Background/Purpose:  The cause for chronic pain in OA is largely unknown. Over 50% of osteoarthritis (OA) patients show synovial inflammation, even at early stages of the disease. However, if and how this synovial activation contributes to joint pathology and pain, is not known. We aimed to identify pathways that predict progression of cartilage damage and osteophyte (OP) formation in OA. In addition, we identified association between gene expression and pain in a cross-sectional approach.

Methods:  From 25 patients with knee OA that entered the CHECK Cohort study (Cohort Hip and Cohort Knee) synovial biopsies were collected at baseline. CHECK is a prospective 10-year follow-up study on patients with early osteoarthritis-related complaints initiated by the Dutch Arthritis Foundation. Progression over 5 years was determined radiographically based on change of joint space width (JSW) and OP size in these radiographs. Pain was assessed at baseline and after 5 years by the WOMAC pain questionnaire. Synovial samples from baseline were studied using histology and microarray (affymetrix U133-plus-2.0), and Functional Annotation Clustering (FAC).

Results:   We identified patients as progressors or non-progressors, either based on JSW (respectively n=13 vs n=8) or OP size (respectively n=10 vs n=11) at baseline and t=5yrs. Among the genes that were differentially expressed by OP progressors were MMP1, 2, 3, 9 and -14, which were not found in JSW-progressors. Specifically in JSW-progressors, macrophage markers (e.g. CD14, S100A8, S100A9, MHC class II genes) were positively associated with progression. This indicates that expression of these factors predict progression of cartilage damage in OA patients. Using FAC we identified inflammatory response, macrophage differentiation, blood vessel formation, ossification and cell migration to be enriched in JSW-progressors. Blood vessel formation, ossification and cell proliferation were enriched in OP-progressors. Histologically, the JSW-progressors showed a thicker synovial lining and cellularity was higher in the sublining compared to non-progressors and OP progressors. Both JSW-progressors and osteophyte-progressors showed increased vascularisation compared to non-progressors. FAC analysis pointed out that dendrite formation (p=0.036), ossification (p=0.027) and wnt signaling (p=0.0065) were annotation clusters that were related to pain at Baseline. Moreover, we found neuronprojection/dendrite formation (p=0.0044), skeletal morphogenesis (p=0.018) and neuron differentiation (p=0.038) enriched in synovium of patients with pain after 5 years. When only upregulated genes were tested these patients showed strong enrichment of inflammatory genes (p=6.4*10^-12) and axogenesis (p=0.005).

Conclusion:  We found evidence for a difference in underlying processes in the synovium regarding progression of cartilage damage and progression of osteophyte formation. The presence of macrophages, in the lining layer, is associated with progression of cartilage damage, whereas synovial expression of MMPs correlated to progression of osteophyte formation. Pain at t=5 yrs was predicted by several nerve fiber related processes and strongly by inflammation.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/differential-synovial-expression-patterns-in-early-osteoarthritis-predict-pain-and-progression-of-joint-damage/