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

Zhang, Yan; Chen, Huiwen; Wu, Jinjin; McVicar, Abigail; Chen, Yilin; Su, Jiacan; Li, Yi-Ping; Chen, Wei

doi:10.7150/ijbs.90250

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Int J Biol Sci 2024; 20(6):1965-1977. doi:10.7150/ijbs.90250 This issue Cite

Research Paper

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

Yan Zhang^1,2, Huiwen Chen¹, Jinjin Wu¹, Abigail McVicar³, Yilin Chen³, Jiacan Su⁴, Yi-Ping Li^1,3✉, Wei Chen^1,3✉

1. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
2. Key Laboratory of Biomedical Information Engineering of Ministry of Education, Biomedical Informatics and Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Shaanxi, Xi'an 710049, P.R. China.
3. Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, 70112, USA.
4. Institute of Translational Medicine, Shanghai University, Shanghai, P.R. China.

Citation:

Zhang Y, Chen H, Wu J, McVicar A, Chen Y, Su J, Li YP, Chen W. Deficiency of Cbfβ in articular cartilage leads to osteoarthritis-like phenotype through Hippo/Yap, TGFβ, and Wnt/β-catenin signaling pathways. Int J Biol Sci 2024; 20(6):1965-1977. doi:10.7150/ijbs.90250. https://www.ijbs.com/v20p1965.htm

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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 Cbfβ^f/fAggrecan-CreER^T mice with Cbfβ-deficiency in articular cartilage developed a spontaneous osteoarthritis-like phenotype with articular cartilage degradation. Immunofluorescence staining showed that Cbfβ^f/fAggrecan-CreER^T 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.

Keywords: Osteoarthritis, Cbfβ, Wnt signaling, Hippo/YAP signaling, TGFβ signaling

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APA

Zhang, Y., Chen, H., Wu, J., McVicar, A., Chen, Y., Su, J., Li, Y.P., Chen, W. (2024). Deficiency of Cbfβ in articular cartilage leads to osteoarthritis-like phenotype through Hippo/Yap, TGFβ, and Wnt/β-catenin signaling pathways. International Journal of Biological Sciences, 20(6), 1965-1977. https://doi.org/10.7150/ijbs.90250.

ACS

Zhang, Y.; Chen, H.; Wu, J.; McVicar, A.; Chen, Y.; Su, J.; Li, Y.P.; Chen, W. Deficiency of Cbfβ in articular cartilage leads to osteoarthritis-like phenotype through Hippo/Yap, TGFβ, and Wnt/β-catenin signaling pathways. Int. J. Biol. Sci. 2024, 20 (6), 1965-1977. DOI: 10.7150/ijbs.90250.

NLM

CSE

Zhang Y, Chen H, Wu J, McVicar A, Chen Y, Su J, Li YP, Chen W. 2024. Deficiency of Cbfβ in articular cartilage leads to osteoarthritis-like phenotype through Hippo/Yap, TGFβ, and Wnt/β-catenin signaling pathways. Int J Biol Sci. 20(6):1965-1977.

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