Mylène Jansen

202 Chapter 10 on the biomechanical environment, viz. fluid vs bone, and that temporarily unloading leads to transcriptional changes in SF-MSCs that may be of importance to cartilage repair. In addition to the reported MSC changes, a different study reported on the molecular profile of SF changes upon KJD. 20 patients who underwent KJD had SF sampled at baseline, midpoint, and endpoint of distraction, in which 10 predefined mechanosensitive molecules were measured. 45 6/10 markers showed statistically significant changes between pre-treatment and 6 weeks (endpoint): activin A, transforming growth factor beta (TGF β ), monocyte chemoattractant protein 1 (MCP-1), IL-6, fibroblast growth factor 2 (FGF2), and Latent-transforming growth factor beta-binding protein 2 (LTBP2). Of these, five showed a predominant increase in levels and one (activin A) mainly a decrease (to within normal range for most individuals). For most analytes, changes were detectable at 3 weeks of distraction (midpoint). For some analytes such as LTBP2, there was diversity of response. The remaining four markers IL-8, matrix metalloproteinase-3 (MMP3), tissue inhibitor of metalloproteinases 1 (TIMP1), TNF-inducible gene 6 protein (TSG-6) did not change significantly over 6 weeks, but two (IL-8, TIMP1) were significantly different at the 3-week midpoint. Although the study lacked power to test in full an association between the marker change and clinical outcome, some indicative associations between changes in markers and subsequent changes in KOOS at 12 months post treatment were seen. Patients achieving the minimum clinically important difference of 10 points of KOOS over a 6-month period showed greater increases in FGF2 and TGF β than those who did not. An increase in IL-8 during the 6-week treatment period was associated with a significantly greater improvement in KOOS over 12 months. Moreover, these increased FGF2 and TGF β levels might be related to the enhanced expressed TGF β receptor 1 and 2 seen in SF MSCs early during KJD 44 , which may signify a enrichment in TGF β -responsive MSCs during these early stages of the treatment. As seen with the SF-MSCs study 44 , detectable, significant molecular changes are observed in SF upon joint distraction, providing additional clues for the clinical and structural changes found. Though new clues are emerging also puzzling effects occur, especially regarding some of the SF pro-inflammatory mediators. The SFMSC study 44 indicated lower expression of the proinflammatory chemokines CCL2/MCP1, whereas the IL-6 and MCP1 SF levels were found increased following KJD. 45 MCP1 is associated with chondrocyte degeneration, synovial inflammation, and implicated in joint pain. 102,103 These results contrast also effects found in animals studies in which KJD was applied and a significant effect on joint inflammation was documented. 92,96 An interesting thought might be that a mechanically-induced response results in both catabolic and reparative responses which are initiated at the moment the joint surfaces are distracted but needs prolonged time to fully shift to a reparative status. Such a thought is supported by the response of the collagen type II synthesis marker (PIIANP) and breakdown marker (CTXII) in patients treated with KJD which indicate a shift from breakdown towards synthesis between 6 and 12 months after treatment. 22,25 This is in line with recent preliminary research 104 in which it was demonstrated that the shift from a catabolic to an anabolic state occurs within the weeks after