Suppression of circadian clock protein cryptochrome 2 promotes osteoarthritis.
Adolescent
Adult
Aged
Animals
Cartilage, Articular
/ metabolism
Case-Control Studies
Chondrocytes
/ metabolism
Circadian Rhythm
Cryptochromes
/ genetics
Extracellular Matrix
/ metabolism
Female
Humans
Immunohistochemistry
Male
Mice
Mice, Knockout
Middle Aged
Osteoarthritis
/ genetics
RNA, Messenger
/ metabolism
Young Adult
Chondrocytes
Circadian rhythm
Cryptochrome
Journal
Osteoarthritis and cartilage
ISSN: 1522-9653
Titre abrégé: Osteoarthritis Cartilage
Pays: England
ID NLM: 9305697
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
24
06
2019
revised:
02
03
2020
accepted:
14
04
2020
pubmed:
28
4
2020
medline:
31
7
2021
entrez:
28
4
2020
Statut:
ppublish
Résumé
Abnormal chondrocyte gene expression promotes osteoarthritis (OA) pathogenesis. A previous RNA-sequencing study revealed that circadian rhythm pathway and expression of core clock gene cryptochrome 2 (CRY2) are dysregulated in human OA cartilage. Here we determined expression patterns and function CRY1 and CRY2. CRY mRNA and protein expression was analyzed in normal and OA human and mouse cartilage. Mice with deletion of Cry1 or Cry2 were analyzed for severity of experimental OA and to determine genes and pathways that are regulated by Cry. In human OA cartilage, CRY2 but not CRY1 staining and mRNA expression was significantly decreased. Cry2 was also suppressed in mice with aging-related OA. Cry2 knock out (KO) but not Cry1 KO mice with experimental OA showed significantly increased severity of histopathological changes in cartilage, subchondral bone and synovium. In OA chondrocytes, the levels of CRY1 and CRY2 and the amplitude of circadian fluctuation were significantly lower. RNA-seq on knee articular cartilage of wild-type and Cry2 KO mice identified 53 differentially expressed genes, including known Cry2 target circadian genes Nr1d1, Nr1d2, Dbp and Tef. Pathway analysis that circadian rhythm and extracellular matrix remodeling were dysregulated in Cry2 KO mice. These results show an active role of the circadian clock in general, and of CRY2 in particular, in maintaining extracellular matrix (ECM) homeostasis in cartilage. This cell autonomous network of circadian rhythm genes is disrupted in OA chondrocytes. Targeting CRY2 has potential to correct abnormal gene expression patterns and reduce the severity of OA.
Identifiants
pubmed: 32339698
pii: S1063-4584(20)30982-1
doi: 10.1016/j.joca.2020.04.004
pmc: PMC7476803
mid: NIHMS1594423
pii:
doi:
Substances chimiques
CRY1 protein, human
0
CRY2 protein, human
0
Cry1 protein, mouse
0
Cry2 protein, mouse
0
Cryptochromes
0
RNA, Messenger
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
966-976Subventions
Organisme : NIA NIH HHS
ID : P01 AG007996
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG049617
Pays : United States
Informations de copyright
Copyright © 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
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