Evaluating the Therapeutic Efficacy of Iopanoic Acid in a DMM-Induced Osteoarthritis Mouse Model and Osteochondral Lesioned Human Explants

Sayedipour, S.; Mazzini, G.; Tuerlings, M.; Nikkels, J.; Koedam, M.; J. Cruz, L.; Mahdad, R.; Weerd, L. van der, L.; van der Eerden, B.; FM Ramos, Y.; Meulenbelt, I.

doi:10.1101/2025.07.15.663868

bioRxiv · 10.1101/2025.07.15.663868

Evaluating the Therapeutic Efficacy of Iopanoic Acid in a DMM-Induced Osteoarthritis Mouse Model and Osteochondral Lesioned Human Explants

Sayedipour, S.·Mazzini, G.·Tuerlings, M.·Nikkels, J.·Koedam, M.·J. Cruz, L.·Mahdad, R.·Weerd, L. van der, L.·van der Eerden, B.·FM Ramos, Y.·Meulenbelt, I.

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Abstract

ObjectiveTo evaluate the therapeutic potential of iopanoic acid (IOP), a thyroid hormone pathway inhibitor, in preserving cartilage and bone integrity in osteoarthritis (OA), using in vivo and ex vivo tissue models. DesignIn the DMM mouse model, IOP was administered through intra-articular (i.a.) injection, either alone or combined with a thermosensitive hydrogel to enable sustained release. Histological analyses included Safranin O/Fast Green staining and OARSI scoring. Immunohistochemistry was performed for COL2, MMP13, and CCDC80 to evaluate anabolic, catabolic, and hypertrophic markers. Micro-CT assessed subchondral bone changes. In the ex vivo studies, IOP was applied to lesioned human osteochondral OA explants. Matrix degradation and repair were evaluated by sulfated glycosaminoglycan (sGAG) release, Mankin histology scores, and RT-qPCR for cartilage matrix genes. ResultsAdministration of IOP significantly reduced cartilage degeneration in DMM mice (P [≤] 1.0x10-4), characterized by increased COL2, and decreased MMP13 and CCDC80 expression. Notably, IOP also prevented pathological subchondral bone thickening. In human explants, IOP treatment led to a significant reduction in sGAG release compared to untreated explants on day 6 of the IOP treatment. Moreover, Mankin scores were significantly improved in IOP-treated compared to untreated explants, indicating reduced cartilage degradation. ConclusionIOP demonstrates strong chondroprotective effects, reducing cartilage degradation and promoting repair in OA models. Its combination with a thermosensitive hydrogel amplifies therapeutic potential, offering a promising strategy for OA treatment. Next steps are to optimize delivery and validate early molecular effects.

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Sayedipour, S., Mazzini, G., Tuerlings, M., Nikkels, J., Koedam, M., J. Cruz, L., Mahdad, R., Weerd, L. van der, L., van der Eerden, B., FM Ramos, Y., Meulenbelt, I.. 2025-07-18. Evaluating the Therapeutic Efficacy of Iopanoic Acid in a DMM-Induced Osteoarthritis Mouse Model and Osteochondral Lesioned Human Explants. https://doi.org/10.1101/2025.07.15.663868

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