Leiden University Scholarly Publications

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Tuerlings, M. (2023)

The bone and cartilage interplay in osteoarthritis: key to effective treatment strategy

Doctoral Thesis
Osteoarthritis (OA) is a prevalent age-related joint disease, determined by diverse changes in pathways maintaining articular cartilage and subchondral bone. This thesis aimed to identify and study gene networks driving interacting etiopathophysiological OA processes in cartilage and subchondral bone. Hereto, characterization of the molecular landscape of bone and cartilage of OA patients showed 305 genes with similar direction of effect, including IL11 and CHADL. Moreover, to capture biological complexity and decipher underlying OA disease mechanisms a variety of human 3D cartilage and bone organoids models were exploited and a human osteochondral construct-on-a-chip was developed. Herein, we showed that the robust OA risk gene WWP2 may initiate OA, via aberrant responses in hypoxia-associated genes and a decrease in anabolic markers. Additionally we showed, as reflected by upregulation of SPP1 and downregulation of WNT16 in cartilage, that treatment of ex vivo human...Show moreOsteoarthritis (OA) is a prevalent age-related joint disease, determined by diverse changes in pathways maintaining articular cartilage and subchondral bone. This thesis aimed to identify and study gene networks driving interacting etiopathophysiological OA processes in cartilage and subchondral bone. Hereto, characterization of the molecular landscape of bone and cartilage of OA patients showed 305 genes with similar direction of effect, including IL11 and CHADL. Moreover, to capture biological complexity and decipher underlying OA disease mechanisms a variety of human 3D cartilage and bone organoids models were exploited and a human osteochondral construct-on-a-chip was developed. Herein, we showed that the robust OA risk gene WWP2 may initiate OA, via aberrant responses in hypoxia-associated genes and a decrease in anabolic markers. Additionally we showed, as reflected by upregulation of SPP1 and downregulation of WNT16 in cartilage, that treatment of ex vivo human osteochondral explants with human recombinant IL11 does not necessarily has a beneficial outcome. Finally, to allow implementation of knowledge on diverse OA pathophysiological processes, the potency of circulating miRNAs to report on ongoing OA pathophysiological process in joint tissues was established. Such insights are crucial to stratify respective OA patients that require different therapeutic mode of action, towards precision medicine.
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Osteoarthritis
Osteochondral construct
OA disease models
Biomarkers
RNA-sequencing
Subchondral bone
Articular cartilage
All authors
Tuerlings, M.
Supervisor
Meulenbelt, I.
Co-supervisor
Coutinho de Almeida, R.; Ramos, Y.F.M.
Committee
Slagboom, P.; Loughlin, J.; Meurs, J.B.J. van; Appelman-Dijkstra, N.M.
Qualification
Doctor (dr.)
Awarding Institution
Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
Date
2023-09-27
ISBN (print)
9789464831917

Funding

Sponsorship
This research was financially supported by the Dutch Scientific Research Council (NWO/ZonMW Vici grant 91816631/528) and was performed in the framework of the Medical Delta program Regenerative Medicine 4D: Generating complex tissues with stem cells and printing technology and Improving Mobility with Technology. Medical Delta and the Nederlandse Vereniging voor Matrix Biologie are gratefully acknowledged for financial support for the printing costs of this thesis.