CCAAT/enhancer binding protein β (C/EBPβ) regulates the transcription of growth arrest and DNA damage-inducible protein 45 β (GADD45β) in articular chondrocytes

Abstract

Osteoarthritis (OA) is a whole joint disease characterized by cartilage degradation, which causes pain and disability in older adults. Our previous work showed that growth arrest and DNA damage-inducible protein 45 β (GADD45β) is upregulated in chondrocyte clusters in OA cartilage, especially in the early stage of this disease. CCAAT/enhancer binding protein β (C/EBPβ) is expressed in the hypertrophic growth plate chondrocytes and functions in synergy with GADD45β. Here, the presence and localization of these proteins was assessed by immunohistochemistry using articular cartilage from OA patients, revealing colocalization of C/EBPβ and GADD45β in OA chondrocytes. GADD45β promoter analysis was performed to determine whether C/EBPβ directly regulates GADD45β transcription. Furthermore, we analyzed the effect of C/EBPβ on Gadd45β gene regulation in articular chondrocytes in vivo and in vitro. Immunohistochemical analysis of C/ebpβ-haploinsufficient mice (C/ebpβ+/−) cartilage showed that C/ebpβ haploinsufficiency led to reduced Gadd45β gene expression in these cells. In vitro, we evaluated the effects of conditional C/EBPβ overexpression driven by the cartilage oligomeric matrix protein (Comp) promoter in mComp-tTA;pTRE-Tight-BI-DsRed-mC/ebpβ transgenic mice. C/EBPβ overexpression significantly stimulated Gadd45β gene expression in articular chondrocytes. Taken together, our data demonstrate that C/EBPβ plays a central role in controlling Gadd45β gene expression in these cells.