Underlying molecular mechanisms of DIO2 susceptibility in symptomatic osteoarthritis
Autor: | Ruud van der Breggen, Annelies E van Eeden, Nico Lakenberg, Steffan D. Bos, Ingrid Meulenbelt, Nils Bomer, Arash Darvishan, Willeke M. C. van Roon-Mom, Barry A. Pepers, Rob G H H Nelissen, Fons J. Verbeek, Bastiaan T. Heijmans, Yolande F. M. Ramos, P. Eline Slagboom, Elmar W. Tobi, Wouter den Hollander, B.J. Duijnisveld, Gerjo J.V.M. van Osch, Erik B. van den Akker |
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Přispěvatelé: | Orthopedics and Sports Medicine, Otorhinolaryngology and Head and Neck Surgery |
Jazyk: | angličtina |
Rok vydání: | 2015 |
Předmět: |
Cartilage
Articular Thyroid Hormones medicine.medical_specialty Immunology Loss of Heterozygosity Biology Iodide Peroxidase Osteoarthritis Hip General Biochemistry Genetics and Molecular Biology Epigenesis Genetic Extracellular matrix 03 medical and health sciences 0302 clinical medicine Rheumatology Downregulation and upregulation Internal medicine Osteoarthritis medicine Humans Immunology and Allergy Gene silencing Genetic Predisposition to Disease Gene Silencing Basic and Translational Research 030304 developmental biology 030203 arthritis & rheumatology Regulation of gene expression 0303 health sciences Cartilage homeostasis ALPL DNA Methylation Osteoarthritis Knee Chondrogenesis Up-Regulation Cell biology Endocrinology Gene Expression Regulation DNA methylation |
Zdroj: | Annals of the Rheumatic Diseases: 74 (8), 2015 Annals of the Rheumatic Diseases, 74(8), 1571-1579. BMJ Publishing Group Annals of the Rheumatic Diseases, 74(8), 1571-1579 Annals of the Rheumatic Diseases |
ISSN: | 0003-4967 1571-1579 |
Popis: | 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 (beta=4.96; p=0.0016). This effect was enhanced and appeared driven specifically by DIO2 rs225014 risk allele carriers (beta=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 alpha/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. |
Databáze: | OpenAIRE |
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