Background Osteoarthritis (OA) is the most common degenerative articular disease and is strongly related to age. Ageing is a source of epigenetic changes that could explain the loss of homeostasis of articular chondrocytes leading them to a terminally hypertrophic/senescence phenotype in OA. The hystone methyltransferase WHSC1 (also known as NSD2 or MMSET) methilates lysine 36 of histone 3 and in this way exerts fine tuning of gene expression. An alteration on WHSC1 expression leads to pitfalls in cartilage formation as it has been reported in Wolff Hirschorn Syndrome, a multicomplex congenital syndrome due to deletion of WHSC1 gene. Furthermore, it has been shown abnormalities in cartilage development in a mouse model with haploinsufficiency of WHSC1 and in zebrafish analysis. The aim of this study is to investigate the role and the regulation of the histone H3K36Me2 methyltranferase, WHSC1 (NSD2/MMSET), on cartilage loss of functions in OA.

Materials and Methods We used primary human OA chondrocytes, specific siRNA interference, western-blot, transient transfection, IL-1b treatment, RT-qPCR, Elisa and statistical analysis.

Results We found that WHSC1 mRNA expression is reduced in OA senescent-like cartilage compared to healthy donors. WHSC1 mRNA and protein levels are as well reduced in human primary chondrocytes following IL-1b chronic treatment and overexpressing Notch pathway. By a loss of function experiment based on specific siRNA against WHSC1, we found an up-regulation of MMP1, MMP13 and ADAMTS5 mRNA accumulation but not pro-inflammatory cytokines (IL-8, IL-6) in primary chondrocytes. As result, WHSC1-depleted chondrocytes show a reduction expression of Aggrecan and an increase production in GAG.

Conclusion Our preliminary data demonstrate that WHSC1 is decreased in Osteoarthritis. The downregulation of this epigenetic regulator impacts cartilage homeostasis by decreasing a major anabolic component of extracelular matrix, Aggrecan, and by increasing hypertrophic‐associated matrix‐remodelling factors. Further experiments are required for understanding changes on histone H3 methylation profile induced by this WHSC1 loss of function.