Down-regulated GAS6 impairs synovial macrophage efferocytosis andpromotes obesity-associated osteoarthritis

  1. Zihao Yao
  2. Weizhong Qi
  3. Hongbo Zhang
  4. Zhicheng Zhang
  5. Liangliang Liu
  6. Yan Shao
  7. Hua Zeng
  8. Jianbin Yin
  9. Haoyan Pan
  10. Xiongtian Guo
  11. Anling Liu
  12. Daozhang Cai  Is a corresponding author
  13. Xiaochun Bai  Is a corresponding author
  14. Haiyan Zhang  Is a corresponding author
  1. Third Affiliated Hospital of Southern Medical University, China
  2. Southern Medical University, China

Abstract

Obesity has always been considered a significant risk factor in OA progression, but the underlying mechanism of obesity-related inflammation in OA synovitis remains unclear. The present study found that synovial macrophages infiltrated and polarized in the obesity microenvironment and identified the essential role of M1 macrophages in impaired macrophage efferocytosis using pathology analysis of obesity-associated OA. The present study revealed that obese OA patients and Apoe-/- mice showed a more pronounced synovitis and enhanced macrophage infiltration in synovial tissue, accompanied by dominant M1 macrophage polarization. Obese OA mice had a more severe cartilage destruction and increased levels of synovial apoptotic cells than OA mice in the control group. Enhanced M1-polarized macrophages in obese synovium decreased growth arrest-specific 6 (GAS6) secretion, resulting in impaired macrophage efferocytosis in synovial apoptotic cells. Intracellular contents released by accumulated apoptotic cells further triggered an immune response and lead to a release of inflammatory factors, such as TNF-α, IL-1β, and IL-6, which induce chondrocyte homeostasis dysfunction in obese OA patients. Intra-articular injection of GAS6 restored the phagocytic capacity of macrophages, reduced the accumulation of local apoptotic cells, and decreased the levels of TUNEL- and caspase-3-positive cells, preserving cartilage thickness and preventing the progression of obesity-associated OA. Therefore, targeting macrophage associated efferocytosis or intra-articular injection of GAS6 is a potential therapeutic strategy for obesity-associated OA.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE53986. Source Data has been uploaded in Dryad , which was named after "Down-regulated GAS6 impairs synovial macrophage efferocytosis and promotes obesity-associated osteoarthritis" https://doi.org/10.5061/dryad.d2547d86d.)

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Zihao Yao

    Department of Orthopedics, Third Affiliated Hospital of Southern Medical University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Weizhong Qi

    Department of Orthopedics, Third Affiliated Hospital of Southern Medical University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Hongbo Zhang

    Department of Orthopedics, Third Affiliated Hospital of Southern Medical University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Zhicheng Zhang

    Department of Orthopedics, Third Affiliated Hospital of Southern Medical University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Liangliang Liu

    Department of Orthopedics, Third Affiliated Hospital of Southern Medical University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Yan Shao

    Department of Orthopedics, Third Affiliated Hospital of Southern Medical University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Hua Zeng

    Department of Orthopedics, Third Affiliated Hospital of Southern Medical University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Jianbin Yin

    Department of Orthopedics, Third Affiliated Hospital of Southern Medical University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Haoyan Pan

    Department of Orthopedics, Third Affiliated Hospital of Southern Medical University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Xiongtian Guo

    Department of Orthopedics, Third Affiliated Hospital of Southern Medical University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Anling Liu

    Department of Biochemistry and Molecular Biology, Third Affiliated Hospital of Southern Medical University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Daozhang Cai

    Department of Orthopedics, Third Affiliated Hospital of Southern Medical University, Guangzhou, China
    For correspondence
    cdz@smu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  13. Xiaochun Bai

    Department of Joint Surgery, Southern Medical University, Guangzhou, China
    For correspondence
    baixc15@smu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9631-4781
  14. Haiyan Zhang

    Department of Orthopedics, Third Affiliated Hospital of Southern Medical University, Guangzhou, China
    For correspondence
    zhhy0704@126.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9361-3134

Funding

National Natural Science Foundation of China (81902229)

  • Haiyan Zhang

National Natural Science Foundation of China (81871745)

  • Anling Liu

Natural Science Foundation of Guangdong Province (2020A1515011062)

  • Haiyan Zhang

This work were fully funded by National Natural Science Foundation of China (NSFC).

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in Chinese Laboratory animal-Guideline for ethical review of animal welfare (GB/T 35892-2018). The protocol was approved by the Southern Medical University Animal Care and Use Review Board(Permit Number: 2021- Ethical review-053). All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.

Human subjects: Informed consent was obtained from all recruited patients and was identified by the ethics committee of the Third Affiliated Hospital of Southern Medical University.

Copyright

© 2023, Yao et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Zihao Yao
  2. Weizhong Qi
  3. Hongbo Zhang
  4. Zhicheng Zhang
  5. Liangliang Liu
  6. Yan Shao
  7. Hua Zeng
  8. Jianbin Yin
  9. Haoyan Pan
  10. Xiongtian Guo
  11. Anling Liu
  12. Daozhang Cai
  13. Xiaochun Bai
  14. Haiyan Zhang
(2023)
Down-regulated GAS6 impairs synovial macrophage efferocytosis andpromotes obesity-associated osteoarthritis
eLife 12:e83069.
https://doi.org/10.7554/eLife.83069

Share this article

https://doi.org/10.7554/eLife.83069

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