Journal
SCIENTIFIC REPORTS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-019-39393-x
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Funding
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) [18K09062]
- Ministry of Health, Labour, and Welfare of Japan (MHLW) [H29-Nanchi-Ippan-030]
- Japan Agency for Medical Research and Development (AMED) [JP18gm1010002, JP18ek0109230, JP17ek0109281, JP18bm0804005]
- Japanese Association of Medical Sciences
- Grants-in-Aid for Scientific Research [18K09062] Funding Source: KAKEN
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Aberrant activation of the Wnt/beta-catenin signaling pathway promotes the progression of osteoarthritis (OA). We previously reported that R-spondin 2 (Rspo2), an activator of the Wnt/beta-catenin signaling, facilitates differentiation of proliferating chondrocytes into hypertrophic chondrocytes by enhancing Wnt/beta-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/beta-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/beta-catenin signaling, increased proteoglycan production, and upregulated chondrogenic marker genes. Mianserin suppressed Rspo2-induced accumulation of beta-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 beta-catenin accumulation and prevented OA progression in a rat model of OA. We conclude that mianserin suppresses abnormally activated Wnt/beta-catenin signaling in OA by inhibiting binding of Rspo2 to Lgr5.
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