Mylène Jansen

Clinical evidence and molecular mechanisms of KJD 201 10 joints less as a result of the frame without distraction. Nonetheless, the actual distraction was superior in this study. This supports that it is more likely that a combination of (hydro) mechanical changes on cartilage as well as bone turnover is needed to obtain the observed effects of distraction. Stem cells and joint milieu An impressive result of KJD is the significant reduction of denuded bone areas as determined by MR imaging, where the gaps were filled in with tissue with a similar signal intensity as the original cartilage. 21,36 It is difficult to envision that this effect is solely due to an increased extracellular matrix synthesis of chondrocytes surrounding the gap. It is postulated that resident mesenchymal stem cells (MSCs) in the joint 93–95 are important for the intra-articular repair activity. The identification of MSCs in the different tissues such as synovium, cartilage, and synovial fluid of the joint supports this hypothesis. 93 The exact contribution is not clear and potentially consist of metabolic stimulation of existing chondrocytes or differentiation in a chondrogenic manner into new chondrocytes. Nonetheless, more recently the first studies of MSCs and mediators released in the context of distraction have emerged. It was demonstrated that OA synovial fluid (SF), as well as purified high molecular weight hyaluronic acid (HA MW), inhibited adhesion of synovial fluid derived MSCs (SF-MSCs). 43 Treatment with hyase of the OA SF could increase this attachment four-fold. This hints that during OA the MSCs are coated with a layer of HA, preventing the cells to attach to the site of injury. Moreover, using the canine KJD model, it was demonstrated that under the influence of distraction MSCs were able to attach to the damaged cartilage, and that this was dependent on the MW of the HA. This supports that under influence of distraction, SF-MSCs can attach, considered key to MSC mediated colonization, differentiation, and cartilage repair. Though the exact mechanisms involved are largely unknown, endogenous subchondral bone (SB) MSCs and SF-MSCs have been suggested as potential contributors to structural improvement and cartilage repair following unloading. 66,96,97 Studying gene expression of SF- MSCs derived from OA patients showed that these cells express lower levels of ossification- and hypothropy-related genes, parathyroid hormone 1 receptor, and runt-related transcription factor than SB-MSCs of these patients did. 44 This might indicate a greater cartilage remodeling ability of the OA SF-MSCs, as compared with SB-MSCs. Interestingly, joint unloading by KJD resulted in a sustained and significant increase in SF-MSC colonies sizes and densities. Also, an upregulation of the key cartilage core protein aggrecan as well as a decrease in the pro-inflammatory C-C motif chemokine ligand 2 (CCL2) expression during the distraction period was noticed. 44 The first 3 weeks of the distraction treatment were marked by significant increases in MSC chondrogenic commitment markers such as gremlin 1, and growth differentiation factor 5 (GDF5) , markers associated with an healthy cartilage homeostasis. 98–101 These results indicate that the transcriptomes differ between joint-resident MSCs depending