Aged human osteochondral explants as biomimetic osteoarthritis model: towards a druggable target in osteoarthritis

Houtman, E. (2022)

Doctoral Thesis

This thesis aims to increase the understanding of human osteoarthritis pathophysiology by developing reliable biomimetic ex vivo human osteochondral explant models and focussing on the role of osteoarthritis-relevant triggers (mechanical stress) and interacting genetic factors for developing treatment targets. Human aged joint tissues were collected in the Research in Articular Osteoarthritis Cartilage (RAAK) biobank. To add knowledge of the osteoarthritis pathophysiological processes, aged human ex vivo osteochondral explants were subject to three osteoarthritis-relevant triggers, being inflammation, hypertrophy and injurious mechanical stress. Next, knowledge on early initiating processes occurring in mechano-pathology was investigated by applying RNA-sequencing to cartilage of aged human osteochondral explants subjected to mechanical stress. In addition, to show that the human osteochondral explant model could also be used for genetic interaction studies, we investigated expression of the osteoarthritis risk gene MGP in relation to rs1800801 genotypes. By combining information from RNA-sequencing datasets of cartilage and bone with osteoarthritis-relevant triggers in cartilage and bone explants we investigated the role of MGP and vitamin K in osteoarthritis. Lastly, the injurious mechanical explant model was exploited to determine the effectivity of inhibiting the osteoarthritis risk gene DIO2 by iopanoic acid treatment either by burst or prolonged release from PLGA-PEG nanoparticles.

• Osteoarthritis
• Osteochondral explants
• Cartilage
• Mechanical stress
• DIO2
• Thyroid hormone
• Iopanoic acid
• MGP
• Vitamin K
• Functional genomics

• All authors: Houtman, E.
• Supervisor: Meulenbelt, I.; Nelissen, R.G.H.H.
• Co-supervisor: Ramos, Y.F.M.
• Committee: Slagboom, P.E.; Lories, R.J.; Kloppenburg, G.; Meurs, J.B.J. van
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2022-10-12
• ISBN (print): 9789464585438
• Sponsorship: ReumaNederland