Schisandrin B ameliorated chondrocytes inflammation and osteoarthritis via suppression of NF-&amp;kappa;B and MAPK signal pathways

Ran, Jisheng; Ma, Chiyuan; Xu, Kai; Xu, Langhai; He, Yuzhe; Moqbel, Safwat Adel Abdo; Hu, Pengfei; Jiang, Lifeng; Chen, Weiping; Bao, Jiapeng; Xiong, Yan; Wu, Lidong

doi:10.2147/dddt.s162014

Cited by 75 publications

(62 citation statements)

References 26 publications

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“…The MAPK kinase p38, ERK and JNK were demonstrated to phosphorylate NR4A1 in other cell lines (Liu et al, 2007;Wang et al, 2009;Li et al, 2015). Our previous study has revealed that the inflammatory stimulation phosphorylated and activated MAPK p38, ERK and JNK in chondrocytes (Ran et al, 2018). In the present study, we observed that NR4A1 was phosphorylated in osteoarthritis tissue or through in vitro inflammatory stimulation, which was significantly blocked by p38, ERK and JNK inhibitors.…”

Section: Discussionsupporting

confidence: 59%

“…Five sham surgeries and ten OA models were developed by simply opening joint cavity or surgical resection of the medial meniscus in SD rat (Male, 6 weeks old, specific pathogen free [SPF])knee joints as described previously (Ran et al, 2018). All the OA model animals were randomized into two groups: the experimental group (n = 5) and the control group (n = 5).…”

Section: Animal Experiments and Histological Analysismentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 59%

Section: Animal Experiments and Histological Analysismentioning

confidence: 99%

Reactivation of NR4A1 Restrains Chondrocyte Inflammation and Ameliorates Osteoarthritis in Rats

Xiong

Ran

et al. 2020

Front. Cell Dev. Biol.

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“…MAPK inhibitors blocked the joint inflammation and destruction in different osteoarthritis animal models [31]. Previous researches have provided ample proofs that the inhibition of the MAPK pathway inhibited the apoptosis and inflammatory response in human OA chondrocytes [22,32]. On the other hand, Sema4D weakened the phosphorylation of p-Erk1/2 in LPS-treated microglia [24].…”

Section: Discussionmentioning

confidence: 97%

Sema4D Aggravated LPS-Induced Injury via Activation of the MAPK Signaling Pathway in ATDC5 Chondrocytes

Lei

Zhuang

et al. 2020

BioMed Research International

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Osteoarthritis (OA) is the most common chronic degenerative joint disease, and it remains the main cause of chronic disability in elderly individuals. Sema4D (semaphorin 4D) is involved in the immune system and related to bone injury, osteoporosis, osteoblast differentiation, and rheumatoid arthritis. However, the role of Sema4D in OA remains unclear. Hence, the LPS-stimulated chondrocyte cell injury model was constructed in this study to investigate the role of Sema4D in OA development. The results showed that Sema4D was increased in LPS-treated ATDC5 cells, and the knockdown of Sema4D suppressed the decline of cell viability, the increase of cell apoptosis, and the increase of IL-6, IL-1β, and TNF-α secretion in ATDC5 cells induced by LPS. Meanwhile, Sema4D overexpression aggravated the cell injury triggered by LPS, and inhibiting Plexin B1 partly abolished the effect of Sema4D overexpression on LPS-induced chondrocyte injury. Furthermore, silencing of Sema4D blocked the activation of the MAPK pathway in LPS-stimulated ATDC5 cells. Enhanced Sema4D promoted the activation of the MAPK pathway in LPS-stimulated ATDC5 cells. What is more, inhibiting the MAPK signaling pathway abolished the promoting effect of Sema4D overexpression on LPS-induced chondrocyte injury. Therefore, our study suggested that the knockdown of Sema4D protects ATDC5 cells against LPS-induced injury through inactivation of the MAPK signaling pathway via interacting with Plexin B1.

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“…Evaluation of joint cartilage is considered critical since the primary tissue degradation in KOA animal models that mimic human KOA occurs in this tissue; however, many studies have been limited. For example, in some KOA animal studies, only local assessment of the cartilage has been done using tissue sections and staining methods to assess cartilage degeneration quantitatively [4][5][6][7]. In addition, microscopic evaluation using India ink staining to confirm cartilage degradation in KOA animal models has demonstrated localized positive and non-positive areas [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Characterization of Osteoarthritis in a Medial Meniscectomy-Induced Animal Model Using Contrast-Enhanced X-Ray Microtomography

Sugasawa¹,

Kuji²,

Aoki³

et al. 2020

Preprint

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The aim of this study was to clarify degradation characteristics in each tissue of the knee complex of a medial meniscectomy (MMx)-induced knee osteoarthritis (KOA) animal model using classical methods and a new comprehensive evaluation method called contrast-enhanced X-ray micro-computed tomography (CEX-μCT), which was developed in the study. Surgical MMx was performed in the right knee joints of five male Wistar rats to induce KOA. At 4 wk post-surgery, the synovitis was evaluated using qPCR. Degradations of the articular cartilage of the tibial plateau were evaluated using classical methods and CEX-μCT. Evaluation of the synovitis demonstrated significantly increased expression levels of inflammation-associated marker genes in MMx-treated knees compared to that in sham-treated knees. Evaluation of the articular cartilage using classical methods showed that MMx fully induced degradation of the cartilage. Evaluation using CEX-μCT showed that local areas of the medial cartilage of the tibial plateau were significantly reduced in MMx-treated knees compared to that in sham-treated knees. On the other hand, total cartilage volumes were significantly increased in MMx-treated knees. Based on the findings of this study, the researchers in KOA research could be helped to select an optimal KOA model to discover new drugs.

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Schisandrin B ameliorated chondrocytes inflammation and osteoarthritis via suppression of NF-κB and MAPK signal pathways

Cited by 75 publications

References 26 publications

Reactivation of NR4A1 Restrains Chondrocyte Inflammation and Ameliorates Osteoarthritis in Rats

Reactivation of NR4A1 Restrains Chondrocyte Inflammation and Ameliorates Osteoarthritis in Rats

Sema4D Aggravated LPS-Induced Injury via Activation of the MAPK Signaling Pathway in ATDC5 Chondrocytes

Characterization of Osteoarthritis in a Medial Meniscectomy-Induced Animal Model Using Contrast-Enhanced X-Ray Microtomography

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