Simvastatin promotes restoration of chondrocyte morphology and phenotype.
Aggrecan
Chondrocyte
Osteoarthritis
Prenylation
SOX9
Simvastatin
Journal
Archives of biochemistry and biophysics
ISSN: 1096-0384
Titre abrégé: Arch Biochem Biophys
Pays: United States
ID NLM: 0372430
Informations de publication
Date de publication:
15 04 2019
15 04 2019
Historique:
received:
31
10
2018
revised:
14
01
2019
accepted:
31
01
2019
pubmed:
19
2
2019
medline:
15
2
2020
entrez:
19
2
2019
Statut:
ppublish
Résumé
In this study we examined whether the action of simvastatin affects re-differentiation of passaged chondrocytes and if so, whether this was mediated via changes in cholesterol or cholesterol intermediates. Bovine articular chondrocytes, of varying passage number, human knee chondrocytes and rat chondrosarcoma chondrocytes were treated with simvastatin and examined for changes in mRNA and protein expression of markers of the chondrocyte phenotype as well as changes in cell shape, proliferation and proteoglycan production. In all three models, while still in monolayer culture, simvastatin treatment alone promoted changes in phenotype and morphology indicative of re-differentiation most prominent being an increase in SOX9 mRNA and protein expression. In passaged bovine chondrocytes, simvastatin stimulated the expression of SOX9, ACAN, BMP2 and inhibited the expression of COL1 and α-smooth muscle actin. Co-treatment of chondrocytes with simvastatin plus exogenous cholesterol-conditions that had previously reversed the inhibition on CD44 shedding, did not alter the effects of simvastatin on re-differentiation. However, the co-treatment of chondrocytes with simvastatin together with other pathway intermediates, mevalonate, geranylgeranylpyrophosphate and to a lesser extent, farnesylpyrophosphate, blocked the pro-differentiation effects of simvastatin. Treatment with simvastatin stimulated expression of SOX9 and COL2a and enhanced SOX9 protein in human OA chondrocytes. The co-treatment of OA chondrocytes with mevalonate or geranylgeranylpyrophosphate, but not cholesterol, blocked the simvastatin effects. These results lead us to conclude that the blocking of critical protein prenylation events is required for the positive effects of simvastatin on the re-differentiation of chondrocytes.
Identifiants
pubmed: 30776329
pii: S0003-9861(18)30890-7
doi: 10.1016/j.abb.2019.01.038
pmc: PMC6450767
mid: NIHMS1522370
pii:
doi:
Substances chimiques
Simvastatin
AGG2FN16EV
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
1-11Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR039507
Pays : United States
Organisme : NIAMS NIH HHS
ID : R21 AR066581
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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