期刊
JOURNAL OF MOLECULAR MEDICINE-JMM
卷 98, 期 10, 页码 1479-1491出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00109-020-01972-1
关键词
Osteoarthritis; Chemically modified curcumin (CMC2.24); Cartilage homeostasis; NF-kappa B; Hif-2 alpha
资金
- National Natural Science Foundation of China [81802203]
- Fundamental Research Funds for the Central Universities [2042018kf0123]
- Guiding Fund of Renmin Hospital of Wuhan University [RMYD2018M43]
- NIH [136706]
- NSF [1722630]
- Div Of Information & Intelligent Systems
- Direct For Computer & Info Scie & Enginr [1722630] Funding Source: National Science Foundation
The disorders of cartilage homeostasis and chondrocyte apoptosis are major events in the pathogenesis of osteoarthritis (OA). Herein, we aim to assess the chondroprotective effect and underlying mechanisms of a novel chemically modified curcumin, CMC2.24, in modulating extracellular matrix (ECM) homeostasis and inhibiting chondrocyte apoptosis. Rats underwent the anterior cruciate ligament transection, and medial menisci resection was treated by intra-articular injection with CMC2.24. In an in vitro study, rat chondrocytes were pretreated with CMC2.24 before stimulation with sodium nitroprusside (SNP). Results from in vivo studies demonstrated that the intra-articular administration of CMC2.24 ameliorated osteoarthritic cartilage destruction by promoting collagen 2a1 production and inhibited cartilage degradation and apoptosis by suppressing hypoxia-inducible factor-2a (Hif-2 alpha), matrix metalloproteinase-3, runt-related transcription factor 2, cleaved caspase-3, and vascular endothelial growth factor and the phosphorylation of I kappa B alpha and NF-kappa B p65. The in vitro results revealed that CMC2.24 exhibited a strong inhibitory effect on SNP-induced chondrocyte catabolism and apoptosis. The SNP-enhanced expression of Hif-2 alpha, a catabolic and apoptotic factor, decreased in a dose-dependent manner after CMC2.24 treatment. CMC2.24 pretreatment effectively inhibited SNP-induced I kappa B alpha and NF-kappa B p65 phosphorylation in rat chondrocytes, whereas pretreatment with the NF-kappa B antagonist BMS-345541 significantly enhanced the effects of CMC2.24. Overall, these results demonstrated that CMC2.24 attenuates OA progression by modulating ECM homeostasis and chondrocyte apoptosis by suppressing the NF-kappa B/Hif-2 alpha axis, thus providing a new perspective for therapeutic strategies in OA. Key messages Intra-articular injection of CMC2.24 ameliorated osteoarthritic cartilage destruction. CMC2.24 promoted cell viability and decreased SNP-induced apoptotic gene expression. SNP-induced activation of Hif-2 alpha is inhibited by CMC2.24. CMC2.24 inhibits NF-kappa B/Hif-2 alpha axis activation to modulate ECM homeostasis and inhibit chondrocyte apoptosis.
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