Dataset Information

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

ABSTRACT: Aberrant activation of the Wnt/?-catenin signaling pathway promotes the progression of osteoarthritis (OA). We previously reported that R-spondin 2 (Rspo2), an activator of the Wnt/?-catenin signaling, facilitates differentiation of proliferating chondrocytes into hypertrophic chondrocytes by enhancing Wnt/?-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/?-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/?-catenin signaling, increased proteoglycan production, and upregulated chondrogenic marker genes. Mianserin suppressed Rspo2-induced accumulation of ?-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 ?-catenin accumulation and prevented OA progression in a rat model of OA. We conclude that mianserin suppresses abnormally activated Wnt/?-catenin signaling in OA by inhibiting binding of Rspo2 to Lgr5.

SUBMITTER: Okura T

PROVIDER: S-EPMC6391487 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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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 Toshiaki T Ohkawara Bisei B Takegami Yasuhiko Y Ito Mikako M Masuda Akio A Seki Taisuke T Ishiguro Naoki N Ohno Kinji K

Scientific reports 20190226 1

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 pat ...[more]

PMID: 30808932

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Project description:Osteoarthritis (OA) is an autoimmune disease associated with increasing age. Typically, chondrocyte senescence is believed to serve an important role in the development and progression of OA. However, the specific mechanisms underlying chondrocyte senescence have not been fully addressed. The present study hypothesized that the Wnt/?-catenin signaling may represent a major regulator of chondrocyte senescence. In addition, the acetylated levels of p53 and sirtuin-1 (SIRT-1) were examined as putative markers for chondrocyte senescence, since activation of p53 is considered an important step in the regulation of senescence. The Wnt/?-catenin signaling pathway was activated using LiCl and inhibited using the Wnt signaling pathway inhibitor, dickkopf-1 (DKK1) in order to evaluate the role of this pathway in the development of OA. Senescent cells were detected using the senescence-associated indicator acidic senescence-associated ?-galactosidase (SA-?-gal). The effects of p53 and p16 on chondrocyte senescence were assessed via activation of Wnt/?-catenin signaling using Wnt-1. In addition, ?-catenin was transfected into chondrocytes to induce activation of the Wnt/?-catenin signaling pathway. Finally, a rabbit model of OA was used to assess whether the observed effects on the Wnt/?-catenin signaling pathway and the induction of chondrocyte senescence were perpetuated. Activation of Wnt/?-catenin signaling increased the expression levels of SA-?-gal, p53, p16 and acetylated p53. Transfection of ?-catenin in chondrocytes increased the expression levels of acetylated p53 and decreased the expression levels of SIRT-1, which in turn deacetylated p53 and modulated its activity. Finally, the role of the Wnt/?-catenin signaling pathway was confirmed in the development of OA using a rabbit model with this condition. The present study suggested that activation of the Wnt/?-catenin signaling pathway promoted chondrocyte senescence, through downregulation of SIRT-1 and increased the expression of acetylated p53.

Dataset Information

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

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.

Similar Datasets

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