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

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 enhanc...

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Bibliographic Details
Published in:Scientific reports 2019-02, Vol.9 (1), p.2808-2808, Article 2808
Main Authors: Okura, Toshiaki, Ohkawara, Bisei, Takegami, Yasuhiko, Ito, Mikako, Masuda, Akio, Seki, Taisuke, Ishiguro, Naoki, Ohno, Kinji
Format: Article
Language:English
Subjects:
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13/95
631/80/86/2368
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692/699/1670/407
Arthritis
Cartilage diseases
Chondrocytes
Chondrogenesis
Endochondral bone
Humanities and Social Sciences
Mianserin
multidisciplinary
Ossification
Osteoarthritis
Phosphorylation
Rodents
Science
Science (multidisciplinary)
Signal transduction
Synovial fluid
Wnt protein
β-Catenin
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-019-39393-x