Cortistatin Binds to TNF-α Receptors and Protects Against Osteoarthritis

Osteoarthritis (OA) is a common degenerative disease worldwide, and tumor necrosis factor (TNF-α) is known to play critical roles in OA. Cortistatin (CST) is a recently discovered neuropeptide that plays a vital role in inflammatory reactions. However, it is unknown whether CST is involved in cartilage degeneration and OA development. This study investigated the interaction between CST and TNF-α receptors, revealing that CST competitively bound to TNFR1 as well as TNFR2. In addition, primary chondrocyte experiments showed that CST suppressed the proinflammatory function of TNF-α. Moreover, both spontaneous and surgically induced OA models were established in wild-type and CSTknockout mice. Deficiency of CST led to an accelerated OA-like phenotype, while exogenous CST attenuated OA development in vivo, causing alterations of cartilage destruction and expression of degenerative biomarkers. Furthermore, TNFR1- and TNFR2-knockout mice were used for analysis and indicated that TNFRs might be involved in the protective role of CST in OA. Additionally, experiments in primary chondrocytes and NF-κB luciferase reporter gene mice revealed that CST inhibited activation of the NF-κB signaling pathway in OA. Overall, this study provides new insight into the pathogenesis and potential therapeutic targets for cartilage degenerative diseases, including OA. Funding Statement: This work was supported by Key Research and Development Projects of Shandong Province (No. 2015GSF118115), the Natural Science Foundation of Shandong Province (BS2014YY048 and BS2015SW028 to Yunpeng Zhao, and ZR2016HM53 to Yuhua Li), the Cross-disciplinary Fund of Shandong University (Grant No. 26010178611010) and the National Natural Science Foundation of China (81501880 to Yunpeng Zhao and 81602761 to Weiwei Li). Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: All the experiments were agreed by the ethical review committee of Qilu Hospital, Shandong University, and additionally, the prior informed consent of the patients. Samples of human cartilage were collected from total knee joint replacement surgery patients for OA, with the detection of MOAKS, according to the agreement of the ethical review committee of Qilu Hospital, Shandong University, and the prior informed consent of the patients. All experiments were conducted in compliance with the relevant guidelines and regulations.