Deficiency of Cbfβ in articular cartilage leads to osteoarthritis-like phenotype through Hippo/Yap, TGFβ, and Wnt/β-catenin signaling pathways.

Abstract

Osteoarthritis (OA) is the most prevalent degenerative joint disorder, causing physical impairments among the elderly. Core binding factor subunit β (Cbfβ) has a critical role in bone homeostasis and cartilage development. However, the function and mechanism of Cbfβ in articular cartilage and OA remains unclear. We found that Cbfβf/fAggrecan-CreERT mice with Cbfβ-deficiency in articular cartilage developed a spontaneous osteoarthritis-like phenotype with articular cartilage degradation. Immunofluorescence staining showed that Cbfβf/fAggrecan-CreERT mice exhibited a significant increase in the expression of articular cartilage degradation markers and inflammatory markers in the knee joints. RNA-sequencing analysis demonstrated that Cbfβ orchestrated Hippo/Yap, TGFβ/Smad, and Wnt/β-catenin signaling pathways in articular cartilage, and Cbfβ deficiency resulted in the abnormal expression of downstream genes involved in maintaining articular cartilage homeostasis. Immunofluorescence staining results showed Cbfβ deficiency significantly increased active β-catenin and TCF4 expression while reducing Yap, TGFβ1, and p-Smad 2/3 expression. Western blot and qPCR validated gene expression changes in hip articular cartilage of Cbfβ-deficient mice. Our results demonstrate that deficiency of Cbfβ in articular cartilage leads to an OA-like phenotype via affecting Hippo/Yap, TGFβ, and Wnt/β-catenin signaling pathways, disrupting articular cartilage homeostasis and leading to the pathological process of OA in mice. Our results indicate that targeting Cbfβ may be a potential therapeutic target for the design of novel and effective treatments for OA.