Session Title: Genetics and Genomics of Rheumatic Disease I
Session Type: Abstract Submissions (ACR)
Background/Purpose: The majority of osteoarthritis (OA) patients show synovial inflammation, even relatively early during the disease. We used microarray analysis of synovial tissue of early OA patients and of experimental OA, to identify common pathways that determine joint damage in this disease.
Methods: Expression analysis was performed on murine synovial tissue at day 7, day 21 and day 42 in collagenase induced OA (CIOA) and the surgically induced DMM model (destabilization of the medial meniscus). CIOA was induced by intra-articular injection of collagenase, which causes joint instability. From a subpopulation of patients (n= 25) that entered the CHECK Cohort study (Cohort Hip and Cohort Knee) and 7 controls, synovial biopsies were collected at year 0, 2 and 5. CHECK is a prospective 10-year follow-up study on participants with early osteoarthritis-related complaints (less than 6 months before inclusion) initiated by the Dutch Arthritis Association. Kellgren&Lawrence-score (KL) at inclusion was determined (n=18) and follow up measurements were performed at 2 and 5 years. Affymetrix was used for microarray, and pathway analysis was done using DAVID.
Results: Among the genes that were strongly upregulated on all 3 time 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-, TGFβ, 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. 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, TGFβ-, BMP- and wnt-signaling. This indicates activation of the synovium in the early OA versus controls. Next we compared synovial tissue of CHECK-patients with radiological damage (KL≥1) with CHECK-patients without joint damage (KL=0). In the top 30 genes that were associated with cartilage damage were MMP-1 (18-fold), 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, complement-activation pathway, TGFβ- and BMP-signaling and TLR-activation were striking.
Conclusion: Activation pathways and processes in the two models for OA were highly similar. A major difference lies in the presence of late synovial activation. The data suggest an active role for the synovium in OA pathology, and identifies pathways that may be involved. Activation of the complement-pathway was strongly associated with damage. In addition, synovial MMP expression was associated with joint damage, underlining an active role of synovium in OA pathology.
A. B. Blom,
P. L. van Lent,
M. H. van den Bosch,
F. H. J. van den Hoogen,
P. M. van der Kraan,
W. B. van den Berg,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/microarray-analysis-of-synovial-specimen-of-early-human-check-and-experimental-osteoarthritis-to-identify-pathways-and-processes-associated-with-pathology/