Modelling and targeting osteoarthritis using human progenitor cell-derived cartilage organoids

Dönges, Laura. Modelling and targeting osteoarthritis using human progenitor cell-derived cartilage organoids. 2023, Doctoral Thesis, University of Basel, Faculty of Science.

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Osteoarthritis (OA) is the most common degenerative joint disease characterized by the progressive loss of cartilage causing functional impairment of the joint. Patients experience severe pain, impaired mobility and reduced quality of their life. Already in 1743, the surgeon William Hunter identified the diseased cartilage as difficult to cure due to the lack of its self-healing capacity. Until today, there is no effective drug that can slow-down or even stop the cartilage degradation in the OA joint. Current treatment options are palliative or – at the end-stage of disease – limited to knee-replacement therapy. Especially patients experiencing early signs of OA miss treatment options. This is mainly due to the lack of understanding of pathogenic mechanisms that regulate early cartilage degeneration and the unmet need of a reliable preclinical disease model for drug discovery research. As the incidence of OA due to societal aging is expected to increase in future, novel treatment strategies are urgently needed to reduce the burden of this disease.
During OA disease progression, articular chondrocytes acquire a phenotype known from longitudinal bone development, called chondrocyte hypertrophy. This phenotype is responsible to induce events in OA cartilage known from endochondral ossification such as tissue calcification and angiogenesis. Next to cartilage aberrations related to chondrocyte hypertrophy, pro-inflammatory cytokines present in the OA joint enhance the expression of catabolic proteases. Both, chondrocyte hypertrophy and inflammation-induced catabolism most likely orchestrate the early onset of the degeneration of cartilage.
Towards effective therapeutical options targeting early pathological events of the joint disease, preclinical research is required to identify novel treatment strategies. To test potential drug candidates, an in vitro OA model which recapitulates specifically the early stage of the joint disease is urgently needed. Currently used in vitro OA models are mostly derived from cells isolated from samples collected from end-stage OA patients that underwent knee-replacement therapy. As these cells or tissues are affected by the chronic disease, they are not suitable to model early events of the pathology.
In my doctoral thesis, I introduce the field of my research (Chapter 1). I describe the lifespan of articular cartilage in the knee – from embryonic development towards the mature tissue and cartilage aging. The joint pathology OA is explained from a pathobiological and clinical point of view. Current treatment options for different stages of the disease are depicted. Examples of existing in vivo and in vitro OA models and the application of proteomics in preclinical OA research are described.
To better understand developmental events related to chondrocyte hypertrophy and their correlation to the OA pathology, we evaluated the current state of the art (Chapter 2). The review “Chondrocyte Hypertrophy in Osteoarthritis: Mechanistic Studies and Models for the Identification of New Therapeutic Strategies” (Cells, 2022) describes common signalling pathways regulating cartilage embryonic developmental processes and cartilage degenerative changes in the OA joint, models used to study these processes, and already proposed therapeutic strategies targeting chondrocyte hypertrophy to counteract OA progression.
I report my experimental efforts towards a preclinical OA model capturing the early degeneration of articular cartilage in OA in the prepared manuscript entitled “Human engineered osteoarthritic cartilage organoids as preclinical disease model” (Chapter 3). We hypothesize that both chondrocyte hypertrophy and cartilage catabolism orchestrate early cartilage degradation. The described model is derived by recapitulating cartilage development using human progenitor cells. Disease traits are induced by pro-hypertrophic and inflammatory factors. I validate the OA articular chondrocyte phenotype in OA cartilage organoids on tissue, protein and molecular level and demonstrate the modulation of induced OA traits by bioactive factors. In an unbiased proteomics approach, I identify pathogenic and therapeutic targets known in the OA field and thus validate the biological relevance of my model. In a proof-of-concept study, I test the possible usage of OA cartilage organoids as preclinical disease model to identify new druggable targets and OA-associated mechanisms.
Furthermore, I provide additional experimental means for future studies intended to investigate the role of subchondral bone-derived progenitor cells, endochondral-related processes, and angiogenesis in OA (Chapter 4).
Prospectively, the OA cartilage organoid model reported in my doctoral thesis will help to identify new therapeutic treatment strategies for OA patients experiencing symptoms of early cartilage degeneration. Next to anti-inflammatory treatment strategies, this model may also be utilized to investigate therapeutics targeting hyperphysiological tissue calcification or aging-induced chondrocyte senescence.
Advisors:Barbero , Andrea
Committee Members:Affolter, Markus and Zenobi-Wong, Marcy
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Cell Biology (Affolter)
UniBasel Contributors:Barbero, Andrea and Affolter, Markus
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:15196
Thesis status:Complete
Number of Pages:161
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss151965
edoc DOI:
Last Modified:16 Dec 2023 05:30
Deposited On:15 Dec 2023 14:31

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