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Targeting FAP-positive chondrocytes in osteoarthritis: a novel lipid nanoparticle siRNA approach to mitigate
Xiang Zhao1, Jieming Lin2, Mingyang Liu1
1Department of Surgery of Spine and Spinal Cord, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, No.7 Weiwu Road, Zhengzhou, Henan Province, 450003, China.
Background:
Osteoarthritis (OA) is a common joint disease that leads to chronic pain and functional limitations. Recent research has revealed soluble fibroblast activation protein (FAP) secreted from OA synovium could degrade type II collagen (Col2) in cartilage to promote the progression of OA. This study aimed to reveal the role of FAP from chondrocytes in OA and develop a novel lipid nanoparticle (LNP)-FAP siRNA delivery system for OA treatment.
Methods:
The expression of FAP in the cartilage of knee OA patients was investigated using [68 Ga]Ga-FAPI-04 PET in vivo and immunofluorescence, western blotting, and RT-qPCR in vitro. Cell senescence was determined by senescence-associated β-galactosidase (SA-β-Gal) assay after FAP overexpressing or knockdown in chondrocytes. An OA model with chondrocyte-specific FAP knockout mice was applied to investigate the role of FAP in chondrocyte senescence and OA development. The therapeutic effects of lipid nanoparticle (LNP) @FAP siRNA on cartilage degeneration were evaluated in the rat OA model.
Results:
Our study found that higher [68 Ga]Ga-FAPI-04 uptake was detected in knee OA patients by PET/CT scan. FAP mRNA and protein levels were highly expressed in OA-damaged cartilage. Moreover, we found that overexpression of FAP promotes chondrocyte senescence, and the genetic knockout of FAP in chondrocytes alleviates OA. Knockdown FAP by siRNA could alleviate chondrocyte senescence and suppress the NF-κB pathway to reduce the senescence-associated secretory phenotype (SASP). In the rat model of OA, intraarticular injection of LNP@FAP siRNA can reduce senescent cells and ameliorate cartilage destruction.
Conclusion:
FAP-positive chondrocytes play a significant role in the pathogenesis of OA. Targeting these cells selectively has the potential to mitigate the progression of the disease. Our study provides valuable insights into the intraarticular injection of LNP@FAP siRNA as a promising strategy for the treatment of OA.
Insights
Fibroblast activation protein (FAP) in chondrocytes drives osteoarthritis (OA) progression by promoting cell senescence. Targeting FAP with lipid nanoparticle (LNP)-FAP siRNA offers a promising therapeutic strategy to alleviate OA and cartilage damage.
Area of Science:
- Biomedical research
- Molecular biology
- Osteoarthritis research
Background:
- Osteoarthritis (OA) is a degenerative joint disease causing pain and disability.
- Soluble fibroblast activation protein (FAP) from OA synovium degrades cartilage, worsening OA.
- The role of FAP in chondrocytes and its therapeutic potential in OA require further investigation.
Purpose of the Study:
- To investigate the role of FAP in chondrocytes in OA pathogenesis.
- To develop a novel lipid nanoparticle (LNP)-FAP siRNA delivery system for OA treatment.
Main Methods:
- Investigated FAP expression in OA cartilage using PET/CT and molecular techniques.
- Assessed chondrocyte senescence after FAP manipulation (overexpression/knockdown).
- Utilized a chondrocyte-specific FAP knockout mouse model and a rat OA model to evaluate therapeutic effects of LNP@FAP siRNA.
Main Results:
- Elevated FAP expression was observed in OA cartilage.
- FAP overexpression promoted chondrocyte senescence; FAP knockout alleviated OA.
- LNP@FAP siRNA treatment reduced senescent cells and cartilage destruction in a rat OA model.
Conclusions:
- FAP-positive chondrocytes are significant contributors to OA pathogenesis.
- Targeting FAP in chondrocytes shows potential for mitigating OA progression.
- Intraarticular LNP@FAP siRNA injection is a promising therapeutic strategy for OA.
