Session Type: Abstract Submissions (ACR)
Synovial activation is present in more than 50% of osteoarthritis (OA) patients and it is thought to be involved in the development of OA pathology. Previously, we found that alarmins S100A8 and S100A9 are elevated in synovium of OA patients and that high S100A8/A9 serum levels correlate with 2-year progression of the disease. Furthermore, in experimental OA, S100A8/A9 proteins regulate cartilage degradation and synovial activation. Paquinimod is a quinoline-3-carboxamide compound with immune modulatory properties that is currently in clinical development for treatment of systemic sclerosis. It targets the S100A9 protein and blocks the binding of S100A9 to RAGE and TLR-4. In the current study we investigated the effect of paquinimod in two experimental osteoarthritis models differing in synovial activation and its effect on S100A9 stimulated OA synovium.
Collagenase induced OA (CIOA) was induced by two times intra-articular injection of 1U collagenase and DMM was induced by transsection of the medial anterior meniscotibial ligament leading to destabilization of the medial meniscus (DMM), both in C57Bl6 mice. Paquinimod (3,75 mg/kg) was administered in the drinking water which was refreshed twice a week . Treatment started 4 days before induction of OA in both CIOA and DMM. Synovial thickening and cellularity was measured using an arbitrary score from 0-3. OA-like cartilage pathology was scored using a modified Pritzker OARSI score. Osteophyte size was assessed by a blinded observer using imaging software. Human OA synovium was anonymously obtained from patients undergoing arthroplasty and stimulated with S100A9 and/or paquinimod. Proteins released by synovium were measured with Luminex.
Paquinimod treatment of CIOA expressing high synovial activation resulted in significantly reduced synovial thickening (57%), osteophyte size at the medial femur (66%) and cruciate ligament formation (67%). Moreover, cartilage damage was reduced by paquinimod in CIOA at the medial tibia (47%) and femur (75%). In contrast, paquinimod did not reduce cartilage damage and reduced osteophyte size only slightly (only at the medial femur) in DMM, in which synovial activation is scant. In addition, human OA synovium comprising lining macrophages, was incubated with human S100A9 and /or paquinimod. S100A9 significantly upregulated pro-inflammatory IL-6, IL-8 and TNFα (9-fold, 12-fold and 20 fold increase respectively) and catabolic factors MMP-1 and 3 (up to 2,5 fold). Adding paquinimod significantly inhibited S100A9-induced levels of IL-6 (35% reduction) and IL-8 (38% reduction) but not TNFα whereas MMP1 and MMP3 were reduced by 39% and 64% respectively.
Paquinimod reduces synovial activation, osteophyte formation and OA-like cartilage pathology in experimental OA with high synovial activation and ex vivo blocks pathological effects of S100A9 in OA synovium. Paquinimod could prove a very promising treatment for osteoarthritis patients expressing high synovial activation.
P. L. van Lent,
A. B. Blom,
W. B. van den Berg,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/s100a9-inhibitor-paquinimod-abr-215757-reduces-joint-destruction-in-experimental-osteoarthritis-and-blocks-activating-effects-of-s100a9-in-oa-synovium/