BAPX-1/NKX-3.2 acts as a chondrocyte hypertrophy molecular switch in osteoarthritis.

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. 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 E2 levels were measured. 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. 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.

Caron MM ，Emans PJ ，Surtel DA ，van der Kraan PM ，van Rhijn LW ，Welting TJ ... -  《-》

Prostaglandin PGE2 at very low concentrations suppresses collagen cleavage in cultured human osteoarthritic articular cartilage: this involves a decrease in expression of proinflammatory genes, collagenases and COL10A1, a gene linked to chondrocyte hypert

Tchetina EV ，Di Battista JA ，Zukor DJ ，Antoniou J ，Poole AR ... -  《-》

Role of dentin matrix protein 1 in cartilage redifferentiation and osteoarthritis.

The aim of this study was to test the possible involvement, relevance and significance of dentin matrix protein 1 (DMP1) in chondrocyte redifferentiation and OA. To examine the function of DMP1 in vitro, bone marrow stromal cells (BMSCs) and articular chondrocytes (ACs) were isolated and differentiated in micromasses in the presence or absence of DMP1 small interfering RNA and analysed for chondrogenic phenotype. The association of DMP1 expression with OA progression was analysed time dependently in the OA menisectomy rat model and in grade-specific OA human samples. It was found that DMP1 was strongly related to chondrogenesis, which was evidenced by the strong expression of DMP1 in the 14.5-day mouse embryonic cartilage development stage and in femoral heads of post-natal days 0 and 4. In vitro chondrogenesis in BMSCs and ACs was accompanied by a gradual increase in DMP1 expression at both the gene and protein levels. In addition, knockdown of DMP1 expression led to decreased chondrocyte marker genes, such as COL2A1, ACAN and SOX9, and an increase in the expression of COL10A and MMP13 in ACs. Moreover, treatment with IL-1β, a well-known catabolic culprit of proteoglycan matrix loss, significantly reduced the expression of DMP1. Furthermore, we also observed the suppression of DMP1 protein in a grade-specific manner in knee joint samples from patients with OA. In the menisectomy-induced OA model, an increase in the Mankin score was accompanied by the gradual loss of DMP1 expression. Observations from this study suggest that DMP1 may play an important role in maintaining the chondrogenic phenotype and its possible involvement in altered cartilage matrix remodelling and degradation in disease conditions like OA.

Prasadam I ，Zhou Y ，Shi W ，Crawford R ，Xiao Y ... -  《-》

Chaperonin 60 regulation of SOX9 ubiquitination mitigates the development of knee osteoarthritis.

Ko JY ，Sun YC ，Li WC ，Wang FS ... -  《-》

Anabolic role of lysyl oxidase like-2 in cartilage of knee and temporomandibular joints with osteoarthritis.

Alshenibr W ，Tashkandi MM ，Alsaqer SF ，Alkheriji Y ，Wise A ，Fulzele S ，Mehra P ，Goldring MB ，Gerstenfeld LC ，Bais MV ... -  《-》