Mianserin suppresses R-spondin 2-induced activation of Wnt/β-catenin signaling in chondrocytes and prevents cartilage degradation in a rat model of osteoarthritis

Okura, Toshiaki; Ohkawara, Bisei; Takegami, Yasuhiko; Ito, Mikako; Matsubara, Akio; Seki, Tomohiro; Ishiguro, Naoki; Ohno, Kinji

doi:10.1038/s41598-019-39393-x

Cited by 21 publications

(35 citation statements)

References 52 publications

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“…In our previous study (Diederichs et al, 2019), aiming to identify factors related to hypertrophic MSC differentiation, RSPO2 was among the most differentially expressed genes between hypertrophic and nonhypertrophic chondrocytes. Additionally, elevated expression of RSPO2 (Takegami et al, 2016;Okura et al, 2019) was found to correlate with the levels of hypertrophy of chondrocytes in OA cartilage of human patients, thus indicating its putative role in the regulation of the pathologic phenotype during OA development. Inhibition of RSPO2 either with a neutralizing antibody or by treatment with the mianserin drug (Okura et al, 2019) has been shown to reduce cartilage degradation in a murine OA model.…”

Section: Rspo2 Is a Target Of Mir-181amentioning

confidence: 94%

MiR-181a Targets RSPO2 and Regulates Bone Morphogenetic Protein – WNT Signaling Crosstalk During Chondrogenic Differentiation of Mesenchymal Stromal Cells

Melnik

Hofmann

Gabler

et al. 2021

Front. Cell Dev. Biol.

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Mechanisms of WNT and bone morphogenetic protein (BMP) signaling crosstalk is in the focus of multiple biological studies, and it also has been discovered to play important roles in human mesenchymal stromal cells (MSC) that are of great interest for neocartilage engineering due to their high chondrogenic differentiation potential. However, MSC-derived chondrocytes undergo hypertrophic degeneration that impedes their clinical application for cartilage regeneration. In our previous study, we established that several microRNAs (miRs) are differentially expressed between articular chondrocytes (AC) – and MSC-derived neocartilage, with miR-181a being the most prominent candidate as key microRNA involved in the regulation of a balance between chondral and endochondral differentiation. The aim of this study was the identification of precise mRNA targets and signaling pathways regulated by miR-181a in MSC during chondrogenesis. MiR-181a was upregulated during chondrogenesis of MSC, along with an increase of the hypertrophic phenotype in resulting cartilaginous tissue. By in silico analysis combined with miR reporter assay, the WNT signaling activator and BMP signaling repressor RSPO2 was suggested as a target of miR-181a. Further validation experiments confirmed that miR-181a targets RSPO2 mRNA in MSC. It was found that in human MSC miR-181a activated BMP signaling manifested by the accumulation of SOX9 protein and increased phosphorylation of SMAD1/5/9. These effects, together with the concomitant reduction of canonical WNT signaling induced by miR-181a mimic, were in accordance with the effects expected by the loss of RSPO2, thus indicating the causative link between miR-181a and RSPO2. Moreover, we observed that a tight correlation between miR-181a and miR-218 expression levels in healthy human cartilage tissue was disrupted in osteoarthritis (OA) highlighting the importance of the WNT-BMP signaling crosstalk for preventing OA.

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Section: Rspo2 Is a Target Of Mir-181amentioning

confidence: 94%

MiR-181a Targets RSPO2 and Regulates Bone Morphogenetic Protein – WNT Signaling Crosstalk During Chondrogenic Differentiation of Mesenchymal Stromal Cells

Melnik

Hofmann

Gabler

et al. 2021

Front. Cell Dev. Biol.

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“…Mianserin suppresses R-spondin 2-induced activation of Wnt/β- catenin signaling in chondrocytes and prevents cartilage degradation in a rat model of osteoarthritis [96]. Fluoxetine, an antidepressant in the class of selective serotonin reuptake inhibitors (SSRI), decreased expressions of Axin2 and MMP13, suppressed degradation of proteoglycans, and increased expression of Sox9 in chondrogenically differentiated ATDC5 cells [97].…”

Section: Therapy For Osteoarthritismentioning

confidence: 99%

Wnt signaling: a promising target for osteoarthritis therapy

et al. 2019

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Osteoarthritis (OA) is the most common joint disease worldwide and a leading cause of disability. Characterized by degradation of articular cartilage, synovial inflammation, and changes in periarticular and subchondral bone, OA can negatively impact an individual's physical and mental well-being. Recent studies have reported several critical signaling pathways as key regulators and activators of cellular and molecular processes during OA development. Wnt signaling is one such pathway whose signaling molecules and regulators were shown to be abnormally activated or suppressed. As such, agonists and antagonists of those molecules are potential candidates for OA treatment. Notably, a recent phase I clinical trial (NCT02095548) demonstrated the potential of SM04690, a small-molecule inhibitor of the Wnt signaling pathway, as a disease-modifying oseoarthritis drug (DMOAD). This review summarizes the role and mechanism of Wnt signaling and related molecules in regulating OA progression, with a view to accelerating the translation of such evidence into the development of strategies for OA treatment, particularly with respect to potential applications of molecules targeting the Wnt signaling pathway.

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“…Numerous signaling pathways are involved in the process of OA, including bone morphogenetic proteins (8), Indian hedgehog (9), hypoxia-induced and Wnt signaling pathways (10,11). As an important component of the Wnt signaling pathway, β-catenin is activated by Wnt family proteins and participates in the pathological process of KOA (12).…”

Section: Introductionmentioning

confidence: 99%

The GSK‑3β/β‑catenin signaling pathway is involved in HMGB1‑induced chondrocyte apoptosis and cartilage matrix degradation

et al. 2020

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Knee osteoarthritis (KOA) is a common joint disease with a high incidence rate among middle-aged and elderly individuals. However, the precise underlying pathological mechanisms and effective treatment of this disease remain to be determined. To explore the effect of high mobility group box 1 (HMGB1) on chondrocyte apoptosis and catabolism, the ATdc5 cell line was cultured as an in vitro model for cartilage research. cultured cells were treated with recombinant HMGB1 at different concentrations. Hoechst staining and flow cytometry demonstrated that HMGB1 administration significantly induced apoptosis of ATdc5 cells, which was the same as the effect of interleukin-1β treatment. HMGB1 also induced cartilage matrix degradation, as shown by Alcian blue staining. Moreover, HMGB1 markedly upregulated the expression levels of matrix metallopeptidases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (AdAMTS), while genetic silencing of HMGB1 significantly suppressed their expressions. The glycogen synthase kinase (GSK)-3β/β-catenin pathway was activated upon HMGB1 treatment. Pharmacological inhibitors or HMGB1 knockdown inactivated the GSK-3β/β-catenin pathway, inhibited the expression levels of downstream genes, including MMPs and AdAMTS, and attenuated the apoptosis of ATdc5 cells. Furthermore, the data demonstrated that HMGB1 promoted chondrocyte dysfunction via the regulation of estrogen sulfotransferase and Runt-related transcription factor 2. Thus, the findings of the present study demonstrated that HMGB1 induces chondrocyte cell apoptosis via activation of GSK-3β/β-catenin and the subsequent expression of multiple targeted genes.

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Mianserin suppresses R-spondin 2-induced activation of Wnt/β-catenin signaling in chondrocytes and prevents cartilage degradation in a rat model of osteoarthritis

Cited by 21 publications

References 52 publications

MiR-181a Targets RSPO2 and Regulates Bone Morphogenetic Protein – WNT Signaling Crosstalk During Chondrogenic Differentiation of Mesenchymal Stromal Cells

MiR-181a Targets RSPO2 and Regulates Bone Morphogenetic Protein – WNT Signaling Crosstalk During Chondrogenic Differentiation of Mesenchymal Stromal Cells

Wnt signaling: a promising target for osteoarthritis therapy

The GSK‑3β/β‑catenin signaling pathway is involved in HMGB1‑induced chondrocyte apoptosis and cartilage matrix degradation

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