Involvement of soluble receptor activator of nuclear factor-κB ligand (sRANKL) in collagenase-induced murine osteoarthritis and human osteoarthritis

Dimitrova, Petya; Toncheva, А.; Gyurkovska, Valeriya; Ivanovska, Nina

doi:10.1007/s00296-010-1723-8

Cited by 4 publications

(5 citation statements)

References 28 publications

(27 reference statements)

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“…At week 1 and 4 after collagenase injection, total knee joints were dissected and processed as previously described (27), stained by Safranin O and Toluidine blue methods and CIOA development was defined in a blinded protocol by the Grade-Stage scoring system recommended by Osteoarthritis Research Society International (28). A tartrate-resistant acid phosphatase (TRAP) kit (Sigma-Aldrich) was used to identify activated osteoclasts.…”

Section: Histological Proceduresmentioning

confidence: 99%

“…A tartrate-resistant acid phosphatase (TRAP) kit (Sigma-Aldrich) was used to identify activated osteoclasts. Van Gieson staining was performed to evaluate collagen elastic fibers in cartilage and subchondral bone (27). The classical Jenner-Giemsa method was used to distinguish osteoblasts (basophilic cytoplasm, blue) from osteoclasts (eosinophilic cytoplasm, purple) in subchondral bone marrow (BM) (29).…”

Section: Histological Proceduresmentioning

confidence: 99%

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CXCR3/CXCL10 Axis Regulates Neutrophil–NK Cell Cross-Talk Determining the Severity of Experimental Osteoarthritis

Benigni

Dimitrova

Antonangeli

et al. 2017

The Journal of Immunology

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Several immune cell populations are involved in cartilage damage, bone erosion, and resorption processes during osteoarthritis. The purpose of this study was to investigate the role of NK cells in the pathogenesis of experimental osteoarthritis and whether and how neutrophils can regulate their synovial localization in the disease. Experimental osteoarthritis was elicited by intra-articular injection of collagenase in wild type and 8-wk old mice. To follow osteoarthritis progression, cartilage damage, synovial thickening, and osteophyte formation were measured histologically. To characterize the inflammatory cells involved in osteoarthritis, synovial fluid was collected early after disease induction, and the cellular and cytokine content were quantified by flow cytometry and ELISA, respectively. We found that NK cells and neutrophils are among the first cells that accumulate in the synovium during osteoarthritis, both exerting a pathogenic role. Moreover, we uncovered a crucial role of the CXCL10/CXCR3 axis, with CXCL10 increasing in synovial fluids after injury and mice being protected from disease development. Finally, in vivo depletion experiments showed that neutrophils are involved in an NK cell increase in the synovium, possibly by expressing CXCL10 in inflamed joints. Thus, neutrophils and NK cells act as important disease-promoting immune cells in experimental osteoarthritis and their functional interaction is promoted by the CXCL10/CXCR3 axis.

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Section: Histological Proceduresmentioning

confidence: 99%

Section: Histological Proceduresmentioning

confidence: 99%

CXCR3/CXCL10 Axis Regulates Neutrophil–NK Cell Cross-Talk Determining the Severity of Experimental Osteoarthritis

Benigni

Dimitrova

Antonangeli

et al. 2017

The Journal of Immunology

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“…In a model of collagenase-induced osteoarthritis glucosamine inhibits bone destruction and decreases the number of RANKL-bearing neutrophils in SF [21]. Our previous studies involving patients with osteoarthritis show altered TNF- α production in response to TLR2 stimulation and elevated TLR2 and RANKL expression on blood neutrophils [22, 23]. In the present work we investigate the bone-destructive activity of Ly6G + CD11b + cells in TLR2 ligand driven arthritis.…”

Section: Introductionmentioning

confidence: 99%

TLR2 Elicits IL-17-Mediated RANKL Expression, IL-17, and OPG Production in Neutrophils from Arthritic Mice

Milanova

Ivanovska

Dimitrova

2014

Mediators of Inflammation

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We investigated the ability of neutrophils to express receptor activator of nuclear factor kappa-B ligand (RANKL), to secrete osteoprotegerin (OPG), and to produce IL-17. Arthritis was induced by intra-articular injection of zymosan, a ligand for Toll-like receptor 2 (TLR2). Frequencies of neutrophils in bone marrow (BM), blood and synovial fluid (SF), receptor expression, and cytokine production were evaluated by flow cytometry. 1A8 antibody (1A8 Ab) was used to deplete neutrophils in zymosan-injected SCID mice. IL-17, RANKL, and OPG amounts in SF, serum, or cell cultures were determined by ELISA. The development of arthritis was associated with increased secretion of IL-17, RANKL, and OPG in serum and SF, elevated frequencies of Ly6G+CD11b+ cells in BM, blood, and SF and upregulated RANKL expression. Both IL-17 and OPG were absent in serum and SF after neutrophil depletion; therefore we assume that they were released by neutrophils. In vitro blood Ly6G+CD11b+ cells from arthritic mice produced spontaneously IL-17, IFN-γ, and OPG and expressed RANKL. This phenotype was sustained by IL-17. TLR2 engagement increased IL-17 and IFN-γ production, potentiated IL-17-mediated RANKL expression, and inhibited OPG secretion. We conclude that TLR2 regulates the destructive potential of neutrophils and its targeting might limit joint alterations in arthritis.

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“…In the present study, the PPI network map of the SIN for the treatment of OA was constructed using String database and Cytoscape software, and 16 underlying core targets, including ALB, IGF1, RXRA, MMP9, PPARG, PTGS2, CTSK, NR3C1, AR, BMP2, CYP2C9, ESR1, ESR2, HSD11B1, MMP1, and TGFBR1, were acquired. Among them, ALB, IGF1, RXRA, MMPs, PPARG, PTGS2, ESRs, CTSK, TGFBR1, NR3C1, and BMP2 genes are positively involved in the OA disease, [25][26][27][28][29][30][31][32] while CYP2C9 and HSD11B1 genes take parts in the inflammatory response. 33,34 The results indicated that these 16 major genes are potential core targets responsible for SIN to treat OA, and are closely associated with inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

Integrated Network Pharmacology, Molecular Docking, and Experimental Validation to Explore Potential Mechanisms of Sinomenine in the Treatment of Osteoarthritis

Wang,

Lai,

Xiang

et al. 2024

Natural Product Communications

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Objective To systematically explore the targets and signaling pathways of sinomenine (SIN) in the treatment of osteoarthritis (OA) using integrated network pharmacology, molecular docking, and experimental validation. Methods The TCMSP, SwissADME, and Pharmmapper databases were used to predict SIN targets, while the databases of GeneCards, DisGeNET, OMIM, and DrugBank were selected to acquire OA targets. Subsequently, the intersection targets of SIN and OA disease were collected using the Veeny platform. Then, the protein-protein interaction (PPI) network map of “SIN-targets-OA” was established using String database and Cytoscape software. Additionally, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed through the Database for Annotation, Visualization and Integrated Discovery (DAVID). Additionally, the potential proteins of SIN against OA were validated via molecular docking technique. Finally, the experimental validation was performed in SW1353 cells induced by interleukin (IL)-1β. Results A total of 315 potential targets of SIN and 4300 OA-associated targets were collected from public databases, and 42 intersecting potential targets of SIN and OA disease acquired. Then, the PPI network diagram of “SIN-targets-OA” was acquired that comprised a total of 43 nodes and 82 edges. Moreover, 173 GO and 21 KEGG pathway entries were screened with a P-value <.05. Among them, peroxisome proliferator-activated receptor (PPAR) and IL-17 are the core signaling pathways. Molecular docking technique indicated strong binding energies of SIN with PPAR (−6.1 kcal/mol) and IL-17 (−6.3 kcal/mol). Lastly, SIN at the concentration of 50 μmol/L has a significant effect on IL-1β-induced SW1353 cells by the inhibition of PPAR-γ and IL-17A proteins without cytotoxicity. Conclusion This work revealed the underlying targets and signaling pathways of SIN against OA using integrated network pharmacology molecular docking, and experimental validation. These findings provide scientific evidence for the clinical application of SIN for OA treatment.

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Involvement of soluble receptor activator of nuclear factor-κB ligand (sRANKL) in collagenase-induced murine osteoarthritis and human osteoarthritis

Cited by 4 publications

References 28 publications

CXCR3/CXCL10 Axis Regulates Neutrophil–NK Cell Cross-Talk Determining the Severity of Experimental Osteoarthritis

CXCR3/CXCL10 Axis Regulates Neutrophil–NK Cell Cross-Talk Determining the Severity of Experimental Osteoarthritis

TLR2 Elicits IL-17-Mediated RANKL Expression, IL-17, and OPG Production in Neutrophils from Arthritic Mice

Integrated Network Pharmacology, Molecular Docking, and Experimental Validation to Explore Potential Mechanisms of Sinomenine in the Treatment of Osteoarthritis

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