Expression pattern analysis of m6A regulators reveals IGF2BP3 as a key modulator in osteoarthritis synovial
Yuheng Lu1,2,3, Hongbo Zhang1,2,3, Haoyan Pan1,2,3
1Department of Orthopedics, Academy of Orthopedics, Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510515, China.
Background:
Disruption of N6 methyl adenosine (m6A) modulation hampers gene expression and cellular functions, leading to various illnesses. However, the role of m6A modification in osteoarthritis (OA) synovitis remains unclear. This study aimed to explore the expression patterns of m6A regulators in OA synovial cell clusters and identify key m6A regulators that mediate synovial macrophage phenotypes.
Methods:
The expression patterns of m6A regulators in the OA synovium were illustrated by analyzing bulk RNA-seq data. Next, we built an OA LASSO-Cox regression prediction model to identify the core m6A regulators. Potential target genes of these m6A regulators were identified by analyzing data from the RM2target database. A molecular functional network based on core m6A regulators and their target genes was constructed using the STRING database. Single-cell RNA-seq data were collected to verify the effects of m6A regulators on synovial cell clusters. Conjoint analyses of bulk and single-cell RNA-seq data were performed to validate the correlation between m6A regulators, synovial clusters, and disease conditions. After IGF2BP3 was screened as a potential modulator in OA macrophages, the IGF2BP3 expression level was tested in OA synovium and macrophages, and its functions were further tested by overexpression and knockdown in vitro.
Results:
OA synovium showed aberrant expression patterns of m6A regulators. Based on these regulators, we constructed a well-fitting OA prediction model comprising six factors (FTO, YTHDC1, METTL5, IGF2BP3, ZC3H13, and HNRNPC). The functional network indicated that these factors were closely associated with OA synovial phenotypic alterations. Among these regulators, the m6A reader IGF2BP3 was identified as a potential macrophage mediator. Finally, IGF2BP3 upregulation was verified in the OA synovium, which promoted macrophage M1 polarization and inflammation.
Conclusions:
Our findings revealed the functions of m6A regulators in OA synovium and highlighted the association between IGF2BP3 and enhanced M1 polarization and inflammation in OA macrophages, providing novel molecular targets for OA diagnosis and treatment.
Insights
N6 methyl adenosine (m6A) dysregulation impacts gene expression and disease. This study identifies key m6A regulators in osteoarthritis (OA) synovitis, revealing IGF2BP3 promotes macrophage M1 polarization and inflammation, offering new OA therapeutic targets.
Area of Science:
- Molecular biology
- Epigenetics
- Immunology
Background:
- N6 methyl adenosine (m6A) modulation is crucial for gene expression and cellular functions, but its role in osteoarthritis (OA) synovitis is not well understood.
- Investigating m6A regulators in OA synovium is essential for understanding disease pathogenesis.
Purpose of the Study:
- To explore m6A regulator expression patterns in OA synovial cell clusters.
- To identify key m6A regulators involved in mediating synovial macrophage phenotypes in OA.
Main Methods:
- Analysis of bulk and single-cell RNA-seq data to profile m6A regulators in OA synovium.
- Development of a LASSO-Cox regression model to identify core m6A regulators.
- Functional analysis using databases like RM2target and STRING, followed by in vitro validation of IGF2BP3.
Main Results:
- Aberrant m6A regulator expression was observed in OA synovium, with a predictive model identifying six key factors (FTO, YTHDC1, METTL5, IGF2BP3, ZC3H13, HNRNPC).
- The m6A reader IGF2BP3 was identified as a key mediator in OA macrophages.
- IGF2BP3 upregulation in OA synovium was confirmed, promoting M1 macrophage polarization and inflammation.
Conclusions:
- m6A regulators play significant roles in OA synovitis.
- IGF2BP3 is associated with enhanced M1 polarization and inflammation in OA macrophages.
- These findings provide novel molecular targets for OA diagnosis and treatment.
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