Osteoarthritis (OA) is a heterogeneous disease mediated by multiple molecular pathways and governed by a complex interplay between various genetic, epigenetic and environmental factors. New findings published in Science Translational Medicine implicate the epigenetic regulator ten-eleven translocation 1 (TET1) as an important activator of multiple OA-associated pathways and as an attractive therapeutic target.

TET enzymes catalyse the initial step of DNA demethylation by converting 5-methylcytosine into 5-hydroxymethylcytosine (5hmC), an epigenetic process associated with gene activation. Previous evidence had shown that 5hmC accumulates on OA-related genes in osteoarthritic chondrocytes. To investigate this process further, the authors of the new study mapped changes in the 5hmC epigenome in mice following induction of OA by destabilization of the medial meniscus (DMM), with and without the expression of Tet1.

Credit: Kristina Kokhanova/Alamy Stock Photo

In wild-type mice, OA induction was accompanied by a genome-wide accumulation of 5hmC, predominantly in gene bodies or intergenic regions, and an upregulation in expression of hundreds of genes. Notably, almost half of the upregulated genes gained sites of 5hmC accumulation, including genes involved in WNT signalling, protein kinase A signalling and inositol metabolism.

The majority of 5hmC deposition was lost in mice lacking TET1. Importantly, loss of Tet1 impeded the initiation and development of DMM-induced OA, including the deterioration of cartilage and osteophyte formation.

TET1 activated various pathways important in OA pathogenesis, including WNT signalling, metalloproteinases and STAT3 signalling. Indeed, shRNA-mediated knockdown of TET1 in chondrocytes from patients with OA decreased the expression of MMP3 and MMP13.

OA induction was accompanied by a genome-wide accumulation of 5hmC

To provide proof of principle that modulating TET1 activity is a promising therapeutic strategy, the researchers tested a small molecular inhibitor of TET1, 2-hydroxyglutarate (2-HG). Intra-articular injection of 2-HG after DMM surgery stalled OA progression in mice, and this inhibitor could replicate the effects of TET1 knockdown in osteoarthritic chondrocytes in vitro.