NOTCH2 sensitizes the chondrocyte to the inflammatory response of tumor necrosis factor α.

Autor:	Canalis E; Department of Orthopaedic Surgery, UConn Health, Farmington, Connecticut, USA; Department of Medicine, UConn Health, Farmington, Connecticut, USA; UConn Musculoskeletal Institute, UConn Health, Farmington, Connecticut, USA. Electronic address: canalis@uchc.edu., Yu J; Department of Orthopaedic Surgery, UConn Health, Farmington, Connecticut, USA; UConn Musculoskeletal Institute, UConn Health, Farmington, Connecticut, USA., Singh V; Computational Biology Core, Institute for System Genomics, UConn, Storrs, Connecticut, USA., Mocarska M; UConn Musculoskeletal Institute, UConn Health, Farmington, Connecticut, USA., Schilling L; UConn Musculoskeletal Institute, UConn Health, Farmington, Connecticut, USA.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2023 Dec; Vol. 299 (12), pp. 105372. Date of Electronic Publication: 2023 Oct 20.
DOI:	10.1016/j.jbc.2023.105372
Abstrakt:	Notch regulates the immune and inflammatory response and has been associated with the pathogenesis of osteoarthritis in humans and preclinical models of the disease. Notch2 tm1.1Ecan mice harbor a NOTCH2 gain-of-function and are sensitized to osteoarthritis, but the mechanisms have not been explored. We examined the effects of tumor necrosis factor α (TNFα) in chondrocytes from Notch2 tm1.1Ecan mice and found that NOTCH2 enhanced the effect of TNFα on Il6 and Il1b expression. Similar results were obtained in cells from a conditional model of NOTCH2 gain-of-function, Notch2 2.1Ecan mice, and following the expression of the NOTCH2 intracellular domain in vitro. Recombination signal-binding protein for immunoglobulin Kappa J region partners with the NOTCH2 intracellular domain to activate transcription; in the absence of Notch signaling it inhibits transcription, and Rbpj inactivation in chondrocytes resulted in Il6 induction. Although TNFα induced IL6 to a greater extent in the context of NOTCH2 activation, there was a concomitant inhibition of Notch target genes Hes1, Hey1, Hey2, and Heyl. Electrophoretic mobility shift assay demonstrated displacement of recombination signal-binding protein for immunoglobulin Kappa J region from DNA binding sites by TNFα explaining the increased Il6 expression and the concomitant decrease in Notch target genes. NOTCH2 enhanced the effect of TNFα on NF-κB signaling, and RNA-Seq revealed increased expression of pathways associated with inflammation and the phagosome in NOTCH2 overexpressing cells in the absence and presence of TNFα. Collectively, NOTCH2 has important interactions with TNFα resulting in the enhanced expression of Il6 and inflammatory pathways in chondrocytes. Competing Interests: Conflict of interest The authors declare no conflicts of interest with the contents of this article. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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