Mylène Jansen

402 Chapter 19 The exploration of KJDworking mechanisms was not limited to only cartilage tissue. In chapter 16 , SF biochemical marker levels were assessed before, during, and directly after treatment. KJD caused a measurable molecular response in SF with significant changes in markers associated both with degeneration and with repair, suggesting remodeling. Interestingly, for some markers such as transforming growth factor- β 1 (TGF β -1), their (biological) response even appeared to be associated with patient-reported clinical outcome in the year after treatment. The in KJD upregulated SF markers like TGF β -1 and interleukin-6 (IL-6) could be related to cartilage regeneration, but also to osteophyte formation, which is why osteophyte formation after KJD and HTO was studied radiographically in chapter 17 . In the 2 years after treatment, a significant increase in osteophyte area was observed, higher than that in patients with natural OA progression in the years before undergoing TKA. The increased osteophyte formation in KJD patients tended to be associated with changes in TGF β -1 but not IL-6. Osteophyte growth may therefore be a bystander effect of cartilage repair activity related to intra-articular factors such as TGF β -1, and not just simply an indicator of joint degeneration as used in different OA grading systems. Lastly, to further evaluate bone changes induced by KJD, the subchondral cortical bone thickness, subchondral trabecular bone density, and bone shape were explored on CT scans before and after treatment in chapter 18 . Before treatment, the more affected weight-bearing part of the joint showed increased cortical thickness and trabecular density. Both parameters seemed to decrease in the first year after treatment, especially in the more affected parts, and this change was prolonged throughout the second year. Furthermore, the femoral condyles became more convex while the tibial condyles became less concave. These alterations suggest KJD treatment may induce a partial normalization of bone shape and structure affected by OA. General discussion For a disease with such a high socio-economic impact as OA, it is rather surprising that until not too long ago it was thought of as simply a disease of cartilage degeneration. Instead it is a whole-joint disease involving bone, cartilage, and synovial tissue that is not simply the result of wear and tear. 11 Proper cartilage regeneration was thought impossible, but it is now more and more accepted that cartilage can at least partly regenerate. 12–15 Still, development of disease- modifying osteoarthritis drugs (DMOADs) has thus far failed. This is partially because we increasingly appreciate that modification of multiple involved tissues and processes is required to have a lasting impact, whereas most drug development approaches thus far only target single molecules or pathways. New approaches such as a IL4-10 fusion protein, improving pain, inflammation and cartilage structure seem promising. 16–18 The research presented in this thesis