07.07 Increased expression of ccn4/wisp1 in osteoarthritic articular cartilage is epigenetically regulated and disrupts cartilage homeostasis

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Abstract

Background

Previously, we described strongly increased expression of Wnt-1-induced signalling protein 1 (Wisp1) in the joint during experimental osteoarthritis (OA). Overexpression of Wisp1 using adenoviruses was detrimental to the articular cartilage, while decreased cartilage degeneration was observed after induction of experimental OA models in Wisp1-deficient mice. These data indicate a direct correlation between WISP1 and OA in mice. In this study we set out to characterise the relation between expression of WISP1 and human OA.

Methods

Articular cartilage from non-OA-diagnosed individuals with femoral neck fractures and preserved and degenerated cartilage from end-stage OA patients was collected. Degeneration was classified using the Mankin scoring system. RNA and DNA were isolated for gene expression and methylation profiles, respectively. Correlation between WISP1 expression and methylation was investigated with Generalised Linear Mixed Model (GLMM). RNA expression was determined with microarray analysis and RNA sequencing. WISP1 protein was visualised using immunohistochemistry. Effects of increased WISP1 levels were tested in a human in vitro chondrogenesis model.

Results

WISP1 expression in the cartilage of OA patients was increased compared to non-OA-diagnosed controls. Within OA patients, WISP1 was increased in OA-affected cartilage compared to preserved regions. WISP1 expression strongly correlated with the Mankin score. When added to cartilage particles from primary articular chondrocytes, WISP1 strongly decreased the pellet circumference and proteoglycan content. Next, we found that WISP1 expression was inversely correlated with the methylation of a positional CpG dinucleotide. Concordantly, within donors, cartilage from OA-affected areas showed hypomethylation for this CpG site compared to preserved cartilage, which correlated with increased RNA expression. This raised the question whether individuals with high WISP1 expression were at increased risk to develop OA. Methylation of the CpG dinucleotide associated with WISP1 expression was found to be controlled by a single nucleotide polymorphism (SNP). Surprisingly, the allele associated with higher methylation and thus lower expression of WISP1, was associated with OA.

Conclusions

Increased WISP1 expression in OA-affected cartilage is associated with cartilage degradation, but low WISP1 expression seems to predispose for OA-induction. Together, our results suggest that tight regulation of WISP1 expression is essential to maintain cartilage homeostasis.

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