Marie De Vries

In contrast to many other tissues, cartilage lacks a self-regenerative potential. Untreated cartilage lesions are generally believed to progress towards osteoarthritis (OA). Several treatments for cartilage lesions are in clinical use for over 20 years, but the molecular mechanisms behind it are largely unknown and the clinical outcomes are variable. In order to improve current treatment procedures as well as to develop new treatment strategies, models are needed to elucidate the mechanisms involved in cell-based cartilage regeneration. This thesis aimed to provide such models. The effects of different tissues present in articular joints on cartilage regeneration using human bone marrow derived mesenchymal stem cells (hBMSCs) were studied.

Chapter 2 provides a review of clinically used strategies and the future potential of regenerative medicine for cartilage regeneration. Randomized clinical trials (RCTs) on microfracture, osteochondral autograft transplantation and autologous chondrocyte implantation (ACI) apply specific inclusion criteria, resulting in a study population with focal cartilage lesions without other joint problems. The results of treatments can therefore be different in other patient populations. Chondrocytes have several drawbacks for use in cell-based cartilage regeneration including the creation of joint defects to obtain the cells and their tendency to dedifferentiate in vitro. Therefore hBMSCs are promising because of their chondrogenic differentiation capacity. Apart from their cartilage regeneration potential, hBMSCs have a trophic activity, which can potentially be used to counteract the catabolic environment present in OA joints.

OA is often accompanied by synovial inflammation, leading to a catabolic joint environment. The inflammatory factors secreted by OA synovium negatively affect chondrogenesis of hBMSCs. In chapter 3 and 4, synovial inflammation is modeled in vitro using conditioned medium prepared from OA synovium. In chapter 3 it is demonstrated that there are factors in OA synovium conditioned medium that signal via the TAK1 and JAK signaling pathways which are involved in the negative effect of OA synovium on hBMSC chondrogenesis, since inhibitors of these pathways partly counteract the negative effect of OA synovium. In chapter 4 a potential role in this process is identified for M1 macrophages that are present in OA synovium. This is demonstrated using both OA synovium conditioned medium as well as peripheral blood derived monocytes stimulated towards M1 and M2 macrophages as model systems. Like OA synovium conditioned medium, M1 macrophage conditioned medium was found to negatively affect hBMSC chondrogenesis, where M2 macrophage conditioned medium did not. Together, these chapters indicate that synovial inflammation should be treated to allow optimal hBMSC chondrogenesis for cartilage regeneration.