Genetic Inactivation of ZCCHC6 Suppresses Interleukin-6 Expression and Reduces the Severity of Experimental Osteoarthritis in Mice.
Animals
Chondrocytes
/ metabolism
Disease Models, Animal
Gene Expression Regulation
Gene Silencing
Humans
Interleukin-6
/ metabolism
Knee Joint
/ metabolism
Mice
Nucleotidyltransferases
/ metabolism
Osteoarthritis
/ genetics
RNA Nucleotidyltransferases
RNA, Small Interfering
/ metabolism
Severity of Illness Index
Up-Regulation
Journal
Arthritis & rheumatology (Hoboken, N.J.)
ISSN: 2326-5205
Titre abrégé: Arthritis Rheumatol
Pays: United States
ID NLM: 101623795
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
11
04
2018
accepted:
03
10
2018
pubmed:
12
10
2018
medline:
28
12
2019
entrez:
11
10
2018
Statut:
ppublish
Résumé
Cytokine expression is tightly regulated posttranscriptionally, but high levels of interleukin-6 (IL-6) in patients with osteoarthritis (OA) indicate that regulatory mechanisms are disrupted in this disorder. The enzyme ZCCHC6 (zinc-finger CCHC domain-containing protein 6; TUT-7) has been implicated in posttranscriptional regulation of inflammatory cytokine expression, but its role in OA pathogenesis is unknown. The present study was undertaken to investigate whether ZCCHC6 directs the expression of IL-6 and influences OA pathogenesis in vivo. Human and mouse chondrocytes were stimulated with recombinant IL-1β. Expression of ZCCHC6 in human chondrocytes was knocked down using small interfering RNAs. IL-6 transcript stability was determined by actinomycin D chase, and 3'-uridylation of microRNAs was determined by deep sequencing. Zcchc6 ZCCHC6 was markedly up-regulated in damaged cartilage from human OA patients and from wild-type mice with surgically induced OA. Overexpression of ZCCHC6 induced the expression of IL-6, and its knockdown reduced IL-6 transcript stability and IL-1β-induced IL-6 expression in chondrocytes. Reintroduction of Zcchc6 in Zcchc6 These findings indicate that ZCCHC6 enhances IL-6 expression in chondrocytes through transcript stabilization and by uridylating miR-26b, which abrogates repression of IL-6. Inhibition of IL-6 expression and significantly reduced OA severity in Zcchc6
Identifiants
pubmed: 30302948
doi: 10.1002/art.40751
pmc: PMC6438766
mid: NIHMS992223
doi:
Substances chimiques
Interleukin-6
0
RNA, Small Interfering
0
Nucleotidyltransferases
EC 2.7.7.-
RNA Nucleotidyltransferases
EC 2.7.7.-
terminal uridylyl transferase 7, mouse
EC 2.7.7.-
TUT7 protein, human
EC 2.7.7.52
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
583-593Subventions
Organisme : NCCIH NIH HHS
ID : R01 AT007373
Pays : United States
Organisme : Northeast Ohio Medical University
Pays : International
Organisme : NCCIH NIH HHS
ID : R01 AT003627
Pays : United States
Organisme : NCCIH NIH HHS
ID : R01 AT005520
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR067056
Pays : United States
Informations de copyright
© 2018, American College of Rheumatology.
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