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DUSP5 suppresses interleukin-1β-induced chondrocyte inflammation and ameliorates osteoarthritis in rats.

ABSTRACT: Osteoarthritis (OA) is a chronic degenerative joint disease characterized by deterioration of articular cartilage. Dual specificity phosphatase 5 (DUSP5), a member of the DUSP subfamily, is known to regulate cellular inflammation. Here, we studied the relationship between DUSP5 and OA by knockdown and overexpression DUSP5, respectively. Results from in vitro experiments demonstrated that the knockdown of DUSP5 increased interleukin-1β (IL-1β)-induced expression of inflammatory genes, such as inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), and matrix metalloproteinases (MMPs) in chondrocytes, whereas it decreased the expression of anti-inflammatory genes, such as tissue inhibitor of metalloproteinase 3 (TIMP3) and IL-10. Conversely, the overexpression of DUSP5 suppressed the IL-1β-induced expression of iNOS, COX-2, and MMPs, and upregulated the expression of TIMP3 and IL-10. Moreover, knockdown of DUSP5 enhanced the IL-1β-induced activation of NF-κB and ERK pathways, whereas its overexpression inhibited these pathways. DUSP5 overexpression prevented cartilage degeneration in a rat OA model, while its knockdown reversed that effect. Our findings reveal that DUSP5 suppresses IL-1β-induced chondrocyte inflammation by inhibiting the NF-κB and ERK signaling pathways and ameliorates OA.

SUBMITTER: Wu Z

PROVIDER: S-EPMC7803505 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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DUSP5 suppresses interleukin-1β-induced chondrocyte inflammation and ameliorates osteoarthritis in rats.

Wu Zhipeng Z Xu Langhai L He Yuzhe Y Xu Kai K Chen Zhonggai Z Moqbel Safwat Adel Abdo SAA Ma Chiyuan C Jiang Lifeng L Ran Jisheng J Wu Lidong L Zhong Ying Y

Aging 20201215 24

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by deterioration of articular cartilage. Dual specificity phosphatase 5 (DUSP5), a member of the DUSP subfamily, is known to regulate cellular inflammation. Here, we studied the relationship between DUSP5 and OA by knockdown and overexpression DUSP5, respectively. Results from <i>in vitro</i> experiments demonstrated that the knockdown of DUSP5 increased interleukin-1β (IL-1β)-induced expression of inflammatory genes, such ...[more]

PMID: 33361528

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Project description: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.

Project description:ObjectiveInterleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) stimulate chondrocyte matrix catabolic responses, thereby compromising cartilage homeostasis in osteoarthritis (OA). AMP-activated protein kinase (AMPK), which regulates energy homeostasis and cellular metabolism, also exerts antiinflammatory effects in multiple tissues. This study was undertaken to test the hypothesis that AMPK activity limits chondrocyte matrix catabolic responses to IL-1β and TNFα.MethodsExpression of AMPK subunits was examined, and AMPKα activity was ascertained by the phosphorylation status of AMPKα Thr(172) in human knee articular chondrocytes and cartilage by Western blotting and immunohistochemistry, respectively. Procatabolic responses to IL-1β and TNFα, such as release of glycosaminoglycan, nitric oxide, and matrix metalloproteinases 3 and 13 were determined by dimethylmethylene blue assay, Griess reaction, and Western blotting, respectively, in cartilage explants and chondrocytes with and without knockdown of AMPKα by small interfering RNA.ResultsNormal human knee articular chondrocytes expressed AMPKα1, α2, β1, β2, and γ1 subunits. AMPK activity was constitutively present in normal articular chondrocytes and cartilage, but decreased in OA articular chondrocytes and cartilage and in normal chondrocytes treated with IL-1β and TNFα. Knockdown of AMPKα resulted in enhanced catabolic responses to IL-1β and TNFα in chondrocytes. Moreover, AMPK activators suppressed cartilage/chondrocyte procatabolic responses to IL-1β and TNFα and the capacity of TNFα and CXCL8 (IL-8) to induce type X collagen expression.ConclusionOur findings indicate that AMPK activity is reduced in OA cartilage and in chondrocytes following treatment with IL-1β or TNFα. AMPK activators attenuate dephosphorylation of AMPKα and procatabolic responses in chondrocytes induced by these cytokines. These observations suggest that maintenance of AMPK activity supports cartilage homeostasis by protecting cartilage matrix from inflammation-induced degradation.

Dataset Information

DUSP5 suppresses interleukin-1β-induced chondrocyte inflammation and ameliorates osteoarthritis in rats.

Publications

DUSP5 suppresses interleukin-1β-induced chondrocyte inflammation and ameliorates osteoarthritis in rats.

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