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

ABSTRACT: BACKGROUND:Osteoarthritis (OA) is a common degenerative disease, and tumor necrosis factor (TNF-?) 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-? 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-?. 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-?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 and Development Projects of Shandong Province and the Cross-disciplinary Fund of Shandong University.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC6443028 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Zhao Yunpeng Y Li Yuhua Y Qu Ruize R Chen Xiaomin X Wang Wenhan W Qiu Cheng C Liu Ben B Pan Xin X Liu Liang L Vasilev Krasimir K Hayball John J Dong Shuli S Li Weiwei W

EBioMedicine 20190228

<h4>Background</h4>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.<h4>Methods</h4>The interaction between CST and TNF-α receptors was investigated through Coimmunoprecipitation and Biotin-based solid-phase bi ...[more]

PMID: 30826358

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Project description:Our novel proposal is that TNF? exerts a direct effect on mitochondrial respiratory function in the heart, independently of its cell surface receptors. TNF?-induced cardioprotection is known to involve reactive oxygen species (ROS) and sphingolipids. We therefore further propose that this direct mitochondrial effect is mediated via ROS and sphingolipids. The protective concentration of TNF? (0.5 ng/ml) was added to isolated heart mitochondria from black 6 × 129 mice (WT) and double TNF receptor knockout mice (TNFR1&2(-/-)). Respiratory parameters and inner mitochondrial membrane potential were analyzed in the presence/absence of two antioxidants, N-acetyl-L: -cysteine or N-tert-butyl-?-(2-sulfophenyl)nitrone or two antagonists of the sphingolipid pathway, N-oleoylethanolamine (NOE) or imipramine. In WT, TNF? reduced State 3 respiration from 279.3 ± 3 to 119.3 ± 2 (nmol O?/mg protein/min), increased proton leak from 15.7 ± 0.6% (control) to 36.6 ± 4.4%, and decreased membrane potential by 20.5 ± 3.1% compared to control groups. In TNFR1&2(-/-) mice, TNF? reduced State 3 respiration from 205.2 ± 4 to 75.7 ± 1 (p < 0.05 vs. respective control). In WT mice, both antioxidants added with TNF? restored State 3 respiration to 269.2 ± 2 and 257.6 ± 2, respectively. Imipramine and NOE also restored State 3 respiration to 248.4 ± 2 and 249.0 ± 2, respectively (p < 0.01 vs. TNF? alone). Similarly, both antioxidant and inhibitors of the sphingolipid pathway restored the proton leak to pre-TNF values. TNF?-treated mitochondria or isolated cardiac muscle fibers showed an increase in respiration after anoxia-reoxygenation, but this effect was lost in the presence of an antioxidant or NOE. Similar data were obtained in TNFR1&2(-/-) mice. TNF? exerts a protective effect on respiratory function in isolated mitochondria subjected to an anoxia-reoxygenation insult. This effect appears to be independent of its cell surface receptors, but is likely to be mediated by ROS and sphingolipids.

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

Publications

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

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