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

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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.

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Acknowledgments

The authors thank Professor Francis Johnson in the Department of Pharmacological Science, the SUNY at Stone Brook, New York, for kindly providing CMC2.24 component.

Funding

This project was funded by National Natural Science Foundation of China (grant number: 81802203), Fundamental Research Funds for the Central Universities (grant number: 2042018kf0123), Guiding Fund of Renmin Hospital of Wuhan University (grant number: RMYD2018M43), NIH R01HL (grant number:136706), and NSF research award (grant number: 1722630).

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Authors and Affiliations

  1. Department of Orthopedics, Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Yan Zhou, Jianghua Ming, Ming Deng, Yaming Li, Yonggang Ma, Zhonghui Chen & Shiqing Liu

  2. Department of Rehabilitation, Wuhan Union Hospital, Huazhong University of Science and Technology, Wuhan, 430022, China

    Bochun Li

  3. College of Acupuncture and Bone Injury, Hubei University of Chinese Medicine, Wuhan, 430061, China

    Jia Li

  4. Department of Surgery, SUNY Upstate Medical University, 750 E. Adams St., Syracuse, NY, 13210, USA

    Guirong Wang

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  1. Yan Zhou
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  2. Jianghua Ming
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Correspondence to Guirong Wang or Shiqing Liu.

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This study was approved by the Animal Care and Use Committee of Medical School, Wuhan University. All of the protocols were approved by the Institutional Ethics Committee of Medical School, Wuhan University.

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Zhou, Y., Ming, J., Deng, M. et al. 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 98, 1479–1491 (2020). https://doi.org/10.1007/s00109-020-01972-1

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