Cortistatin binds to TNF-α receptors and protects against osteoarthritis

Background: Osteoarthritis (OA) is a common degenerative disease, and tumor necrosis factor (TNF-alpha) is known to play a critical role in OA. Cortistatin (CST) is a neuropeptide discovered over 20 years ago, which plays a vital role in inflammatory reactions. However, it is unknownwhether CST is involved in cartilage degeneration and OA development. Methods: The interaction between CST and TNF-alpha receptors was investigated through Coimmunoprecipitation and Biotin-based solid-phase binding assay. Western blot, Real-time PCR, ELISA, immunofluorescence staining, nitrite production assay andDMMB assay ofGAGwere performed for the primary chondrocyte experiments. Surgically induced and spontaneous OA models were established and western blot, flow cytometry, Real-time PCR, ELISA, immunohistochemistry and fluorescence in vivo imaging were performed for in vivo experiments. Findings: CST competitively bound to TNFR1 aswell as TNFR2. CST suppressed proinflammatory function of TNF alpha. Both spontaneous and surgically induced OA models indicated that deficiency of CST led to an accelerated OA-like phenotype, while exogenous CST attenuated OA development in vivo. Additionally, TNFR1- and TNFR2-knockout mice were used for analysis and indicated that TNFRs might be involved in the protective role of CST in OA. CST inhibited activation of the NF-kappa B signaling pathway in OA. Interpretation: This study provides new insight into the pathogenesis and therapeutic strategy of cartilage degenerative diseases, including OA. Fund: The National Natural Science Foundation of China, the Natural Science Foundation of Shandong Province, Key Research andDevelopment Projects of Shandong Province and the Cross-disciplinary Fund of Shandong University. (c) 2019 The Authors. Published by Elsevier B. V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).