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Underlying molecular mechanisms of DIO2 susceptibility in symptomatic osteoarthritis.

ABSTRACT: 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.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).OA-related changes in methylation at a specific CpG dinucleotide upstream of DIO2 caused significant upregulation of its expression (?=4.96; p=0.0016). This effect was enhanced and appeared driven specifically by DIO2 rs225014 risk allele carriers (?=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-2?/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.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.

SUBMITTER: Bomer N

PROVIDER: S-EPMC4516000 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Underlying molecular mechanisms of DIO2 susceptibility in symptomatic osteoarthritis.

Bomer Nils N den Hollander Wouter W Ramos Yolande F M YF Bos Steffan D SD van der Breggen Ruud R Lakenberg Nico N Pepers Barry A BA van Eeden Annelies E AE Darvishan Arash A Tobi Elmar W EW Duijnisveld Bouke J BJ van den Akker Erik B EB Heijmans Bastiaan T BT van Roon-Mom Willeke Mc WM Verbeek Fons J FJ van Osch Gerjo J V M GJ Nelissen Rob G H H RG Slagboom P Eline PE Meulenbelt Ingrid I

Annals of the rheumatic diseases 20140402 8

<h4>Objectives</h4>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.<h4>Methods</h4>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 h ...[more]

PMID: 24695009

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Project description:Fever implies a significant increase in corporal temperature that aids toward the resolution of infective processes such as viral disease. The majority of vertebrate species are not homeothermic therefore must rely upon the environment for temperature regulation. Here we show that in the zebrafish an artificial viral infection, induced by poly (I:C), induces a fever response regulated by the behavioral choice of temperature. We recorded 12 h of the diurnal cycle in zebrafish previously treated (first 12 hours dark cycle) with the pyrogen, poly (I:C) [10 μg⋅kg-1]. Fish, n=10, were held in a thermal gradient (36-180C) separated into 7 interconnected chambers. Presence or absence of individuals in each chamber was recorded each 15 minutes throughout the 12 hour period. After the experimental period we dissected whole brains for microarray analysis. In monitored zebrafish intraperitoneal treatment with poly (I:C) induced a febrile behaviour with significantly elevated temperature preference (T of about 32ºC) in stark contrast with the observed frequency for saline-injected fish (28ºC). Microarray analyses uncovered significant shifts in transcriptional activity that were highly directed in the poly (I:C)-treated fish housed in the thermal gradient. When compared to gene expression profiles from poly (I:C)-treated fish deprived of a thermal gradient we observed a less intense specific to the poly (I:C) challenge and interestingly observed a scattered generalised stress response. Our results highlight the influence of temperature preference in the development of the immune response in zebrafish. Fever induced gene expression in zebrafish brain was measured at 24 after intra peritoneal injection with 1mg*Kg-1 of Poly (I:C) in zebrafish. Four independent experiments were performed to explore the transcriptomic profile induced by animals injected by Poly (I:C) with/whithout thermal gradient, saline solution (PBS), or control using different animals for each experiment.

Dataset Information

Underlying molecular mechanisms of DIO2 susceptibility in symptomatic osteoarthritis.

Publications

Underlying molecular mechanisms of DIO2 susceptibility in symptomatic osteoarthritis.

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