Pseudolaric acid B ameliorates synovial inflammation and vessel formation by stabilizing PPARγ to inhibit NF‐κB signalling pathway

Lu, Jiansen; Guan, Hong; Wu, Dan; Hu, Zhiqiang; Jiang, Huaji; Yu, Jingquan; Zeng, Ke; Li, Hongyu; Zhang, Haiyan; Pan, Chenglong; Cai, Daozhang; Xiao, Yu

doi:10.1111/jcmm.16670

Cited by 16 publications

(13 citation statements)

References 74 publications

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“…Previous studies indicated that PPARG reduction in osteoarthritic cartilage was highly correlated with increased expression of inflammatory and catabolic factors. [41][42][43] To further validate the results of network pharmacological analysis, we first confirmed that the level of PPARG in articular cartilage of DMM-induced mice was reduced significantly, which could be rescued with E.G. treatment.…”

Section: Discussionmentioning

confidence: 72%

Chondroprotective Mechanism of Eucommia ulmoides Oliv.-Glycyrrhiza uralensis Fisch. Couplet Medicines in Knee Osteoarthritis via Experimental Study and Network Pharmacology Analysis

Wang¹,

Xu²,

Sun³

et al. 2023

DDDT

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Background: Knee osteoarthritis (KOA) is the primary prevalent disabling joint disorder among osteoarthritis (OA), and there is no particularly effective treatment at the clinic. Traditional Chinese medicine (TCM) herbs, such as Eucommia ulmoides Oliv. and Glycyrrhiza uralensis Fisch. (E.G.) couplet medicines, have been reported to exhibit beneficial health effects on KOA, exact mechanism of E.G. nevertheless is not fully elucidated. Purpose: We assess the therapeutic effects of E.G. on KOA and explore its underlying molecular mechanism. Methods: UPLC-Q-TOF/MS technique was used to analyze the active chemical constituents of E.G. The destabilization of the medial meniscus model (DMM) was employed to evaluate the chondroprotective action of E.G. in KOA mice using histomorphometry, μCT, behavioral testing and immunohistochemical staining. Additionally, network pharmacology and molecular docking were used to predict potential targets for anti-KOA activities of E.G., which was further verified through in vitro experiments. Results: In vivo studies have shown that E.G. could significantly ameliorate DMM-induced KOA phenotypes including subchondral bone sclerosis, cartilage degradation, gait abnormality and thermal pain reaction sensibility. E.G. treatment could also promote extracellular matrix synthesis to protect articular chondrocytes, which was indicated by Col2 and Aggrecan expressions, as well as reducing matrix degradation by inhibiting MMP13 expression. Interestingly, network pharmacologic analysis showed that PPARG might be a therapeutic center. Further study proved that E.G.-containing serum (EGS) could up-regulate PPARG mRNA level in IL-1β-induced chondrocytes. Notably, significant effects of EGS on the increment of anabolic gene expressions (Col2, Aggrecan) and the decrement of catabolic gene expressions (MMP13, Adamts5) in KOA chondrocytes were abolished due to the silence of PPARG. Conclusion: E.G. played a chondroprotective role in anti-KOA by inhibiting extracellular matrix degradation, which might be related to PPARG.

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Section: Discussionmentioning

confidence: 72%

Chondroprotective Mechanism of Eucommia ulmoides Oliv.-Glycyrrhiza uralensis Fisch. Couplet Medicines in Knee Osteoarthritis via Experimental Study and Network Pharmacology Analysis

Wang¹,

Xu²,

Sun³

et al. 2023

DDDT

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“…At the same time, PAB inhibits NF-κB signaling by stabilizing peroxisome proliferator activated receptor γ to prevent M1 polarization and angiogenesis, thereby further reducing synovitis and OA progression ( 51 ). In vivo , mice treated with PAB show significantly reduced cartilage destruction and improved synovitis ( 52 ). These results expand the potential clinical application of PAB and strengthen the possibility that early targeting of synovitis or inhibiting angiogenesis may prevent OA ( 52 ).…”

Section: Macrophages Are Emerging Targets For Oa Treatmentmentioning

confidence: 99%

“…In vivo , mice treated with PAB show significantly reduced cartilage destruction and improved synovitis ( 52 ). These results expand the potential clinical application of PAB and strengthen the possibility that early targeting of synovitis or inhibiting angiogenesis may prevent OA ( 52 ).…”

Section: Macrophages Are Emerging Targets For Oa Treatmentmentioning

confidence: 99%

Role of macrophage polarization in osteoarthritis (Review)

Chen

Hong

Sun³

et al. 2022

Exp Ther Med

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Osteoarthritis (OA) is a disease involving the whole joint that seriously reduces the living standards of individuals. Traditional treatments include physical therapy, administration of anti-inflammatory and analgesic drugs and injection of glucocorticoids or hyaluronic acid into the joints. However, these methods have limited efficacy and it is difficult to reverse the progression of OA, therefore it is urgent to find new effective treatment methods. Immune microenvironment is significant in the occurrence and development of OA. Recent studies have shown that macrophages are important targets for the treatment of OA. Macrophages are polarized into M1 pro-inflammatory phenotype and M2 anti-inflammatory phenotype under stimulation of different factors, which release and regulate inflammatory response and cartilage growth. Accumulating studies have tried to alleviate OA by regulating macrophage homeostasis. The present study summarized the related studies, discuss the mechanism of various therapeutic reagents on OA, expound the molecular mechanism of drug effect on OA and attempted to provide clues for the treatment of OA.

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“…Specifically targeting monocyte-derived macrophages might be a more efficient strategy, due to their supposedly important role in skewing synovial macrophage phenotype as shown by the evidence presented in this review. Using factors that stabilize PPARγ could aid in skewing macrophage phenotype to become more anti-inflammatory [ 85 ]. Alternatively, inhibiting monocyte infiltration by blocking CCL2 or CCR2 (a phase 2 clinical trial using CCR antagonist CNTX-6970 is currently ongoing), or inducing innate immune tolerance via vaccination with BCG, are some of many possible options to interfere in this process in an attempt to find a novel therapy for OA.…”

Section: Implications For Therapeutic Optionsmentioning

confidence: 99%

Activation of circulating monocytes by low-density lipoprotein—a risk factor for osteoarthritis?

et al. 2022

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Synovial macrophages are key mediators of OA pathology, and skewing of macrophage phenotype in favour of an M1-like phenotype is thought to underlie the chronicity of synovial inflammation in OA. Components of the metabolic syndrome (MetS), such as dyslipidaemia, can affect macrophage phenotype and function, which could explain the link between MetS and OA development. Recently published studies have provided novel insights into the different origins and heterogeneity of synovial macrophages. Considering these findings, we propose an important role for monocyte-derived macrophages in particular, as opposed to yolk-sac derived residential macrophages, in causing a pro-inflammatory phenotype shift. We will further explain how this can start even prior to synovial infiltration; in the circulation, monocytes can be trained by metabolic factors such as low-density lipoprotein to become extra responsive to chemokines and damage-associated molecular patterns. The concept of innate immune training has been widely studied and implicated in atherosclerosis pathology, but its involvement in OA remains uncharted territory. Finally, we evaluate the implications of these insights for targeted therapy directed to macrophages and metabolic factors.

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Pseudolaric acid B ameliorates synovial inflammation and vessel formation by stabilizing PPARγ to inhibit NF‐κB signalling pathway

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 16 publications

References 74 publications

Chondroprotective Mechanism of Eucommia ulmoides Oliv.-Glycyrrhiza uralensis Fisch. Couplet Medicines in Knee Osteoarthritis via Experimental Study and Network Pharmacology Analysis

Chondroprotective Mechanism of Eucommia ulmoides Oliv.-Glycyrrhiza uralensis Fisch. Couplet Medicines in Knee Osteoarthritis via Experimental Study and Network Pharmacology Analysis

Role of macrophage polarization in osteoarthritis (Review)

Activation of circulating monocytes by low-density lipoprotein—a risk factor for osteoarthritis?

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