Inhibition of YAP with siRNA prevents cartilage degradation and ameliorates osteoarthritis development

• Published in: Journal of molecular medicine (Berlin, Germany) Vol. 97; no. 1; pp. 103 - 114
• Main Authors: Gong, Yong, Li, Song-Jian, Liu, Rui, Zhan, Jian-Feng, Tan, Chao, Fang, Yi-Fei, Chen, Yan, Yu, Bo
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2019; Springer Nature B.V
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Animals; Apoptosis; Arthritis; Biomedical and Life Sciences; Biomedicine; Bone growth; Cartilage (articular); Cartilage diseases; Cartilage, Articular - metabolism; Cartilage, Articular - pathology; Cell Cycle Proteins - genetics; Cells, Cultured; Chondrocytes; Chondrocytes - metabolism; Chondrocytes - pathology; Computed tomography; Gene expression; Homeostasis; Human Genetics; Humans; Hypertrophy; IL-1β; Immunohistochemistry; Injection; Internal Medicine; Male; Mice, Inbred C57BL; Molecular Medicine; Original Article; Osteoarthritis; Osteoarthritis - genetics; Osteoarthritis - pathology; Osteoarthritis - therapy; Osteogenesis; RNA, Small Interfering - genetics; RNA, Small Interfering - therapeutic use; RNAi Therapeutics; Signal transduction; siRNA; Subchondral bone; Transcription Factors - genetics; Up-Regulation; Western blotting; Yes-associated protein; Cartilage; YAP siRNA; Osteoarthritis
• ISSN: 0946-2716; 1432-1440; 1432-1440
• DOI: 10.1007/s00109-018-1705-y

The Hippo/YAP signaling pathway is important for mediating organ size and tissue homeostasis, but its role in osteoarthritis (OA) remains unclear. We aimed to investigate the role of Hippo/YAP signaling pathway in OA development. YAP expression in OA cartilage was assessed by immunohistochemistry, RT-qPCR, and Western blotting. The effects of YAP overexpression or knockdown on gene expression related to chondrocyte hypertrophy induced by IL-1β were examined. The in vivo effects of YAP inhibition were studied. Subchondral bone was analyzed by micro-CT. YAP was increased in mice and human OA articular cartilage and chondrocytes. YAP mRNA expression level was also increased in IL-1β-induced chondrocytes. YAP overexpression resulted in increased expression of catabolic genes in response to IL-1β. Suppression of YAP by siRNA inhibited IL-1β stimulated catabolic genes expression and chondrocytes apoptosis. Intra-articular injection of YAP siRNA ameliorated OA development in mice. Micro-CT results showed the aberrant subchondral bone formation was also reduced. We provided evidence that YAP was upregulated in OA cartilage. Inhibition of YAP using YAP siRNA is a promising way to prevent cartilage degradation in OA. Key messages YAP was upregulated in human and mice osteoarthritis cartilage and chondrocytes. YAP siRNA decreased IL-1β-induced catabolic gene expression. Intra-articular injection of YAP siRNA ameliorated OA development. Intra-articular injection of YAP siRNA reduced aberrant subchondral bone formation.