Cbfβ Is a Novel Modulator against Osteoarthritis by Maintaining Articular Cartilage Homeostasis through TGF-β Signaling
Xiangguo Che,
Xian Jin,
Na Rae Park,
Hee-June Kim,
Hee-Soo Kyung,
Hyun-Ju Kim,
Jane B. Lian,
Janet L. Stein,
Gary S. Stein,
Je-Yong Choi
Affiliations
Xiangguo Che
Korea Mouse Phenotyping Center (KMPC), Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
Xian Jin
Korea Mouse Phenotyping Center (KMPC), Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
Na Rae Park
Korea Mouse Phenotyping Center (KMPC), Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
Hee-June Kim
Department of Orthopedic Surgery, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
Hee-Soo Kyung
Department of Orthopedic Surgery, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
Hyun-Ju Kim
Korea Mouse Phenotyping Center (KMPC), Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
Jane B. Lian
University of Vermont Cancer Center, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA
Janet L. Stein
University of Vermont Cancer Center, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA
Gary S. Stein
University of Vermont Cancer Center, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA
Je-Yong Choi
Korea Mouse Phenotyping Center (KMPC), Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
TGF-β signaling is a vital regulator for maintaining articular cartilage homeostasis. Runx transcription factors, downstream targets of TGF-β signaling, have been studied in the context of osteoarthritis (OA). Although Runx partner core binding factor β (Cbfβ) is known to play a pivotal role in chondrocyte and osteoblast differentiation, the role of Cbfβ in maintaining articular cartilage integrity remains obscure. This study investigated Cbfβ as a novel anabolic modulator of TGF-β signaling and determined its role in articular cartilage homeostasis. Cbfβ significantly decreased in aged mouse articular cartilage and human OA cartilage. Articular chondrocyte-specific Cbfb-deficient mice (Cbfb△ac/△ac) exhibited early cartilage degeneration at 20 weeks of age and developed OA at 12 months. Cbfb△ac/△ac mice showed enhanced OA progression under the surgically induced OA model in mice. Mechanistically, forced expression of Cbfβ rescued Type II collagen (Col2α1) and Runx1 expression in Cbfβ-deficient chondrocytes. TGF-β1-mediated Col2α1 expression failed despite the p-Smad3 activation under TGF-β1 treatment in Cbfβ-deficient chondrocytes. Cbfβ protected Runx1 from proteasomal degradation through Cbfβ/Runx1 complex formation. These results indicate that Cbfβ is a novel anabolic regulator for cartilage homeostasis, suggesting that Cbfβ could protect OA development by maintaining the integrity of the TGF-β signaling pathway in articular cartilage.
