NF-κB and MAPK pathways

Jiang, Ting; Gong, Yuhang; Zhang, Wekang; Qiu, Jianxin; Zheng, Xiaohang; Li, Ze; Yang, Guangtao; Hong, Zhenghua

doi:10.1016/j.bioorg.2022.106321

Cited by 19 publications

(17 citation statements)

References 33 publications

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“… 98 Ting et al conducted similar experiments that yielded comparable outcomes. 79 These findings demonstrate a significant correlation between pyroptosis and subchondral bone changes during OA development. The severity of OA is directly proportional to the duration and intensity of pyroptosis effects, resulting in more prolonged and intense pyroptosis effects in severe cases.…”

Section: Pyroptosis and Subchondral Bone In Oamentioning

confidence: 57%

“… 78 In an OA model, the expression of NLRP3 was found to be higher in medial cartilage than in lateral cartilage, and inhibition of the MAPK/NF-κB/NLRP3 can alleviate chondrocyte pyroptosis, proteoglycan loss, collagen degradation, articular cartilage degeneration, and subchondral bone destruction. 79 Pyroptosis, induced by activators that promote chondrocyte NLRP3 inflammasome activation via the MAPK/NF-κB pathway, can exacerbate these conditions. 37 , 38 , 79 Bai et al conducted a study that revealed the potential role of pyroptosis in OA.…”

Section: Pyroptosis and Cartilage In Oamentioning

confidence: 99%

“… 79 Pyroptosis, induced by activators that promote chondrocyte NLRP3 inflammasome activation via the MAPK/NF-κB pathway, can exacerbate these conditions. 37 , 38 , 79 Bai et al conducted a study that revealed the potential role of pyroptosis in OA. Their findings showed that selective inhibition of NLRP3 and caspase-1 led to a reduction in the expression of pyroptosis-related molecules such as NLRP3, ASC, caspase-1, and GSDMD in both an OA animal model and rat chondrocytes stimulated with hydrogen peroxide (H₂O₂).…”

Section: Pyroptosis and Cartilage In Oamentioning

confidence: 99%

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Pyroptosis in Osteoarthritis: Molecular Mechanisms and Therapeutic Implications

Chen,

Zeng,

Wei

et al. 2024

JIR

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Osteoarthritis (OA) is a chronic disease that causes pain and functional impairment by affecting joint tissue. Its global impact is noteworthy, causing significant economic losses and property damage. Despite extensive research, the underlying pathogenesis of OA remain an area of ongoing investigation. It has recently been discovered that the OA progression is significantly influenced by pyroptosis. Pyroptosis is a complex process that involves three pathways culminating in the assembly of Gasdermin-D (GSDMD)-N-terminal (GSDMD-NT) into pores through aggregation on the plasma membrane. The aggregation of GSDMD-NT proteins stimulates the release of inflammatory mediators, such as Interleukin-1β (IL-1β), Interleukin-18 (IL-18), and Matrix Metallopeptidase 13 (MMP13), ultimately leading to cellular lysis. The pyroptosis process in specific cells, including synovial macrophages, fibroblast-like synoviocytes (FLS), chondrocytes, and subchondral osteoblasts, contributs factor to the development of OA. Currently, the specific cells that undergo pyroptosis first are not yet fully understood, and it remains unknown whether pyroptosis in one cell can trigger the same process in other cells. Therefore, targeting pyroptosis could potentially offer a novel treatment approach for OA patients. We present a comprehensive analysis of the molecular mechanisms and key features of pyroptosis. We also outline the current research progress on various aspects, including synovial tissue, articular cartilage, extracellular matrix (ECM), and subchondral bone, with a focus on pyroptosis. The aim is to provide theoretical references for the effective management of OA.

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Section: Pyroptosis and Subchondral Bone In Oamentioning

confidence: 57%

Section: Pyroptosis and Cartilage In Oamentioning

confidence: 99%

Section: Pyroptosis and Cartilage In Oamentioning

confidence: 99%

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Pyroptosis in Osteoarthritis: Molecular Mechanisms and Therapeutic Implications

Chen,

Zeng,

Wei

et al. 2024

JIR

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“… 60 Reducing the level of Mapk1 can reduce the level of inflammation, inhibit catabolism, inhibit chondrocyte apoptosis, promote cartilage repair and delay the course of OA. 61 …”

Section: Discussionmentioning

confidence: 99%

Integrated Network Pharmacology and Experimental Validation Approach to Investigate the Mechanisms of Radix Rehmanniae Praeparata - Angelica Sinensis - Radix Achyranthis Bidentatae in Treating Knee Osteoarthritis

Liu,

Zhang,

Zhou

et al. 2024

DDDT

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Background Knee osteoarthritis (KOA) is a persistent degenerative condition characterized by the deterioration of cartilage. The Chinese herbal formula Radix Rehmanniae Praeparata- Angelica Sinensis-Radix Achyranthis Bidentatae (RAR) has often been used in effective prescriptions for KOA as the main functional drug, but its underlying mechanism remains unclear. Therefore, network pharmacology and verification experiments were employed to investigate the impact and mode of action of RAR in the treatment of KOA. Methods The destabilization of the medial meniscus model (DMM) was utilized to assess the anti-KOA effect of RAR by using gait analysis, micro-computed tomography (Micro-CT), and histology. Primary chondrocytes were extracted from the rib cartilage of a newborn mouse. The protective effects of RAR on OA cells were evaluated using a CCK‐8 assay. The antioxidative effect of RAR was determined by measuring reactive oxygen species (ROS), superoxide dismutase (SOD), and glutathione (GSH) production. Furthermore, network pharmacology and molecular docking were utilized to propose possible RAR targets for KOA, which were further verified through experiments. Results In vivo, RAR significantly ameliorated DMM-induced KOA characteristics, such as subchondral bone sclerosis, cartilage deterioration, gait abnormalities, and the degree of knee swelling. In vitro, RAR stimulated chondrocyte proliferation and the expression of Col2a1, Comp, and Acan. Moreover, RAR treatment significantly reduced ROS accumulation in an OA cell model induced by IL-1β and increased the activity of antioxidant enzymes (SOD and GSH). Network pharmacology analysis combined with molecular docking showed that Mapk1 might be a key therapeutic target. Subsequent research showed that RAR could downregulate Mapk1 mRNA levels in IL-1β-induced chondrocytes and DMM-induced rats. Conclusion RAR inhibited extracellular matrix (ECM) degradation and oxidative stress response via the MAPK signaling pathway in KOA, and Mapk1 may be a core target.

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“…The study explored the mechanism by which cas inhibits osteoclast activation, which has been shown to be multi-pathway. Studies on NF-κB, MAPK, AKT and other conventional pathways have been widely carried out (27,50), and most studies use pathway inhibitors as experimental controls (51)(52)(53), thus, in the future, the mechanism of cas inhibition of osteoclast activation using inhibitors of the ERK/AKT/GSK3β pathway will be further investigated. The association between the cas-inhibited RANKL-induced ERK/AKT/GSK3β signaling pathway and NFATc1 and its downstream proteins requires further study.…”

Section: Discussionmentioning

confidence: 99%

Casticin suppresses RANKL‑induced osteoclastogenesis and prevents ovariectomy‑induced bone loss by regulating the AKT/ERK and NF‑κB signaling pathways

Yang

Liang

et al. 2023

Int J Mol Med

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Postmenopausal osteoporosis is a systemic metabolic disease that chronically endangers public health and is typically characterized by low bone mineral density and marked bone fragility. The excessive bone resorption activity of osteoclasts is a major factor in the pathogenesis of osteoporosis; therefore, strategies aimed at inhibiting osteoclast activity may prevent bone decline and attenuate the process of osteoporosis. casticin (cas), a natural compound, has anti-inflammatory and antitumor properties. However, the role of cas in bone metabolism remains largely unclear. The present study found that the receptor activator of nuclear factor-κΒ (NF-κB) ligand-induced osteoclast activation and differentiation were inhibited by cas. Tartrate-resistant acid phosphatase staining revealed that cas inhibited osteoclast differentiation, and bone resorption pit assays demonstrated that Cas affected the function of osteoclasts. Cas significantly reduced the expression of osteoclast-specific genes and related proteins, such as nuclear factor of activated T cells, cytoplasmic 1 and c-Fos at the mRNA and protein level in a concentration-dependent manner. cas inhibited osteoclast formation by blocking the AKT/ERK and NF-κB signaling pathways, according to the intracellular signaling analysis. The microcomputed tomography and tissue staining of tibiae from ovariectomized mice revealed that cas prevented the bone loss induced by estrogen deficiency and reduced osteoclast activity in vivo. Collectively, these findings indicated that Cas may be used to prevent osteoporosis.

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PD0325901, an ERK inhibitor, attenuates RANKL‐induced osteoclast formation and mitigates cartilage inflammation by inhibiting the NF-κB and MAPK pathways

Cited by 19 publications

References 33 publications

Pyroptosis in Osteoarthritis: Molecular Mechanisms and Therapeutic Implications

Pyroptosis in Osteoarthritis: Molecular Mechanisms and Therapeutic Implications

Integrated Network Pharmacology and Experimental Validation Approach to Investigate the Mechanisms of Radix Rehmanniae Praeparata - Angelica Sinensis - Radix Achyranthis Bidentatae in Treating Knee Osteoarthritis

Casticin suppresses RANKL‑induced osteoclastogenesis and prevents ovariectomy‑induced bone loss by regulating the AKT/ERK and NF‑κB signaling pathways

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