The following is a summary of the “WWP2 confers risk to osteoarthritis by affecting cartilage matrix deposition via hypoxia associated genes,” published in the February 2023 issue of Osteoarthritis and Cartilage by Tuerlings, et al.

The goal of this study was to use a human 3D in vitro model of cartilage to investigate the co-expression network of the osteoarthritis risk gene WWP2 in articular cartilage and to analyze cartilage features when simulating the effect of the osteoarthritis (OA) risk allele rs1052429-A on WWP2 expression. Researchers investigated the WWP2 gene’s co-expression pattern with genes expressed in OA articular cartilage with lesions (N = 35 samples). The effects of upregulation on cartilage matrix deposition were examined using lentiviral particle-mediated WWP2 upregulation in 3D in vitro pellet cultures of human primary chondrocytes (N = 8 donors). 

Finally, they tested whether miR-140 and WWP2 participate in the same pathways by transfecting primary chondrocytes with miR-140 mimics. Spearman correlations in OA cartilage with lesions revealed 98 highly correlating genes (|ρ|>0.7). Specifically, investigators located GJA1, GDF10, STC2, WDR1, and WNK4 in this group of genes. As a result, when WWP2 was upregulated in 3D chondrocyte pellet cultures, expression of COL2A1 and ACAN was reduced, while expression of EPAS1 was elevated. 

They also saw the reduced expression of GDF10, STC2, and GJA1. Proteomics analysis revealed that the upregulation of WWP2 led to the differential expression of 42 proteins, many of which were enriched for ubiquitin-conjugating enzyme activity. Finally, miR-140 upregulation in 2D chondrocytes led to robust WWP2 and WDR1 upregulation. By mimicking the effect of the OA risk allele rs1052429-A on WWP2 expression, they found that hypoxia-associated genes (EPAS1, GDF10, and GJA1) respond, while anabolic markers (COL2A1 and ACAN) are down-regulated.