Osteoarthritis and Toll-Like Receptors: When Innate Immunity Meets Chondrocyte Apoptosis

Barreto, Gonçalo; Manninen, Mikko; Eklund, Kari K.

doi:10.3390/biology9040065

Cited by 53 publications

(51 citation statements)

References 98 publications

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“…Actually, 10 functional TLRs were identified in humans numbered TLR1–10. TLR-1,−2,−4,−5,−6, and−10 are located at the cell surface, while TLR-3,−7,−8, and−9 are present at the endolysosomal membrane ( 81 ). The signaling pathways activated by TLR involve the recruitment of adapter proteins such as MyD88, TIR domain-containing adaptor-inducing interferon (TRIF), TRIF-related adaptor molecule (TRAM), MyD88-adaptor like (Mal), and the activation of nuclear factors among which NF-κB.…”

Section: Cellular Receptors Involved In Damage-associated Molecular Pmentioning

confidence: 99%

The Damage-Associated Molecular Patterns (DAMPs) as Potential Targets to Treat Osteoarthritis: Perspectives From a Review of the Literature

et al. 2021

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During the osteoarthritis (OA) process, activation of immune systems, whether innate or adaptive, is strongly associated with low-grade systemic inflammation. This process is initiated and driven in the synovial membrane, especially by synovium cells, themselves previously activated by damage-associated molecular patterns (DAMPs) released during cartilage degradation. These fragments exert their biological activities through pattern recognition receptors (PRRs) that, as a consequence, induce the activation of signaling pathways and beyond the release of inflammatory mediators, the latter contributing to the vicious cycle between cartilage and synovial membrane. The primary endpoint of this review is to provide the reader with an overview of these many molecules categorized as DAMPs and the contribution of the latter to the pathophysiology of OA. We will also discuss the different strategies to control their effects. We are convinced that a better understanding of DAMPs, their receptors, and associated pathological mechanisms represents a decisive issue for degenerative joint diseases such as OA.

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Section: Cellular Receptors Involved In Damage-associated Molecular Pmentioning

confidence: 99%

The Damage-Associated Molecular Patterns (DAMPs) as Potential Targets to Treat Osteoarthritis: Perspectives From a Review of the Literature

et al. 2021

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“…In the pathogenesis of OA, inflammatory mediators, mechanical stimulation, oxidative stress, and cellular damage collude in the function and viability of chondrocytes, reprogramming them to undergo hypertrophic differentiation and initial aging, leading them to be responsive to the effects of proinflammatory and procatabolic mediators [4]. The fundamental pathophysiological pathways encompassed in OA involve some the typical assumes, so called proinflammatory TNF-α and interleukins (IL-1β, IL-6, and IL-8), and procatabolic mediators through their signaling pathways and the well-defined effects of MAPK and NF-κB signaling responses in addition to reprogramming are 'switching' pathways in transcriptional networks [25].…”

Section: Discussionmentioning

confidence: 99%

In Vitro Evaluation of the Anti-Inflammatory Effect of KMUP-1 and In Vivo Analysis of Its Therapeutic Potential in Osteoarthritis

et al. 2021

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Osteoarthritis is a degenerative arthropathy that is mainly characterized by dysregulation of inflammatory responses. KMUP-1, a derived chemical synthetic of xanthine, has been shown to have anti-inflammatory and antioxidant properties. Here, we aimed to investigate the in vitro anti-inflammatory and in vivo anti-osteoarthritis effects of KMUP-1. Protein and gene expressions of inflammation markers were determined by ELISA, Western blotting and microarray, respectively. RAW264.7 mouse macrophages were cultured and pretreated with KMUP-1 (1, 5, 10 μM). The productions of TNF-α, IL-6, MMP-2 and MMP- 9 were reduced by KMUP-1 pretreatment in LPS-induced inflammation of RAW264.7 cells. The expressions of iNOS, TNF-α, COX-2, MMP-2 and MMP-9 were also inhibited by KMUP-1 pretreatment. The gene expression levels of TNF and COX families were also downregulated. In addition, KMUP-1 suppressed the activations of ERK, JNK and p38 as well as phosphorylation of IκBα/NF-κB signaling pathways. Furthermore, SIRT1 inhibitor attenuated the inhibitory effect of KMUP-1 in LPS-induced NF-κB activation. In vivo study showed that KMUP-1 reduced mechanical hyperalgesia in monoiodoacetic acid (MIA)-induced rats OA. Additionally, KMUP-1 pretreatment reduced the serum levels of TNF-α and IL-6 in MIA-injected rats. Moreover, macroscopic and histological observation showed that KMUP-1 reduced articular cartilage erosion in rats. Our results demonstrated that KMUP-1 inhibited the inflammatory responses and restored SIRT1 in vitro, alleviated joint-related pain and cartilage destruction in vivo. Taken together, KMUP-1 has the potential to improve MIA-induced articular cartilage degradation by inhibiting the levels and expression of inflammatory mediators suggesting that KMUP-1 might be a potential therapeutic agent for OA.

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“…TLRs are expressed in articular cartilage and are upregulated in OA cartilage. TLR expression and signal transduction are related to the pathogenesis of OA [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology Approach to Uncover the Mechanism Governing the Effect of Simiao Powder on Knee Osteoarthritis

Huang

Shi

et al. 2020

BioMed Research International

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Objective. To explore the molecular mechanism of Simiao powder in the treatment of knee osteoarthritis. Methods. Based on oral bioavailability and drug-likeness, the main active components of Simiao powder were screened using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). GeneCard, OMIM, DisGeNET, DrugBank, PharmGkb, and the Therapeutic Target Database were used to establish target databases for knee osteoarthritis. Cytoscape software was used to construct a visual interactive network diagram of “active ingredient - action target – disease.” The STRING database was used to construct a protein interaction network and analyze related protein interaction relationships. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) biological process enrichment analysis were performed on the core targets. Additionally, Discovery Studio software was used for molecular docking verification of active pharmaceutical ingredients and disease targets. Results. Thirty-seven active components of Simiao powder were screened, including 106 common targets. The results of network analysis showed that the targets were mainly involved in regulating biological processes such as cell metabolism and apoptosis. Simiao powder components were predicted to exert their therapeutic effect on the AGE-RAGE signaling pathway in diabetic complications, IL-17 signaling pathway, TNF signaling pathway, Toll-like receptor signaling pathway, and HIF-1 signaling pathway. The molecular docking results showed that the active components of Simiao powder had a good match with the targets of IL1B, MMP9, CXCL8, MAPK8, JUN, IL6, MAPK1, EGF, VEGFA, AKT1, and PTGS2. Conclusion. Simiao powder has multisystem, multicomponent, and multitarget characteristics in treating knee osteoarthritis. Its possible mechanism of action includes inhibiting the inflammatory response, regulating immune function, and resisting oxidative stress to control the occurrence and development of the disease. Quercetin, wogonin, kaempferol, beta-sitosterol, and other active ingredients may be the material basis for the treatment of knee osteoarthritis.

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Osteoarthritis and Toll-Like Receptors: When Innate Immunity Meets Chondrocyte Apoptosis

Cited by 53 publications

References 98 publications

The Damage-Associated Molecular Patterns (DAMPs) as Potential Targets to Treat Osteoarthritis: Perspectives From a Review of the Literature

The Damage-Associated Molecular Patterns (DAMPs) as Potential Targets to Treat Osteoarthritis: Perspectives From a Review of the Literature

In Vitro Evaluation of the Anti-Inflammatory Effect of KMUP-1 and In Vivo Analysis of Its Therapeutic Potential in Osteoarthritis

Network Pharmacology Approach to Uncover the Mechanism Governing the Effect of Simiao Powder on Knee Osteoarthritis

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