Perlecan is required for chondrogenic differentiation of mesenchymal synovial cells

Abstract

points after induction of CIOA were MMP-3 (6-fold), MMP-13 (16-fold), MMP-14 (6-fold). Wound healing, phagocytosis, chemotaxis and metalloproteases were significantly enriched, as were the complement pathway, the TLR-, TGFb, BMP and wnt-signaling pathways. Highly similar results were obtained in the DMM model for OA. However, at day 42 in this model very view genes were still regulated in the synovium compared to other time points or CIOA, indicating that synovial activation differs late between the models. This was underlined by histological examination, that shows thickened synovial lining mainly in CIOA. All in all, the expression patterns in experimental OA showed compelling similarities with human OA synovium. Gene expression profiles of control synovia were compared to CHECK synovia. Analysis using DAVID indicated enrichment of several biological processes and signaling pathways, including macrophage presence, cell migration, TGFb-, BMPand wnt-signaling. This indicates clear activation of the synovium in the CHECK patients compared to controls. Next we compared synovial tissue of CHECK-patients with radiological damage (KL 1) with CHECK-patients without joint damage (KL1⁄40). In the top 30 genes that were associated with cartilage damage were MMP-1 (18fold), MMP-3 (10-fold) and S100A8 (6-fold), all of which have been associated with cartilage damage. FAC analysis further underlined response to wounding, chemotaxis, innate immune response and metalloproteases to be strongly enriched. In particular, complementactivation pathway, TGFband BMP-signaling and TLR-activation were striking. Conclusions: Activation pathways and processes in the two models for OA were highly similar. A major difference lies in the presence of late synovial activation. This may direct the choice for the most optimal model to study certain OA subpopulations, since this difference was obvious in human OA, where roughly 50% shows marked synovitis. The FAC data suggest an active role for the synovium in OA pathology, and identifies pathways likely to be involved. One of the strongest associations was of the complement-pathway with cartilage damage. In addition, synovial MMP expression was associated with cartilage damage, underlining an active role of synovium in OA pathology.