Mylène Jansen

406 Chapter 19 and tibia, which in dogs showed (some) repair even without distraction. 31 Furthermore, this thesis shows that KJD does not only induce regenerative processes over time, but also processes that could be categorized as degenerative or inflammatory during and shortly after treatment. It has previously been indicated that KJD results in a significant increase in SF- resident mesenchymal stem cell (MSC) promoting cartilage repair. 32 SF biochemical marker evaluation showed upregulation associated with repair, but at the same time markers associated with degeneration were upregulated as well, indicating activation of traditionally inflammatory pathways ( chapter 16 ). KJD also causes increased osteophyte formation ( chapter 17 and chapter 18 ), a process that is generally considered a sign of OA progression. Systemic biomarkers showed an initial net collagen type II synthesis decrease, meaning more breakdown than regeneration of collagen type II, 1 of the most important molecules providing cartilage its mechanical integrity ( chapter 4 ). Only from 1 year after treatment onward a net synthesis increase was observed, indicating an initial phase of breakdown (or turnover) is followed by regeneration in the long term. This was confirmed by T2-mapping, as in the first year after treatment cartilage T2 values significantly increased (deterioration of structure), but between 1 and 2 years a plateau or even a decrease was seen (improvement in structure), again indicating short-term breakdown followed by improvement ( chapter 15 ). While there is clearly an initial boost in cartilaginous tissue regeneration in especially the first year after treatment ( chapter 3 , chapter 4 , chapter 9 , chapter 13 , and chapter 14 ), it is plausible that it takes a bit more time for this tissue to become of similar quality as that of the native cartilage ( chapter 15 ). It might well be, for example, that if aggrecan molecules are enzymatically truncated but not removed from the hyaluronic acid core in the process of OA and with that from the matrix, this aggrecan molecule cannot be replaced, leaving an impaired aggrecan complex. Only when further degradation is facilitated first, the truncated molecule can be fully replaced in the repair phase after the initial breakdown. Subchondral bone, in contrast to cartilage, showed early remodeling, which seemed to be a normalization, already in the first year after treatment ( chapter 3 and chapter 18 ), with shape improvement following shortly after ( chapter 18 ). Interestingly, this was also followed by osteophyte growth ( chapter 17 and chapter 18 ). These bone changes are in line with previous results after ankle distraction, where especially the first year after treatment, a subchondral bone density normalization was seen, as the overall bone density decreased but the density in cystic areas increased. 33 Yet also bone goes through a breakdown phase by distraction, as clear osteopenia is caused during treatment because the load on the bone is taken over by the external distraction device. Clearly, KJD significantly alters the joint homeostasis by inducing both anabolic and catabolic processes in the initial phase, resulting in changes in SF, bone, and cartilage, that manage to finally cause long-term repair. The research presented in this thesis moved our understanding of KJD treatment forward by evaluating these different components, and by partially identifying patient characteristics that are considered important for the effect. Male patients responded significantly better to KJD treatment ( chapter 3 ), as is the case with ankle