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

OBJECTIVES: To investigate whether deiodinase inhibitor iopanoic acid (IOP) has chondroprotective properties, a mechanically stress induced model of human aged explants was used to test both repeated dosing and slow-released IOP.

METHODS: Human osteochondral explants subjected to injurious mechanical stress (65%MS) were treated with IOP or IOP incapsulated in Poly lactic-co-glycolic acid (PLGA)-polyethylene glycol (PEG) nanoparticles (NP) (PLGA-PEG NPs (NP(IOP)). Changes to cartilage integrity and signalling was 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 IOPs mode of action.

RESULTS: Damage of injurious mechanical stress was confirmed by increased cartilage surface damage in the Mankin score, increased sGAG release, consistent upregulation of catabolic markers and downregulation of anabolic markers. IOP and, though less effective, PLGA NP(IOP) treatment, reduced MMP13 and increased COL2A1 expression. In line with this, IOP and PLGA 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 as IOPs mode of action to be mainly 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.