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Cholesterol-induced LRP3 downregulation promotes cartilage degeneration in osteoarthritis by targeting Syndecan-4

Author

Listed:
  • Chenxi Cao

    (Peking University Third Hospital
    Institute of Sports Medicine of Peking University
    Beijing Key Laboratory of Sports Injuries)

  • Yuanyuan Shi

    (Peking University Third Hospital
    Institute of Sports Medicine of Peking University
    Beijing Key Laboratory of Sports Injuries)

  • Xin Zhang

    (Peking University Third Hospital
    Institute of Sports Medicine of Peking University
    Beijing Key Laboratory of Sports Injuries)

  • Qi Li

    (Peking University Third Hospital
    Institute of Sports Medicine of Peking University
    Beijing Key Laboratory of Sports Injuries)

  • Jiahao Zhang

    (Peking University Third Hospital
    Institute of Sports Medicine of Peking University
    Beijing Key Laboratory of Sports Injuries)

  • Fengyuan Zhao

    (Peking University Third Hospital
    Institute of Sports Medicine of Peking University
    Beijing Key Laboratory of Sports Injuries)

  • Qingyang Meng

    (Peking University Third Hospital
    Institute of Sports Medicine of Peking University
    Beijing Key Laboratory of Sports Injuries)

  • Wenli Dai

    (Peking University Third Hospital
    Institute of Sports Medicine of Peking University
    Beijing Key Laboratory of Sports Injuries)

  • Zhenlong Liu

    (Peking University Third Hospital
    Institute of Sports Medicine of Peking University
    Beijing Key Laboratory of Sports Injuries)

  • Wenqiang Yan

    (Peking University Third Hospital
    Institute of Sports Medicine of Peking University
    Beijing Key Laboratory of Sports Injuries)

  • Xiaoning Duan

    (Peking University Third Hospital
    Institute of Sports Medicine of Peking University
    Beijing Key Laboratory of Sports Injuries)

  • Jiying Zhang

    (Peking University Third Hospital
    Institute of Sports Medicine of Peking University
    Beijing Key Laboratory of Sports Injuries)

  • Xin Fu

    (Peking University Third Hospital
    Institute of Sports Medicine of Peking University
    Beijing Key Laboratory of Sports Injuries)

  • Jin Cheng

    (Peking University Third Hospital
    Institute of Sports Medicine of Peking University
    Beijing Key Laboratory of Sports Injuries)

  • Xiaoqing Hu

    (Peking University Third Hospital
    Institute of Sports Medicine of Peking University
    Beijing Key Laboratory of Sports Injuries)

  • Yingfang Ao

    (Peking University Third Hospital
    Institute of Sports Medicine of Peking University
    Beijing Key Laboratory of Sports Injuries)

Abstract

Emerging evidence suggests that osteoarthritis is associated with high cholesterol levels in some osteoarthritis patients. However, the specific mechanism under this metabolic osteoarthritis phenotype remains unclear. We find that cholesterol metabolism-related gene, LRP3 (low-density lipoprotein receptor-related protein 3) is significantly reduced in high-cholesterol diet mouse’s cartilage. By using Lrp3−/− mice in vivo and LRP3 lentiviral-transduced chondrocytes in vitro, we identify that LRP3 positively regulate chondrocyte extracellular matrix metabolism, and its deficiency aggravate the degeneration of cartilage. Regardless of diet, LRP3 overexpression in cartilage attenuate anterior cruciate ligament transection induced osteoarthritis progression in rats and Lrp3 knockout-induced osteoarthritis progression in mice. LRP3 knockdown upregulate syndecan-4 by activating the Ras signaling pathway. We identify syndecan-4 as a downstream molecular target of LRP3 in osteoarthritis pathogenesis. These findings suggest that cholesterol-LRP3- syndecan-4 axis plays critical roles in osteoarthritis development, and LRP3 gene therapy may provide a therapeutic regimen for osteoarthritis treatment.

Suggested Citation

  • Chenxi Cao & Yuanyuan Shi & Xin Zhang & Qi Li & Jiahao Zhang & Fengyuan Zhao & Qingyang Meng & Wenli Dai & Zhenlong Liu & Wenqiang Yan & Xiaoning Duan & Jiying Zhang & Xin Fu & Jin Cheng & Xiaoqing Hu, 2022. "Cholesterol-induced LRP3 downregulation promotes cartilage degeneration in osteoarthritis by targeting Syndecan-4," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34830-4
    DOI: 10.1038/s41467-022-34830-4
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    References listed on IDEAS

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    1. Heather Stanton & Fraser M. Rogerson & Charlotte J. East & Suzanne B. Golub & Kate E. Lawlor & Clare T. Meeker & Christopher B. Little & Karena Last & Pamela J. Farmer & Ian K. Campbell & Anne M. Four, 2005. "ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro," Nature, Nature, vol. 434(7033), pages 648-652, March.
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    Cited by:

    1. Nan Hu & Jian-Xin Shi & Chong Chen & Hai-Huan Xu & Zhe-Han Chang & Peng-Fei Hu & Di Guo & Xiao-Wang Zhang & Wen-Wei Shao & Xiu Fan & Jia-Chen Zuo & Dong Ming & Xiao-Hong Li, 2024. "Constructing organoid-brain-computer interfaces for neurofunctional repair after brain injury," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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