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BAPX‐1/NKX‐3.2 Acts as a Chondrocyte Hypertrophy Molecular Switch in Osteoarthritis
Author(s) -
Caron Marjolein M. J.,
Emans Pieter J.,
Surtel Don A. M.,
van der Kraan Peter M.,
van Rhijn Lodewijk W.,
Welting Tim J. M.
Publication year - 2015
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.39293
Subject(s) - chondrocyte , osteoarthritis , chondrogenesis , aggrecan , cartilage , chemistry , prostaglandin e2 , synovial fluid , matrix metalloproteinase , alkaline phosphatase , andrology , endocrinology , medicine , microbiology and biotechnology , pathology , anatomy , biology , articular cartilage , biochemistry , enzyme , alternative medicine
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‐1β (IL‐1β), 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 E 2 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.