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  2. Chemically modified curcumin (CMC2.24) alleviates osteoarthritis progression by restoring cartilage homeostasis and inhibiting chondrocyte apoptosis via the NF-κB/HIF-2α axis

Chemically modified curcumin (CMC2.24) alleviates osteoarthritis progression by restoring cartilage homeostasis and inhibiting chondrocyte apoptosis via the NF-κB/HIF-2α axis

  • J Mol Med (Berl). 2020 Oct;98(10):1479-1491. doi: 10.1007/s00109-020-01972-1.
Yan Zhou 1 Jianghua Ming 1 Ming Deng 1 Yaming Li 1 Bochun Li 2 Jia Li 3 Yonggang Ma 1 Zhonghui Chen 1 Guirong Wang 4 Shiqing Liu 5
Affiliations

Affiliations

  • 1 Department of Orthopedics, Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
  • 2 Department of Rehabilitation, Wuhan Union Hospital, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 3 College of Acupuncture and Bone Injury, Hubei University of Chinese Medicine, Wuhan, 430061, China.
  • 4 Department of Surgery, SUNY Upstate Medical University, 750 E. Adams St., Syracuse, NY, 13210, USA. Wangg@upstate.edu.
  • 5 Department of Orthopedics, Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China. liusqrm@163.com.
Abstract

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-2α), matrix metalloproteinase-3, runt-related transcription factor 2, cleaved Caspase-3, and vascular endothelial growth factor and the phosphorylation of IκBα and NF-κB 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-2α, a catabolic and apoptotic factor, decreased in a dose-dependent manner after CMC2.24 treatment. CMC2.24 pretreatment effectively inhibited SNP-induced IκBα and NF-κB p65 phosphorylation in rat chondrocytes, whereas pretreatment with the NF-κB 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-κB/Hif-2α 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-2α is inhibited by CMC2.24. • CMC2.24 inhibits NF-κB/Hif-2α axis activation to modulate ECM homeostasis and inhibit chondrocyte Apoptosis.

Keywords

Cartilage homeostasis; Chemically modified curcumin (CMC2.24); Hif-2α; NF-κB; Osteoarthritis.

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