Background Many osteoarthritis (OA) patients show synovial inflammation, even relatively early during the disease. Mechanisms through which synovial activation contributes to the joint pathology that characterizes OA, are not known.
Objectives To identify common pathways in the synovium that determine cartilage damage during OA.
Methods From patients that entered the CHECK Cohort study (Cohort Hip and Cohort Knee) and from controls (n=7) synovial biopsies were collected. CHECK is a prospective 10-year follow-up study on participants with early osteoarthritis-related complaints. Kellgrenn&Lawrence score (KL) was determined at inclusion (n=18). In addition, biopsies of 7 control synovia were collected. A longitudinal expression analysis was performed on murine synovial tissue at day 7, 21 and 42 after induction of collagenase induced OA (CIOA). CIOA was induced by intra-articular injection of collagenase and contra lateral knee joints served as controls. Microarray experiments were performed on all synovial tissues. Functional annotation clustering (FAC) and pathway analysis was done using DAVID.
Results Gene expression profiles of control synovia were compared to CHECK synovia. Enrichment analysis revealed several annatations, including regulation of macrophage differentiation, innate immune responses, cell migration, TGFβ-, BMP- and wnt-signaling. This signifies clear activation of the synovium in CHECK patients compared to controls. Next we compared synovial tissue of patients with radiological damage (KL≥1) with patients without damage (KL=0). Genes that showed the strongest association with cartilage damage were MMP-1, MMP-3, S100A8 and cartilage glycoprotein-39 (18, 10, 6 and 6-fold), all of which have been associated with cartilage damage. Immunohistochemical staining revealed that expression of MMP-1 and MMP-3 was highest in the synovial lining layer. Response to wounding, chemotaxis, innate immune response and metalloproteases were strongly and significantly enriched and thus associated with joint damage. Pathway analysis demonstrated that in the synovium of patients with joint damage the complement-activation pathway, TGFβ- and BMP-signaling and TLR-activation were significantly upregulated. These results were underlined by analysis of synovium from CIOA. Among the genes that were strongly upregulated on all time points after induction were MMP-3, MMP-13, MMP-14 and COMP (6, 16, 6 an 13-fold). Again, wound healing, innate immune response and metalloproteases were significantly enriched, as were the complement pathway, the TLR-, TGFβ, BMP and wnt-signaling pathways. A recent publication demonstrated complement to be essential in experimental OA. We therefore determined expression of complement binding proteins, and found a strong upregulation of COMP, lumican, osteomodulin, biglycan, decorin and fibromodulin.
Conclusions These data suggest an active role for the synovium in OA pathology, and identify pathways that are likely to be involved. In particular the association of cartilage damage with the complement pathway was strong. In addition, TGFβ-, BMP- and wnt-signaling in the synovium, may contribute to further joint damage. The enhanced expression of cartilage damaging MMP-1, MMP-3 and MMP-13 suggests an active role of the synovium in OA pathology.
Disclosure of Interest None Declared
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