Fluoxetine ameliorates cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling

Miyamoto, Kentaro; Ohkawara, Bisei; Ito, Mikako; Matsubara, Akio; Hirakawa, Akihiro; Sasajima, Tadahiro; Hiraiwa, Hideki; Hamada, Takashi; Ishiguro, Naoki; Ohno, Kinji

doi:10.1371/journal.pone.0184388

Cited by 28 publications

(23 citation statements)

References 48 publications

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“…We previously reported that another antidepressant, fluoxetine, ameliorates cartilage degradation in OA by inhibiting Wnt/β-catenin signaling. The putative target of fluoxetine, however, is likely to be a degradation complex including β-catenin or its downstream signaling, and not Rspo2 10 .…”

Section: Resultsmentioning

confidence: 99%

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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

Okura

Ohkawara

Takegami

et al. 2019

Sci Rep

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Aberrant activation of the Wnt/β-catenin signaling pathway promotes the progression of osteoarthritis (OA). We previously reported that R-spondin 2 (Rspo2), an activator of the Wnt/β-catenin signaling, facilitates differentiation of proliferating chondrocytes into hypertrophic chondrocytes by enhancing Wnt/β-catenin signaling in endochondral ossification. However, the role of Rspo2 in OA remains elusive. Here, we showed that the amounts of Rspo2 protein in synovial fluid were increased in OA patients. We searched for a preapproved drug that suppresses Rspo2-induced Wnt/β-catenin signaling in chondrogenic cells and reduces joint pathology in a rat model of OA. In Rspo2-treated ATDC5 cells, mianserin, a tetracyclic antidepressant, inhibited Wnt/β-catenin signaling, increased proteoglycan production, and upregulated chondrogenic marker genes. Mianserin suppressed Rspo2-induced accumulation of β-catenin and phosphorylation of Lrp6. We identified that mianserin blocked binding of Rspo2 to its receptor Lgr5. We also observed that intraarticular administration of mianserin suppressed β-catenin accumulation and prevented OA progression in a rat model of OA. We conclude that mianserin suppresses abnormally activated Wnt/β-catenin signaling in OA by inhibiting binding of Rspo2 to Lgr5.

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Section: Resultsmentioning

confidence: 99%

“…Activation of Wnt/β-catenin signaling promotes hypertrophic differentiation of articular chondrocytes which, in turn, induces cartilage degradation and subsequent OA aggravation 7 . Indeed, OA progression is mitigated by inhibiting the Wnt/β-catenin signaling 8–10 .…”

Section: Introductionmentioning

confidence: 99%

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

Ohkawara

Takegami

et al. 2019

Sci Rep

Self Cite

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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]. Thus, intraarticular injection of fluoxetine may improve OA progression and inhibited the accumulation of β-catenin in rats OA model.…”

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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“…In chondrocytes, the effects of wnt3a are described repeatedly to stimulate chondrogenic dedifferentiation. 13,27,[45][46][47][48][49][58][59][60] The origin of the chondrocytes studied ranged from humans, large animals (i.e., bovine), to smaller animals (i.e., rat or chicken). Despite the differences in the supplementation method and the origin of the cells, all articles reported either a loss of chondrogenic gene marker expression, decreased proteoglycan production or a combination of these.…”

Section: Chondrocytesmentioning

confidence: 99%

Wnt3a and wnt5a as Potential Chondrogenic Stimulators for Nucleus Pulposus Cell Induction: A Comprehensive Review

et al. 2020

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Low back pain remains a highly prevalent pathology engendering a tremendous socioeconomic burden. Low back pain is generally associated with intervertebral disc (IVD) degeneration, a process involving the deterioration of nucleus pulpous (NP) cells and IVD matrix. Scientific interest has directed efforts to restoring cell numbers as a strategy to enable IVD regeneration. Currently, mesenchymal stromal cells (MSCs) are being explored as cell therapy agents, due to their easy accessibility and differentiation potential. For enhancement of MSCs, growth factor supplementation is commonly applied to induce differentiation towards a chondrogenic (NP) cell phenotype. The wnt signaling pathways play a crucial role in chondrogenesis, nonetheless, literature appears to present controversies with regard to wnt3a and wnt5a for the induction of NP cells, chondrocytes, and MSCs. This review aims to summarize the reporting on wnt3a/wnt5a mediated NP cell differentiation, and to elucidate the mechanisms involved in wnt3a and wnt5a mediated chondrogenesis for potential application as cell therapy supplements for IVD regeneration. Our review suggests that wnt3a, subsequently replaced with a chondrogenic stimulating growth factor, can enhance the chondrogenic potential of MSCs in vitro. Contrariwise, wnt5a is suggested to play a role in maintaining cell potency of differentiated NP or chondrogenic cells.

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Fluoxetine ameliorates cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling

Cited by 28 publications

References 48 publications

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

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

Wnt signaling: a promising target for osteoarthritis therapy

Wnt3a and wnt5a as Potential Chondrogenic Stimulators for Nucleus Pulposus Cell Induction: A Comprehensive Review

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