Abstract
IntroductionThe objective of this study was to investigate the possible role of UDP-glucose dehydrogenase (UGDH) in osteoarthritis (OA) and uncover whether, furthermore how interleukin-1beta (IL-1β) affects UGDH gene expression.MethodsUGDH specific siRNAs were applied to determine the role of UGDH in proteoglycan (PG) synthesis in human articular chondrocytes. Protein levels of UGDH and Sp1 in human and rat OA cartilage were detected. Then, human primary chondrocytes were treated with IL-1β to find out whether and how IL-1β could regulate the gene expression of UGDH and its trans-regulators, that is Sp1, Sp3 and c-Krox. Finally, p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 and stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) inhibitor SP600125 were used to pick out the pathway that mediated the IL-1β-modulated PGs synthesis and gene expression of UGDH, Sp1, Sp3 and c-Krox.ResultsUGDH specific siRNAs markedly inhibited UGDH mRNA and protein expression, and thus led to an obvious suppression of PGs synthesis in human articular chondrocytes. UGDH protein level in human and rat OA cartilage were much lower than the corresponding controls and negatively correlated to the degree of OA. Decrease in Sp1 protein level was also observed in human and rat OA cartilage respectively. Meanwhile, IL-1β suppressed UGDH gene expression in human articular chondrocytes in the late phase, which also modulated gene expression of Sp1, Sp3 and c-Krox and increased both Sp3/Sp1 and c-Krox/Sp1 ratio. Moreover, the inhibition of SAP/JNK and p38 MAPK pathways both resulted in an obvious attenuation of the IL-1β-induced suppression on the UGDH gene expression.ConclusionsUGDH is essential in the PGs synthesis of articular chondrocytes, while the suppressed expression of UGDH might probably be involved in advanced OA, partly due to the modulation of p38 MAPK and SAP/JNK pathways and its trans-regulators by IL-1β.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-014-0484-2) contains supplementary material, which is available to authorized users.
Highlights
The objective of this study was to investigate the possible role of UDP-glucose dehydrogenase (UGDH) in osteoarthritis (OA) and uncover whether, how interleukin-1beta (IL-1β) affects UGDH gene expression
UGDH was essential in PG synthesis of human articular chondrocytes Obvious decreases in UGDH mRNA and protein levels were observed in human articular chondrocytes treated with three different UGDH-specific small interfering RNA (siRNA) (Figure 1A, B and C, P
The staining of chondrocytes treated with UGDH-specific siRNA by Alcian blue was much lower than the control (Figure 1E and F, P
Summary
The objective of this study was to investigate the possible role of UDP-glucose dehydrogenase (UGDH) in osteoarthritis (OA) and uncover whether, how interleukin-1beta (IL-1β) affects UGDH gene expression. IL-1β is a key pro-inflammatory cytokine in the progression of OA, which attenuates the anabolism but enhances the catabolism in the chondrocytes, through activating the downstream signaling pathways, including those of stressactivated protein kinase/c-Jun N-terminal kinase (SAP/ JNK) and p38 mitogen-activated protein kinase (p38 MAPK) [8,9,10]. It is well-known that IL-1β is one of the key pro-inflammatory factors responsible for the PG loss in OA pathogenesis. Whether UGDH is involved in the IL-1β-induced PG loss is unknown
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