Inhibiting thyroid activation in aged human explants prevents mechanical induced detrimental signalling by mitigating metabolic processes

Lara D. Veeken, vol. 62, pp. 457–466

Abstract

OBJECTIVES: To investigate whether the deiodinase inhibitor iopanoic acid (IOP) has chondroprotective properties, a mechanical stress induced model of human aged explants was used to test both repeated dosing and slow release of IOP. METHODS: Human osteochondral explants subjected to injurious mechanical stress (65%MS) were treated with IOP or IOP encapsulated in poly lactic-co-glycolic acid-polyethylene glycol nanoparticles (NP-IOP). Changes to cartilage integrity and signalling were determined by Mankin scoring of histology, sulphated glycosaminoglycan (sGAG) release and expression levels of catabolic, anabolic and hypertrophic markers. Subsequently, on a subgroup of samples, RNA sequencing was performed on 65%MS (n = 14) and 65%MS+IOP (n = 7) treated cartilage to identify IOP's mode of action. RESULTS: Damage from injurious mechanical stress was confirmed by increased cartilage surface damage in the Mankin score, increased sGAG release, and consistent upregulation of catabolic markers and downregulation of anabolic markers. IOP and, though less effective, NP-IOP treatment, reduced MMP13 and increased COL2A1 expression. In line with this, IOP and NP-IOP reduced cartilage surface damage induced by 65%MS, while only IOP reduced sGAG release from explants subjected to 65%MS. Lastly, differential expression analysis identified 12 genes in IOP's mode of action to be mainly involved in reducing metabolic processes (INSIG1, DHCR7, FADS1 and ACAT2) and proliferation and differentiation (CTGF, BMP5 and FOXM1). CONCLUSION: Treatment with the deiodinase inhibitor IOP reduced detrimental changes of injurious mechanical stress. In addition, we identified that its mode of action was likely on metabolic processes, cell proliferation and differentiation.

Authors 13

1. Evelyn Houtman Aachen Molecular Epidemiology Department of Biomedical Data Sciences

   Leiden University Medical Center

   Affiliation as printed

   Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center , Leiden, The Netherlands

2. Margo Tuerlings Aachen Molecular Epidemiology Department of Biomedical Data Sciences

   Leiden University Medical Center

   Affiliation as printed

   Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center , Leiden, The Netherlands

3. H. Eka D. Suchiman Aachen Molecular Epidemiology Department of Biomedical Data Sciences

   Leiden University Medical Center

   Affiliation as printed

   Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center , Leiden, The Netherlands

4. Nico Lakenberg Aachen Molecular Epidemiology Department of Biomedical Data Sciences

   Leiden University Medical Center

   Affiliation as printed

   Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center , Leiden, The Netherlands

5. Frederique M. F. Cornelis

   KU Leuven

   Affiliation as printed

   Department of Development and Regeneration, Skeletal Biology and Engineering Research Centre, Laboratory of Tissue Homeostasis and Disease, KU Leuven , Leuven, Belgium

6. Hailiang Mei
   Affiliation as printed

   Sequencing Analysis Support Core

7. Demiën Broekhuis Aachen Department of Orthopaedics, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Orthopaedics, Leiden University Medical Center , Leiden, The Netherlands

8. Rob G. H. H. Nelissen Aachen Department of Orthopaedics, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Orthopaedics, Leiden University Medical Center , Leiden, The Netherlands

9. Rodrigo Coutinho de Almeida Aachen Molecular Epidemiology Department of Biomedical Data Sciences

   Leiden University Medical Center

   Affiliation as printed

   Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center , Leiden, The Netherlands

10. Y.F. Ramos Aachen Molecular Epidemiology Department of Biomedical Data Sciences

    Leiden University Medical Center

    Affiliation as printed

    Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center , Leiden, The Netherlands

11. Rik Jozef Urbain Lories

    Universitair Ziekenhuis Leuven · KU Leuven

    Affiliation as printed

    Department of Development and Regeneration, Skeletal Biology and Engineering Research Centre, Laboratory of Tissue Homeostasis and Disease, KU Leuven , Leuven, Belgium

    Division of Rheumatology, University Hospitals Leuven , Leuven, Belgium

12. Luis Javier Cruz Aachen Translational Nanobiomaterials and Imaging (TNI) Group Department of Radiology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Translational Nanobiomaterials and Imaging (TNI) Group, Department of Radiology, Leiden University Medical Center , Leiden, the Netherlands

13. Ingrid Meulenbelt corresponding Aachen Molecular Epidemiology Department of Biomedical Data Sciences

    Leiden University Medical Center

    Affiliation as printed

    Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center , Leiden, The Netherlands