Cortistatin binds to TNF-α receptors and protects against osteoarthritis.

Abstract

BACKGROUND:

Osteoarthritis (OA) is a common degenerative disease, and tumor necrosis factor (TNF-α) 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 unknown whether CST is involved in cartilage degeneration and OA development.

METHODS:

The interaction between CST and TNF-α receptors was investigated through Coimmunoprecipitation and Biotin-based solid-phase binding assay. Western blot, Real-time PCR, ELISA, immunofluorescence staining, nitrite production assay and DMMB assay of GAG were 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 as well as TNFR2. CST suppressed proinflammatory function of TNF-α. 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-κB 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 and Development Projects of Shandong Province and the Cross-disciplinary Fund of Shandong University.

• Authors: Yunpeng Zhao, Yuhua Li, Ruize Qu, Xiaomin Chen, Wenhan Wang, Cheng Qiu, Ben Liu, Xin Pan, Liang Liu, Krasimir Vasilev, John Hayball, Shuli Dong, Weiwei Li
• Journal: EBioMedicine (EBioMedicine) Vol. 41 Pg. 556-570 (Mar 2019) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 30826358 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Interleukin-1beta
• NF-kappa B
• Neuropeptides
• Receptors, Tumor Necrosis Factor, Type I
• Receptors, Tumor Necrosis Factor, Type II
• Tumor Necrosis Factor-alpha
• cortistatin
• Caspase 3
• Matrix Metalloproteinase 13

Topics

• Animals
• Cartilage, Articular (cytology)
• Caspase 3 (metabolism)
• Chondrocytes (cytology, drug effects, metabolism)
• Disease Models, Animal
• Humans
• Interleukin-1beta (blood)
• Knee Joint (pathology)
• Matrix Metalloproteinase 13
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (metabolism)
• Neuropeptides (genetics, metabolism, pharmacology, therapeutic use)
• Osteoarthritis (drug therapy, metabolism, pathology)
• Protein Binding
• Receptors, Tumor Necrosis Factor, Type I (chemistry, genetics, metabolism)
• Receptors, Tumor Necrosis Factor, Type II (chemistry, genetics, metabolism)
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism, pharmacology)