Nils Bomer1, Frederique M F Cornelis2, Yolande F M Ramos3, Wouter den Hollander3, Lies Storms2, Ruud van der Breggen3, Nico Lakenberg3, P Eline Slagboom4, Ingrid Meulenbelt5, Rik J L Lories6. 1. Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands Integrated Research of Developmental Determinants of Ageing and Longevity (IDEAL), Leiden, Netherlands. 2. Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Centre, KU Leuven, Leuven, Belgium. 3. Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands. 4. Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands Integrated Research of Developmental Determinants of Ageing and Longevity (IDEAL), Leiden, Netherlands The Netherlands Genomics Initiative, sponsored by the NCHA, Leiden-Rotterdam, The Netherlands. 5. Department of Molecular Epidemiology, LUMC, Leiden, The Netherlands The Netherlands Genomics Initiative, sponsored by the NCHA, Leiden-Rotterdam, The Netherlands. 6. Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Centre, KU Leuven, Leuven, Belgium Division of Rheumatology, University Hospitals Leuven, Leuven, Belgium.
Abstract
OBJECTIVE: To further explore deiodinase iodothyronine type 2 (DIO2) as a therapeutic target in osteoarthritis (OA) by studying the effects of forced mechanical loading on in vivo joint cartilage tissue homeostasis and the modulating effect herein of Dio2 deficiency. METHODS: Wild-type and C57BL/6-Dio2(-/-) -mice were subjected to a forced running regime for 1 h per day for 3 weeks. Severity of OA was assessed by histological scoring for cartilage damage and synovitis. Genome-wide gene expression was determined in knee cartilage by microarray analysis (Illumina MouseWG-6 v2). STRING-db analyses were applied to determine enrichment for specific pathways and to visualise protein-protein interactions. RESULTS: In total, 158 probes representing 147 unique genes showed significantly differential expression with a fold-change ≥1.5 upon forced exercise. Among these are genes known for their association with OA (eg, Mef2c, Egfr, Ctgf, Prg4 and Ctnnb1), supporting the use of forced running as an OA model in mice. Dio2-deficient mice showed significantly less cartilage damage and signs of synovitis. Gene expression response upon exercise between wild-type and knockout mice was significantly different for 29 genes. CONCLUSIONS: Mice subjected to a running regime have significant increased cartilage damage and synovitis scores. Lack of Dio2 protected against cartilage damage in this model and was reflected in a specific gene expression profile, and either mark a favourable effect in the Dio2 knockout (eg, Gnas) or an unfavourable effect in wild-type cartilage homeostasis (eg, Hmbg2 and Calr). These data further support DIO2 activity as a therapeutic target in OA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
OBJECTIVE: To further explore deiodinase iodothyronine type 2 (DIO2) as a therapeutic target in osteoarthritis (OA) by studying the effects of forced mechanical loading on in vivo joint cartilage tissue homeostasis and the modulating effect herein of Dio2 deficiency. METHODS: Wild-type and C57BL/6-Dio2(-/-) -mice were subjected to a forced running regime for 1 h per day for 3 weeks. Severity of OA was assessed by histological scoring for cartilage damage and synovitis. Genome-wide gene expression was determined in knee cartilage by microarray analysis (Illumina MouseWG-6 v2). STRING-db analyses were applied to determine enrichment for specific pathways and to visualise protein-protein interactions. RESULTS: In total, 158 probes representing 147 unique genes showed significantly differential expression with a fold-change ≥1.5 upon forced exercise. Among these are genes known for their association with OA (eg, Mef2c, Egfr, Ctgf, Prg4 and Ctnnb1), supporting the use of forced running as an OA model in mice. Dio2-deficient mice showed significantly less cartilage damage and signs of synovitis. Gene expression response upon exercise between wild-type and knockout mice was significantly different for 29 genes. CONCLUSIONS:Mice subjected to a running regime have significant increased cartilage damage and synovitis scores. Lack of Dio2 protected against cartilage damage in this model and was reflected in a specific gene expression profile, and either mark a favourable effect in the Dio2 knockout (eg, Gnas) or an unfavourable effect in wild-type cartilage homeostasis (eg, Hmbg2 and Calr). These data further support DIO2 activity as a therapeutic target in OA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Authors: Kasper Huétink; Paul van der Voort; Johan L Bloem; Rob G H H Nelissen; Ingrid Meulenbelt Journal: Clin Med Insights Arthritis Musculoskelet Disord Date: 2016-04-28
Authors: Nils Bomer; Frederique M F Cornelis; Yolande F M Ramos; Wouter den Hollander; Nico Lakenberg; Ruud van der Breggen; Lies Storms; P Eline Slagboom; Rik J U Lories; Ingrid Meulenbelt Journal: PLoS One Date: 2016-05-10 Impact factor: 3.240