Role of TET1 Mediated 5hmC in Osteoarthritis [RNA-seq]

No disease-modifying drugs exist to treat osteoarthritis (OA), a degenerative disease of the joint.  The complexity of OA necessitates a combinational and broad therapeutic approach. Epigenetic regulators are able to control large programs of genes, and recent work from our group and others have showcased systemic epigenetic dysregulation in OA. Previously, we demonstrated that OA chondrocytes accumulate 5-fold more 5-hydroxymethylcytosine (5hmC), an oxidized derivative of methylcytosine (5mC) associated with gene activation, at disease relevant sites. To test if 5hmC has a role in the early onset of OA, we utilized a mouse model of surgically induced OA, destabilization of the medial meniscus (DMM), and found that DMM mice gained ~40,000 differentially hydroxymethylated sites. Genetic loss of TET1, the enzyme responsible for 5hmC deposition, prevented pathologic gain of 5hmC, activation of many OA pathways, and protected mice from OA development. To test the clinical potential of a TET1 based OA therapy, we injected 2-hydroxyglutarate (2-HG), a TET inhibitor, into the joint after DMM induction and  observed stalled disease progression. Collectively, these data show that TET1 mediated 5hmC deposition regulates multiple OA pathways and that its modulation can be a powerful clinical tool for OA. DMM was induced on male mice 3-4 months of age. RNA was extracted from the joint at 6 or 12 weeks post surgery. Age-matched sham controls are also included. All groups contain 3 biological replicates, except 6weeks sham (n=2).