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Published on: October 4, 2021
Potential predictive and therapeutic applications of small extracellular vesicles-derived circPARD3B in
Zhiguo Lin1, Yeye Ma1, Xiaoying Zhu1
1Department of Rheumatology, The First Affiliated Hospital, Harbin Medical University, Harbin, China.
Abstract:
Background: Heterogeneous phenotypes that display distinct common characteristics of osteoarthritis (OA) are not well defined and will be helpful in identifying more customized therapeutic options for OA. Circular RNAs (circRNAs) have attracted more and more attention due to their role in the progression of OA. Investigating the role of circRNAs in the pathogenesis of OA will contribute to the phenotyping of OA and to individualized treatment. Methods: Small extracellular vesicles (sEV) were isolated from serum samples from patients with OA of different stages and sEV-derived circPARD3B was determined using RT-qPCR analysis. CircPARD3B expression in a stimulated coculture that included OA fibroblast-like synoviocytes (OA-FLS) as well as human dermal microvascular endothelial cells (HDMECs), plus the effects of circPARD3B on the expression of vascular endothelial growth factor (VEGF) long with angiogenic activity, were evaluated in vitro. Based on bioinformatics analysis and luciferase reporter assay (LRA), MiR-326 and sirtuin 1 (SIRT1) were found to be interactive partners of circPARD3B. Mesenchymal stem cells (SMSCs) overexpressing circPARD3B were constructed and SMSCs-derived sEV with overexpressed circPARD3B (OE-circPARD3B-SMSCs-sEV) were obtained to explore the effect of the intervention of circPARD3B combined with SMSCs-sEV-based therapy in vitro and in a OA model induced by collagenase in vivo. Results: Serum sEV-linked circPARD3B was indentified to be significantly decreased in the inflammatory phenotype of OA. Overexpression of circPARD3B was found to inhibit the expression of VEGF, as well as the angiogenesis induced by VEGF in a IL-1β stimulated the co-culture of OA-FLS as well as HDMECs. CircPARD3B is directly bound to miR-326. SIRT1 was considered a novel miR-326 target gene. OE-circPARD3B-SMSCs-sEV significantly reduced VEGF expression in coculture of OA-FLS and HDMECs. Injection of OE-circPARD3B-SMSCs-sEV could also reduce synovial VEGF; additionally, it could further ameliorate OA in the mouse model of OA in vivo. Conclusion: Serum sEV circPARD3B is a potential biomarker that enables the identification of the inflammatory phenotype of patients with OA. Correspondingly, intracellular transfer of circPARD3B through OE-circPARD3B-SMSCs-sEV could postpone disease progression through a functional module regulated angiogenesis of circPARD3B-miR-326-SIRT1, providing a novel therapeutic strategy for OA.
Insights
Serum exosomal circPARD3B can identify inflammatory osteoarthritis (OA) phenotypes. Transferring circPARD3B via engineered stem cell-derived extracellular vesicles shows therapeutic potential for OA by regulating angiogenesis.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Osteoarthritis (OA) presents heterogeneous phenotypes, hindering targeted therapies.
- Circular RNAs (circRNAs) are implicated in OA pathogenesis, offering potential for phenotyping and personalized treatment.
Purpose of the Study:
- To investigate the role of circPARD3B in OA pathogenesis and its potential as a therapeutic target.
- To explore circPARD3B as a biomarker for OA inflammatory phenotypes.
Main Methods:
- Serum small extracellular vesicles (sEVs) from OA patients were analyzed for circPARD3B expression via RT-qPCR.
- In vitro studies assessed circPARD3B's effect on vascular endothelial growth factor (VEGF) and angiogenesis in co-cultures.
- Bioinformatics and luciferase reporter assays identified miR-326 and SIRT1 as interaction partners.
- Engineered mesenchymal stem cell-derived sEVs overexpressing circPARD3B (OE-circPARD3B-SMSCs-sEV) were used for in vitro and in vivo OA models.
Main Results:
- Serum sEV-circPARD3B levels were significantly lower in the inflammatory OA phenotype.
- Overexpression of circPARD3B inhibited VEGF expression and angiogenesis in IL-1β-stimulated co-cultures.
- CircPARD3B directly binds to miR-326, and SIRT1 is a novel miR-326 target.
- OE-circPARD3B-SMSCs-sEV treatment reduced VEGF and ameliorated OA in a mouse model.
Conclusions:
- Serum sEV circPARD3B serves as a biomarker for identifying inflammatory OA phenotypes.
- Intracellular transfer of circPARD3B via OE-circPARD3B-SMSCs-sEV can delay OA progression.
- The circPARD3B-miR-326-SIRT1 pathway offers a novel therapeutic strategy for OA by regulating angiogenesis.
