Targeting β-catenin dependent Wnt signaling via peptidomimetic inhibitors in murine chondrocytes and OA cartilage

Held, Annelena; Glas, Adrian; Dietrich, L.; Bollmann, M.; Brandstädter, K.; Grossmann, Tom N.; Lohmann, Christoph H.; Pap, Thomas; Bertrand, Jessica

doi:10.1016/j.joca.2018.02.908

Cited by 37 publications

(26 citation statements)

References 16 publications

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“…Additionally, SOX9 expression in chondrocytes is strictly controlled by other factors (e.g., HIF1α, miR-145, SOX5) [ 63 – 65 ]. Wnt signaling plays an important role during chondrogenesis and hypertrophic differentiation [ 43 ]. Multiple studies have shown that the genes encoding the Wnt signaling regulatory components GSK-3β, adenomatous polyposis coli, and Wnt3a are direct targets of miR-27b [ 66 – 68 ].…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA-27b targets CBFB to inhibit differentiation of human bone marrow mesenchymal stem cells into hypertrophic chondrocytes

Liu

Chen

et al. 2020

Stem Cell Res Ther

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Background Human bone marrow-derived mesenchymal stem cells (hBMSCs) have chondrocyte differentiation potential and are considered to be a cell source for cell-transplantation-mediated repair of cartilage defects, including those associated with osteoarthritis (OA). However, chondrocyte hypertrophic differentiation is a major obstacle for the application of hBMSCs in articular cartilage defect treatment. We have previously shown that microRNA-27b (miR-27b) inhibits hypertrophy of chondrocytes from rat knee cartilage. In this study, we investigated the role of miR-27b in chondrocyte hypertrophic differentiation of hBMSCs. Methods Chondrogenic marker and microRNA expression in hBMSC chondrogenic pellets were evaluated using RT-qPCR and immunohistochemistry. The hBMSCs were transfected with miR-27b before inducing differentiation. Gene and protein expression levels were analyzed using RT-qPCR and western blot. Coimmunoprecipitation was used to confirm interaction between CBFB and RUNX2. Luciferase reporter assays were used to demonstrate that CBFB is a miR-27b target. Chondrogenic differentiation was evaluated in hBMSCs treated with shRNA targeting CBFB. Chondrogenic hBMSC pellets overexpressing miR-27b were implanted into cartilage lesions in model rats; therapeutic effects were assessed based on histology and immunohistochemistry. Results The hBMSCs showed typical MSC differentiation potentials. During chondrogenic differentiation, collagen 2 and 10 (COL2 and COL10), SOX9, and RUNX2 expression was upregulated. Expression of miR-140, miR-143, and miR-181a increased over time, whereas miR-27b and miR-221 were downregulated. Cartilage derived from hBMSC and overexpressing miR-27b exhibited higher expression of COL2 and SOX9, but lower expression of COL10, RUNX2, and CBFB than did the control cartilage. CBFB and RUNX2 formed a complex, and CBFB was identified as a novel miR-27b target. CBFB knockdown by shRNA during hBMSC chondrogenic differentiation led to significantly increased COL2 and SOX9 expression and decreased COL10 expression. Finally, miR-27b-overexpressing hBMSC chondrogenic pellets had better hyaline cartilage morphology and reduced expression of hypertrophic markers and tend to increase repair efficacy in vivo. Conclusion MiR-27b plays an important role in preventing hypertrophic chondrogenesis of hBMSCs by targeting CBFB and is essential for maintaining a hyaline cartilage state. This study provides new insights into the mechanism of hBMSC chondrocyte differentiation and will aid in the development of strategies for treating cartilage injury based on hBMSC transplantation.

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Section: Discussionmentioning

confidence: 99%

“…SOX9 is a negative regulator of chondrocyte hypertrophic differentiation [42], and the β-catenin pathway is involved in controlling SOX9 expression [43]. Thus, we examined whether miR-27b enhanced SOX9 expression through the β-catenin pathway.…”

Section: Mir-27b Inhibits Hbmsc Hypertrophic Chondrocyte Differentiatmentioning

confidence: 99%

MicroRNA-27b targets CBFB to inhibit differentiation of human bone marrow mesenchymal stem cells into hypertrophic chondrocytes

Liu

Chen

et al. 2020

Stem Cell Res Ther

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“…In this study, we found that Wnt-3-b-catenin pathway rather than Wnt10a was up-regulated with the OA grade. Previous studies showed that the Wnt pathway participated in a series of cell homeostasis processes, including cell differentiation, proliferation, migration and adhesion [22,23]. Further studies found that the Wnt pathway was inhibited in normal cartilage, whereas its activation promoted OA [23].…”

Section: Discussionmentioning

confidence: 99%

Cyclin D1 regulates osteoarthritis chondrocyte apoptosis via WNT3/β-catenin signalling

Chen

You

Wang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Objective: Cyclin D1 was an important molecular involved in the pathological process of osteoarthritis (OA). The purpose of this study was to identify the effect and potential mechanism of Cyclin D1 for the proliferation and apoptosis of OA chondrocytes. Methods: We used polymerase chain reaction (PCR) method to identify the expression levels of Cyclin D1 and downstream Wnt/b-catenin pathway-related genes in OA chondrocytes according to the grade of OA. Small interfering RNA (siRNA) or overexpression of Cyclin D1 were used to identify the role of Cyclin D1 in cell proliferation and apoptosis. Next, we used XAV-939 to inhibit the Wnt/b-catenin pathway and explore the relevant mechanism. Results: Cyclin D1 was significantly decreased with OA grade (p < .05). After siCyclin D1 transfection, the expression level of WNT3 and nuclear b-catenin were significantly increased, while Wnt10a and total b-catenin were not obviously changed. Co-cultured with XAV-939 and siCyclin D1 abolished the effects of siCyclin D1 on proliferation and apoptosis of OA chondrocytes (p < .05). Conclusions: Cyclin D1 regulated chondrocyte proliferation and apoptosis through Wnt3/b-catenin instead of Wnt10a/b-catenin signalling pathway.

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“…A promising recent reagent is SM04690 (Samumed), an inhibitor of WNT receptor binding that is now in a phase III clinical trial, which has been shown to elicit protective effects on cartilage during joint destruction in an acute cruciate ligament tear and partial medial meniscectomy rodent OA model [48]. Inhibition of β-catenin, an intracellular signal transducer of WNT, by StAx-35R inhibits chondrocyte phenotypic shifting of human OA cartilage explants, and has been reported to result in increased SRY-Box transcription factor 9 (SOX9) and aggrecan gene expression and decreased collagen type X α1 chain (COL10A1) gene expression [49,50].…”

Section: Traumamentioning

confidence: 99%

Pathogenesis of Osteoarthritis: Risk Factors, Regulatory Pathways in Chondrocytes, and Experimental Models

Alexander

et al. 2020

Biology

162

115

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As the most common chronic degenerative joint disease, osteoarthritis (OA) is the leading cause of pain and physical disability, affecting millions of people worldwide. Mainly characterized by articular cartilage degradation, osteophyte formation, subchondral bone remodeling, and synovial inflammation, OA is a heterogeneous disease that impacts all component tissues of the articular joint organ. Pathological changes, and thus symptoms, vary from person to person, underscoring the critical need of personalized therapies. However, there has only been limited progress towards the prevention and treatment of OA, and there are no approved effective disease-modifying osteoarthritis drugs (DMOADs). Conventional treatments, including non-steroidal anti-inflammatory drugs (NSAIDs) and physical therapy, are still the major remedies to manage the symptoms until the need for total joint replacement. In this review, we provide an update of the known OA risk factors and relevant mechanisms of action. In addition, given that the lack of biologically relevant models to recapitulate human OA pathogenesis represents one of the major roadblocks in developing DMOADs, we discuss current in vivo and in vitro experimental OA models, with special emphasis on recent development and application potential of human cell-derived microphysiological tissue chip platforms.

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Targeting β-catenin dependent Wnt signaling via peptidomimetic inhibitors in murine chondrocytes and OA cartilage

Abstract: These data indicate that blockade of canonical Wnt signaling might be a therapeutic strategy to treat early OA cases and protect further cartilage degradation by preventing chondrocyte hypertrophic differentiation.

Cited by 37 publications

References 16 publications

MicroRNA-27b targets CBFB to inhibit differentiation of human bone marrow mesenchymal stem cells into hypertrophic chondrocytes

MicroRNA-27b targets CBFB to inhibit differentiation of human bone marrow mesenchymal stem cells into hypertrophic chondrocytes

Cyclin D1 regulates osteoarthritis chondrocyte apoptosis via WNT3/β-catenin signalling

Pathogenesis of Osteoarthritis: Risk Factors, Regulatory Pathways in Chondrocytes, and Experimental Models

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