Targeting FAP-positive chondrocytes in osteoarthritis: a novel lipid nanoparticle siRNA approach to mitigate cartilage degeneration.
Animals
Chondrocytes
/ metabolism
Nanoparticles
/ chemistry
Humans
RNA, Small Interfering
/ pharmacology
Mice
Male
Rats
Membrane Proteins
/ metabolism
Endopeptidases
/ metabolism
Gelatinases
/ metabolism
Osteoarthritis
/ metabolism
Mice, Knockout
Cartilage, Articular
/ metabolism
Serine Endopeptidases
/ metabolism
Rats, Sprague-Dawley
Cellular Senescence
Female
Middle Aged
Aged
Liposomes
FAP
LNP
Osteoarthritis
Senescence
[68 Ga]Ga-FAPI-04 PET/CT
Journal
Journal of nanobiotechnology
ISSN: 1477-3155
Titre abrégé: J Nanobiotechnology
Pays: England
ID NLM: 101152208
Informations de publication
Date de publication:
26 Oct 2024
26 Oct 2024
Historique:
received:
13
08
2024
accepted:
20
10
2024
medline:
26
10
2024
pubmed:
26
10
2024
entrez:
26
10
2024
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
CONCLUSIONS
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.
Identifiants
pubmed: 39456041
doi: 10.1186/s12951-024-02946-y
pii: 10.1186/s12951-024-02946-y
doi:
Substances chimiques
RNA, Small Interfering
0
fibroblast activation protein alpha
EC 3.4.21.-
Membrane Proteins
0
Endopeptidases
EC 3.4.-
Gelatinases
EC 3.4.24.-
Lipid Nanoparticles
0
Serine Endopeptidases
EC 3.4.21.-
Liposomes
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
659Subventions
Organisme : National Natural Science Foundation of China
ID : 82101648
Organisme : National Natural Science Foundation of China
ID : 82171896
Organisme : National Natural Science Foundation of China
ID : 82172438
Organisme : China Postdoctoral Science Foundation
ID : 2023M731009
Organisme : Natural Science Foundation of Shanghai Municipality
ID : 22ZR1450300
Informations de copyright
© 2024. The Author(s).
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