NR4A1 promotes TNF‑α‑induced chondrocyte death and migration injury via activating the�AMPK/Drp1/mitochondrial fission pathway

Zheng, Zhibo; Xiang, Shuai; Wang, Yingjie; Dong, Yixiao; Zeng, Li; Xiang, Yongbo; Bian, Yanyan; Feng, Bin; Yang, Bo

doi:10.3892/ijmm.2019.4398

Cited by 15 publications

(12 citation statements)

References 46 publications

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“…The α subunit of AMPK exists in two isoforms in the mammalian, including AMPKα1 and AMPKα2, where both serve as catalytic subunits [40]. Increased NR4A1 acts on the AMPK/dynaminrelated protein 1 (Drp1) pathway to trigger mitochondrial ssion, leading to mitochondrial permeability transition pore related chondrocyte cell death [41]. Such results are consistent with that of the present study and highlight the credibility of the enrichment analysis.…”

Section: Discussionsupporting

confidence: 92%

Identification of Key Genes and Pathways Associated with Differences of Subchondral Bone in Osteoarthritis

Zhang¹,

Yu²,

Zhang³

et al. 2020

Preprint

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BackgroundOsteoarthritis (OA) is a common chronic disease worldwide. Subchondral bone is an important pathological change in OA and responds more rapidly to adverse loading and events compared to cartilage. However, the pathogenic genes and pathways of subchondral bone are largely unclear.ObjectiveThis study aimed to identify signature differences in genes involved in knee lateral tibial (LT) and medial tibial (MT) plateaus of subchondral bone tissue while exploring their potential molecular mechanisms via bioinformatics analysis.MethodsFirst, the gene expression data of GSE51588 was downloaded from the GEO database. Differentially expressed genes (DEGs) between knee LT and MT were identified, and functional enrichment analyses were performed. Then, a protein-protein interactive network was constructed in order to acquire the hub genes, and modules analysis was conducted using STRING and Cytoscape for further analysis. The enriched hub genes were queried in DGIdb database to find suitable drug candidates in OA.ResultsA total of 202 DEGs (112 upregulated genes and 84 downregulated genes) were determined. In the PPI network, ten hub genes were identified. Five significant modules were identified using the MCODE plugin unit. Functional enrichment analysis revealed the most important signaling pathways. Six of the ten hub genes were targetable by a total of 35 drugs, suggesting their possible therapeutic use for OA .ConclusionsThe identified hub genes and functional enrichment pathways were implicated in the development and progression of subchondral bone in OA, thus improving our understanding of OA and offering molecular targets for future therapeutic modalities.

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Section: Discussionsupporting

confidence: 92%

Identification of Key Genes and Pathways Associated with Differences of Subchondral Bone in Osteoarthritis

Zhang¹,

Yu²,

Zhang³

et al. 2020

Preprint

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“…Shi et al (2017) found that the upregulated NR4A1 in OA was mostly located in mitochondria and knockdown of NR4A1 could decrease the cleaved PARP1 expression and avoid apoptosis of OA chondrocytes. Zheng et al (2020) also revealed that NR4A1 promotes TNF-α-induced chondrocyte death via activating mitochondrial fission. These reports seemed to indicate that NR4A1 acted as a harmful factor in OA.…”

Section: Discussionmentioning

confidence: 89%

Reactivation of NR4A1 Restrains Chondrocyte Inflammation and Ameliorates Osteoarthritis in Rats

Xiong

Ran

et al. 2020

Front. Cell Dev. Biol.

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Osteoarthritis (OA) is the most prevalent joint disease and uncontrolled inflammation is now recognized to play vital roles in OA development. Targeting the endogenous counterpart of inflammation may develop new therapeutic approaches in resolving inflammation persistence and treating inflammatory disease including OA. The orphan nuclear receptor 4A1 (NR4A1) is a key negative regulator of inflammatory responses but its role in osteoarthritis remains unclear. In the present study, we found that the NR4A1 expression was elevated in human osteoarthritis cartilage and in vitro OA model, which could be blocked by NF-κB signal inhibitor JSH23. The overexpression of NR4A1 inhibited, whereas knockdown of NR4A1 enhanced IL-1β induced COX-2, iNOS, MMP3, MMP9 and MMP13 expression, and luciferase reporter activity of NF-κB response element. Though NR4A1 was upregulated in inflammatory stimulation and creates a negative feedback loop, persistent inflammatory stimulation inhibited NR4A1 expression and activation. The expression of NR4A1 declined rapidly after an initial peak in conditions of chronic IL-1β stimulation, which could be partially restored by HDACs inhibitor SAHA. The phosphorylation of NR4A1 was increased in human osteoarthritis cartilage, and p38 inhibitor SB203580, JNK inhibitor SP600125 and ERK inhibitor FR180204 could significantly inhibited IL-1β induced NR4A1 phosphorylation. Reactivation of NR4A1 by its agonist cytosporone B could inhibit IL-1β induced chondrocyte inflammation and expression of COX-2, iNOS, MMP3, MMP9, and MMP13. In rat OA model, intra-articular injection of cytosporone B protected cartilage damage and ameliorated osteoarthritis. Thus, our study demonstrated that the NR4A1 is a key endogenous inhibitor of chondrocyte inflammation, which was relatively inactivated under chronic inflammatory stimulation through HDACs mediated transcriptional suppression and MAKP dependent phosphorylation in osteoarthritis. NR4A1 agonist cytosporone B could reactivate and restore the inhibitory regulatory ability of NR4A1, prevent excessive inflammation, and ameliorates osteoarthritis.

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“… Terkeltaub et al (2011) suggest that AMPK restrained matrix degradation in chondrocytes in the presence of inflammatory cytokines IL-1β and tumor necrosis factor α (TNF-α) in both human and mouse ( Figure 3I ). Zheng et al (2020) showed that activation of AMPK/Drp1/mitochondrial fission pathway mediates chondrocyte death and migration injury ( Figure 3I ). Moreover, AMPK participated in chondrocyte dysfunction, hypertrophy, and fibrotic differentiation ( Liu N. et al, 2020 ; Liu Z. et al, 2020 ).…”

Section: Ampk In Chondrocytesmentioning

confidence: 99%

AMPK Signaling in Energy Control, Cartilage Biology, and Osteoarthritis

Ruan

Ding

et al. 2021

Front. Cell Dev. Biol.

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The adenosine monophosphate (AMP)–activated protein kinase (AMPK) was initially identified as an enzyme acting as an “energy sensor” in maintaining energy homeostasis via serine/threonine phosphorylation when low cellular adenosine triphosphate (ATP) level was sensed. AMPK participates in catabolic and anabolic processes at the molecular and cellular levels and is involved in appetite-regulating circuit in the hypothalamus. AMPK signaling also modulates energy metabolism in organs such as adipose tissue, brain, muscle, and heart, which are highly dependent on energy consumption via adjusting the AMP/ADP:ATP ratio. In clinics, biguanides and thiazolidinediones are prescribed to patients with metabolic disorders through activating AMPK signaling and inhibiting complex I in the mitochondria, leading to a reduction in mitochondrial respiration and elevated ATP production. The role of AMPK in mediating skeletal development and related diseases remains obscure. In this review, in addition to discuss the emerging advances of AMPK studies in energy control, we will also illustrate current discoveries of AMPK in chondrocyte homeostasis, osteoarthritis (OA) development, and the signaling interaction of AMPK with other pathways, such as mTOR (mechanistic target of rapamycin), Wnt, and NF-κB (nuclear factor κB) under OA condition.

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NR4A1 promotes TNF‑α‑induced chondrocyte death and migration injury via activating the�AMPK/Drp1/mitochondrial fission pathway

Cited by 15 publications

References 46 publications

Identification of Key Genes and Pathways Associated with Differences of Subchondral Bone in Osteoarthritis

Identification of Key Genes and Pathways Associated with Differences of Subchondral Bone in Osteoarthritis

Reactivation of NR4A1 Restrains Chondrocyte Inflammation and Ameliorates Osteoarthritis in Rats

AMPK Signaling in Energy Control, Cartilage Biology, and Osteoarthritis

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