BAPX-1/NKX-3.2 Acts as a Chondrocyte Hypertrophy Molecular Switch in Osteoarthritis
SourceArthritis & Rheumatology, 67, 11, (2015), pp. 2944-2956
Article / Letter to editor
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Arthritis & Rheumatology
SubjectRadboudumc 5: Inflammatory diseases RIMLS: Radboud Institute for Molecular Life Sciences
OBJECTIVE: Osteoarthritis (OA) development involves a shift of the articular chondrocyte phenotype toward hypertrophic differentiation via still poorly characterized mechanisms. The purpose of this study was to test our hypothesis that the function of BAPX-1/NKX-3.2 is impaired in OA chondrocytes and leads directly to loss of hypertrophic protection of the articular chondrocyte, which is central in the changing chondrocyte phenotype that drives OA. METHODS: Human articular chondrocytes (HACs; from healthy and OA donors) and SW-1353 chondrocytic cells were exposed to bone morphogenetic protein 7 (BMP-7), interleukin-1beta (IL-1beta), tumor necrosis factor, or OA synovial fluid (SF; 20% [volume/volume]). Loss-of-function and gain-of-function experiments for BAPX-1/NKX-3.2 were performed. Mouse experimental models of OA were used, and (immuno)histochemistry of tissue sections was performed. Gene and protein expression of BAPX-1/NKX-3.2 and chondrogenic, hypertrophic, and OA-related mediators were determined by real-time quantitative polymerase chain reaction analysis and immunoblotting. In addition, alkaline phosphatase (AP) activity and prostaglandin E2 levels were measured. Results : BAPX-1/NKX-3.2 expression correlated negatively with expression of chondrocyte hypertrophic markers (RUNX-2, COL10A1, AP), cartilage-degrading enzymes (matrix metalloproteinase 13, ADAMTS-5), and mediators of inflammation (cyclooxygenase 2, IL-6) in healthy and OA chondrocytes, as well as in OA induced chondrocytes. BAPX-1/NKX-3.2 positivity was diminished in articular chondrocytes in the knee joints of mice with experimental OA. Knockdown of BAPX-1/NKX-3.2 in HACs did not influence the expression of SOX9, COL2A1, or aggrecan, but led to an acute hypertrophic shift in the HAC phenotype. Overexpression of BAPX-1/NKX-3.2 decreased hypertrophic gene expression in HACs. Furthermore, the hypertrophic OA chondrocyte phenotype could be counteracted by overexpression of BAPX-1/NKX-3.2 and by BMP-7 in a BAPX-1/NKX-3.2 dependent manner. CONCLUSION: Our findings indicate that BAPX-1/NKX-3.2 is a molecular switch that is involved in controlling the hypertrophic phenotype of the postdevelopmental (OA) articular chondrocyte.
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