Cbfβ regulates Wnt/β-catenin, Hippo/Yap, and Tgfβ signaling pathways in articular cartilage homeostasis and protects from ACLT surgery-induced osteoarthritis.
Wei ChenYun LuYan ZhangJinjin WuAbigail McVicarYilin ChenSiyu ZhuGuochun ZhuYou LuJiayang ZhangMatthew McConnellYi-Ping LiPublished in: eLife (2024)
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 CBFB (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 Cbfb in tamoxifen-induced Cbfb f/f ;Col2a1-CreER T 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 Tgfβ 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 Cbfb overexpression promoted Yap expression and diminished active β-catenin expression in OA lesions. Remarkably, AAV-mediated Cbfb 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 Cbfb 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 Cbfb overexpression could be an effective strategy for treatment of OA.
Keyphrases
- knee osteoarthritis
- rna seq
- poor prognosis
- cell proliferation
- single cell
- transcription factor
- inflammatory response
- epithelial mesenchymal transition
- binding protein
- stem cells
- transforming growth factor
- minimally invasive
- mouse model
- oxidative stress
- rheumatoid arthritis
- endothelial cells
- multiple sclerosis
- healthcare
- high glucose
- signaling pathway
- long non coding rna
- type diabetes
- south africa
- adipose tissue
- skeletal muscle
- diabetic rats
- lipopolysaccharide induced
- gene expression
- dna methylation
- gene therapy
- genome wide
- pain management
- high fat diet induced
- percutaneous coronary intervention
- smoking cessation
- induced pluripotent stem cells
- bioinformatics analysis