Down-regulated GAS6 impairs synovial macrophage efferocytosis andpromotes obesity-associated osteoarthritis
- Third Affiliated Hospital of Southern Medical University, China
- 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.)
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Down-regulated GAS6 impairs synovial macrophage efferocytosis and promotes obesity-associated osteoarthritisDryad Digital Repository, doi:10.5061/dryad.d2547d86d.
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NRROS negatively regulates ROS in phagocytes during host defense and autoimmunityNCBI Gene Expression Omnibus, GSE53986.
Article and author information
Author details
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).
Reviewing Editor
- Di Chen, Chinese Academy of Sciences, China
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.
Version history
- Received: August 30, 2022
- Preprint posted: September 21, 2022 (view preprint)
- Accepted: May 4, 2023
- Accepted Manuscript published: May 5, 2023 (version 1)
- Version of Record published: May 17, 2023 (version 2)
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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Down-regulated GAS6 impairs synovial macrophage efferocytosis andpromotes obesity-associated osteoarthritis
eLife 12:e83069.
https://doi.org/10.7554/eLife.83069
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