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| Status |
Public on Jan 19, 2024 |
| Title |
Cbfβ regulates Wnt/β-catenin, Hippo/Yap, and TGFβ signaling pathways in articular cartilage homeostasis and protects from ACLT surgery-induced osteoarthritis |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
As the most common degenerative joint disease, osteoarthritis (OA) contributes significantly to pain and disability during aging. Several genes of interest involved in articular cartilage damage in OA have been identified. However, the direct causes of OA are poorly understood. Evaluating the public human RNA-seq dataset showed that Cbfβ, (subunit of a heterodimeric Cbfβ/Runx1,Runx2, or Runx3 complex) expression is decreased in the cartilage of patients with OA. Here, we found that the chondrocyte-specific deletion of Cbfβ in tamoxifen-induced Cbfβf/fCol2α1-CreERT mice caused a spontaneous OA phenotype, worn articular cartilage, increased inflammation, and osteophytes. RNA-sequencing analysis showed that Cbfβ deficiency in articular cartilage resulted in reduced cartilage regeneration, increased canonical Wnt signaling and inflammatory response, and decreased Hippo/YAP signaling and TGF-β signaling. Immunostaining and western blot validated these RNA-seq analysis results. ACLT surgery-induced OA decreased Cbfβ and Yap expression and increased active β-catenin expression in articular cartilage, while local AAV-mediated Cbfβ overexpression promoted Yap expression and diminished active β-catenin expression in OA lesions. Remarkably, AAV-mediated Cbfβ overexpression in knee joints of mice with OA showed the significant protective effect of Cbfβ on articular cartilage in the ACLT OA mouse model. Overall, this study, using loss-of-function and gain-of-function approaches, uncovered that low expression of Cbfβ may be the cause of OA. Moreover, Local admission of Cbfβ may rescue and protect OA through decreasing Wnt/β-catenin signaling, and increasing Hippo/Yap signaling and TGFβ/Smad2/3 signaling in OA articular cartilage, indicating that local Cbfβ overexpression could be an effective strategy for treatment of OA.
Using unbiased genome-wide RNA-seq data from Cbfβf/f;Col2α1-Cre hip joint articular cartilage and Cbfβf/f;Aggrecan-cre knee joint articular cartilage and their controls, we examined Cbfβ-mediated transcriptional targets for articular cartilage regeneration in OA.
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| Overall design |
Comparative gene expression profiling analysis of RNA-seq data for mice WT, Cbfβf/f;Col2α1-Cre hip joint articular cartilage and Cbfβf/f;Aggrecan-cre articular cartilage
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| Contributor(s) |
Li Y, Chen W, Zhu S, McVicar A |
| Citation(s) |
38293189, 38805545 |
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| Submission date |
Jan 14, 2024 |
| Last update date |
Jun 12, 2024 |
| Contact name |
Yi-Ping Li |
| E-mail(s) |
yli81@tulane.edu
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| Organization name |
Tulane University School of Medicine
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| Department |
Pathology and Laboratory Medicine
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| Street address |
1441 Canal St, Room 318
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| City |
New Orleans |
| State/province |
LA |
| ZIP/Postal code |
70112 |
| Country |
USA |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (4)
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| GSM8016353 |
Hip joint articular cartilage, Cbfβf/f, |
| GSM8016354 |
Hip joint articular cartilage, Tamoxifen injected Cbfβf/f;Col2α1-CreERT |
| GSM8016355 |
Knee joint articular cartilage, Oil injected Cbfβf/f;Aggrecan-CreERT |
| GSM8016356 |
Knee joint articular cartilage, Tamoxifen injected Cbfβf/f;Aggrecan-CreERT |
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| Relations |
| BioProject |
PRJNA1064570 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE253210_RAW.tar |
850.0 Kb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
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