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Prediction and validation based on scRNA-seq: ETS2 targets CEBPB to mediate osteoclast differentiation in
Qu Xu1, Penggang Ma1, Rui Wang1
1The third ward of orthopaedic department, General Hospital of Ningxia Medical University, 804 Shengli South Street, Yinchuan, Ningxia Hui Autonomous Region 750004, China.
Abstract:
This study aims to identify key molecular targets driving osteoclast (OC)-mediated osteoarthritis (OA) progression and to explore the underlying mechanisms. Analysis of OA-related scRNA-seq data revealed that the transcription factor (TFs) ETS2 is identified as a hub gene promoting OC differentiation in OA progression. In Silico Perturbation and in vitro perturbation experiments demonstrated that knockdown of ETS2 inhibits OC differentiation. Transcriptional regulatory network analysis and combined Cut&Tag with ATAC-seq analysis indicated that ETS2 regulates OC differentiation by targeting and enhancing the expression of CEBPB. This conclusion was validated by in vitro rescue experiments. In vivo experiments showed that knockdown of ETS2 decreases the number of OCs in the subchondral bone of DMM model mice and inhibits subchondral bone remodeling and OA progression. In summary, our findings indicate that ETS2 regulates OC differentiation by targeting and modulating the expression of CEBPB. Knockdown of ETS2 can alleviate subchondral bone remodeling and OA progression in DMM model mice, providing new insights into the pathogenesis and treatment of OA.
Insights
This study identifies ETS2 as a key factor in osteoclast-driven osteoarthritis progression. Reducing ETS2 inhibits osteoclast differentiation and alleviates bone remodeling, offering potential therapeutic strategies for osteoarthritis.
Area of Science:
- Molecular Biology
- Immunology
- Orthopedics
Background:
- Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage breakdown and subchondral bone remodeling.
- Osteoclasts (OCs) play a critical role in OA pathogenesis by mediating bone resorption and inflammation.
- Identifying molecular targets that regulate osteoclast activity is crucial for developing effective OA treatments.
Purpose of the Study:
- To identify key molecular targets driving osteoclast-mediated OA progression.
- To elucidate the mechanisms by which these targets regulate osteoclast differentiation.
- To evaluate the therapeutic potential of targeting these molecules in OA models.
Main Methods:
- Analysis of OA-related single-cell RNA sequencing (scRNA-seq) data.
- In silico and in vitro perturbation experiments (e.g., gene knockdown).
- Transcriptional regulatory network analysis, Cut&Tag, and ATAC-seq.
- In vivo studies using a DMM mouse model of OA.
Main Results:
- ETS2 was identified as a hub gene promoting osteoclast differentiation in OA.
- Knockdown of ETS2 inhibited osteoclast differentiation in vitro.
- ETS2 was found to regulate osteoclast differentiation by targeting and enhancing CEBPB expression.
- In vivo, ETS2 knockdown reduced osteoclast numbers, inhibited subchondral bone remodeling, and alleviated OA progression in DMM mice.
Conclusions:
- ETS2 is a critical regulator of osteoclast differentiation and OA progression.
- ETS2 targets and modulates CEBPB expression to drive osteoclast-mediated bone remodeling.
- Targeting ETS2 presents a promising therapeutic strategy for mitigating OA progression and subchondral bone changes.
