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Peer-reviewedCC BY-NC-NDJournal of nanobiotechnology

Spermidine, a chondrocyte apoptotic metabolite, delays osteoarthritis by regulating macrophage M2c polarization.

  • Jiajia Lu1
  • Hongbiao Sun2
  • Fan Zhang3
  • Guangnan Wang4
  • Xianan Song5
  • Qinling Jiang2
  • Zhibin Zhou6
  • Jun Ma7
  • Qiang Fu8
  • Lei Zhu9
9 affiliations
  1. 1Department of Orthopedic Trauma, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200000, China.
  2. 2Department of Radiology, Second Affiliated Hospital of Navy Medical University, Naval Medical University, Shanghai, 200000, China.
  3. 3Department of Orthopedic Trauma, Second Affiliated Hospital of Navy Medical University, Naval Medical University, Shanghai, 200000, China.
  4. 4Department of Orthopedics, The 968th Hospital of the Joint Logistics Support Force of PLA, Jinzhou, 121000, Liaoning, China.
  5. 5Department of Orthopedics, General Hospital of Northern Theater Command, Shenyang, 110016, Liaoning, China.
  6. 6Department of Orthopedics, General Hospital of Northern Theater Command, Shenyang, 110016, Liaoning, China. [email protected].
  7. 7Department of Orthopaedics, Naval Medical Center of PLA, Naval Medical University, Shanghai, 200000, China. [email protected].
  8. 8Department of Orthopedic Trauma, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200000, China. [email protected].
  9. 9Department of Orthopedic Trauma, Second Affiliated Hospital of Navy Medical University, Naval Medical University, Shanghai, 200000, China. [email protected].
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Abstract

Background

Chondrocyte apoptosis and synovial macrophage polarization represent two key pathological hallmarks of osteoarthritis (OA), but the interplay between them remains largely unknown. This study aimed to investigate the roles and mechanisms of the chondrocyte apoptotic secretome in mediating macrophage polarization during the pathological process of OA.Methods

In vitro cultures of chondrocytes and macrophages, along with an in vivo surgically induced OA mouse model, were used to evaluate the effect of the chondrocyte apoptotic secretome. Untargeted metabolomics, mitochondrial function assessment, and macrophage-specific AMPKα knockout mice were used to identify key metabolites and their regulatory mechanisms. A sustained-release delivery system for spermidine (SPD) was constructed using lipid nanoparticles (LNPs) and sodium hyaluronate.Results

Apoptotic chondrocytes increased the secretion of SPD in the metabolite secretome. SPD acts as a signaling metabolite to increase AMPKα activation in macrophages, which in turn drives increased oxidative phosphorylation (OXPHOS) and improves mitochondrial function, ultimately promoting M2c macrophage polarization during OA. Exogenous supplementation with SPD via a ROS-responsive SH@LNP@SPD hydrogel alleviated OA progression by promoting M2c macrophage polarization in vivo. Furthermore, elevated SPD levels in synovial fluid correlated with milder clinical symptoms and less severe pathological features.Conclusions

Our findings underscore a significant protective role of chondrocyte apoptosis in early OA mediated through the secretion of SPD, which acts on macrophages. Mechanistically, SPD-induced enhancement of AMPKα activation and OXPHOS occurs specifically in macrophages, driving their beneficial M2c polarization. Synovial fluid SPD may hold diagnostic value for early-stage OA and strategies aimed at sustaining SPD levels may represent effective therapeutic approaches for OA.

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Cite

BibTeXRIS
BibTeX
@article{lu2026spermidine,
  title = {{Spermidine, a chondrocyte apoptotic metabolite, delays osteoarthritis by regulating macrophage M2c polarization.}},
  author = {Jiajia Lu and Hongbiao Sun and Fan Zhang and Guangnan Wang and Xianan Song and Qinling Jiang and Zhibin Zhou and Jun Ma and Qiang Fu and Lei Zhu},
  journal = {Journal of nanobiotechnology},
  year = {2026},
  month = jul,
  doi = {10.1186/s12951-026-04832-1},
  url = {https://europepmc.org/article/MED/42908004},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Spermidine, a chondrocyte apoptotic metabolite, delays osteoarthritis by regulating macrophage M2c polarization.
AU  - Jiajia Lu
AU  - Hongbiao Sun
AU  - Fan Zhang
AU  - Guangnan Wang
AU  - Xianan Song
AU  - Qinling Jiang
AU  - Zhibin Zhou
AU  - Jun Ma
AU  - Qiang Fu
AU  - Lei Zhu
PY  - 2026
DA  - 2026/07/01
JO  - Journal of nanobiotechnology
DO  - 10.1186/s12951-026-04832-1
UR  - https://europepmc.org/article/MED/42908004
AB  - Background  Chondrocyte apoptosis and synovial macrophage polarization represent two key pathological hallmarks of osteoarthritis (OA), but the interplay between them remains largely unknown. This study aimed to investigate the roles and mechanisms of the chondrocyte apoptotic secretome in mediating macrophage polarization during the pathological process of OA.Methods  In vitro cultures of chondrocytes and macrophages, along with an in vivo surgically induced OA mouse model, were used to evaluate the effect of the chondrocyte apoptotic secretome. Untargeted metabolomics, mitochondrial function assessment, and macrophage-specific AMPKα knockout mice were used to identify key metabolites and their regulatory mechanisms. A sustained-release delivery system for spermidine (SPD) was constructed using lipid nanoparticles (LNPs) and sodium hyaluronate.Results  Apoptotic chondrocytes increased the secretion of SPD in the metabolite secretome. SPD acts as a signaling metabolite to increase AMPKα activation in macrophages, which in turn drives increased oxidative phosphorylation (OXPHOS) and improves mitochondrial function, ultimately promoting M2c macrophage polarization during OA. Exogenous supplementation with SPD via a ROS-responsive SH@LNP@SPD hydrogel alleviated OA progression by promoting M2c macrophage polarization in vivo. Furthermore, elevated SPD levels in synovial fluid correlated with milder clinical symptoms and less severe pathological features.Conclusions  Our findings underscore a significant protective role of chondrocyte apoptosis in early OA mediated through the secretion of SPD, which acts on macrophages. Mechanistically, SPD-induced enhancement of AMPKα activation and OXPHOS occurs specifically in macrophages, driving their beneficial M2c polarization. Synovial fluid SPD may hold diagnostic value for early-stage OA and strategies aimed at sustaining SPD levels may represent effective therapeutic approaches for OA.
SN  - 1477-3155
ER  -