Cbfβ regulates Wnt/β-catenin, Hippo/Yap, and TGFβ signaling pathways in articular cartilage homeostasis and protects from ACLT surgery-induced osteoarthritis

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 thatCbfβ,(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 ofCbfβin tamoxifen-inducedCbfβ^f/fCol2α1-CreER^Tmice caused a spontaneous OA phenotype, worn articular cartilage, increased inflammation, and osteophytes. RNA-sequencing analysis showed thatCbfβdeficiency 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 decreasedCbfβand Yap expression and increased active β-catenin expression in articular cartilage, while local AAV-mediatedCbfβoverexpression promoted Yap expression and diminished active β-catenin expression in OA lesions. Remarkably, AAV-mediatedCbfβoverexpression in knee joints of mice with OA showed the significant protective effect ofCbfβon articular cartilage in the ACLT OA mouse model. Overall, this study, using loss-of-function and gain-of-function approaches, uncovered that low expression ofCbfβmay be the cause of OA. Moreover, Local admission ofCbfβmay 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 localCbfβoverexpression could be an effective strategy for treatment of OA.