RT Journal Article SR Electronic T1 Underlying molecular mechanisms of DIO2 susceptibility in symptomatic osteoarthritis JF Annals of the Rheumatic Diseases JO Ann Rheum Dis FD BMJ Publishing Group Ltd and European League Against Rheumatism SP 1571 OP 1579 DO 10.1136/annrheumdis-2013-204739 VO 74 IS 8 A1 Nils Bomer A1 Wouter den Hollander A1 Yolande F M Ramos A1 Steffan D Bos A1 Ruud van der Breggen A1 Nico Lakenberg A1 Barry A Pepers A1 Annelies E van Eeden A1 Arash Darvishan A1 Elmar W Tobi A1 Bouke J Duijnisveld A1 Erik B van den Akker A1 Bastiaan T Heijmans A1 Willeke MC van Roon-Mom A1 Fons J Verbeek A1 Gerjo J V M van Osch A1 Rob G H H Nelissen A1 P Eline Slagboom A1 Ingrid Meulenbelt YR 2015 UL http://ard.bmj.com/content/74/8/1571.abstract AB Objectives To investigate how the genetic susceptibility gene DIO2 confers risk to osteoarthritis (OA) onset in humans and to explore whether counteracting the deleterious effect could contribute to novel therapeutic approaches.Methods Epigenetically regulated expression of DIO2 was explored by assessing methylation of positional CpG-dinucleotides and the respective DIO2 expression in OA-affected and macroscopically preserved articular cartilage from end-stage OA patients. In a human in vitro chondrogenesis model, we measured the effects when thyroid signalling during culturing was either enhanced (excess T3 or lentiviral induced DIO2 overexpression) or decreased (iopanoic acid).Results OA-related changes in methylation at a specific CpG dinucleotide upstream of DIO2 caused significant upregulation of its expression (β=4.96; p=0.0016). This effect was enhanced and appeared driven specifically by DIO2 rs225014 risk allele carriers (β=5.58, p=0.0006). During in vitro chondrogenesis, DIO2 overexpression resulted in a significant reduced capacity of chondrocytes to deposit extracellular matrix (ECM) components, concurrent with significant induction of ECM degrading enzymes (ADAMTS5, MMP13) and markers of mineralisation (ALPL, COL1A1). Given their concurrent and significant upregulation of expression, this process is likely mediated via HIF-2α/RUNX2 signalling. In contrast, we showed that inhibiting deiodinases during in vitro chondrogenesis contributed to prolonged cartilage homeostasis as reflected by significant increased deposition of ECM components and attenuated upregulation of matrix degrading enzymes.Conclusions Our findings show how genetic variation at DIO2 could confer risk to OA and raised the possibility that counteracting thyroid signalling may be a novel therapeutic approach.