Cbfβ regulates Wnt/β-catenin, Hippo/Yap, and Tgfβ signaling pathways in articular cartilage homeostasis and protects from ACLT surgery-induced osteoarthritis
Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, United States; Department of Pathology, School of Medicine, University of Alabama at Birmingham, Birmingham, United States
Department of Pathology, School of Medicine, University of Alabama at Birmingham, Birmingham, United States
Yan Zhang
Department of Pathology, School of Medicine, University of Alabama at Birmingham, Birmingham, United States
Jinjin Wu
Department of Pathology, School of Medicine, University of Alabama at Birmingham, Birmingham, United States
Abigail McVicar
Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, United States
Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, United States
Siyu Zhu
Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, United States
Guochun Zhu
Department of Pathology, School of Medicine, University of Alabama at Birmingham, Birmingham, United States
You Lu
Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, United States
Jiayang Zhang
Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, United States
Matthew McConnell
Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, United States
Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, United States; Department of Pathology, School of Medicine, University of Alabama at Birmingham, Birmingham, United States
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 Cbfbf/f;Col2a1-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 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.
