Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
Synovial activation is present in a large subset of osteoarthritis (OA) patients and it is thought to play an important role in the development of OA pathology. Previously, we found that alarmins S100A8 and S100A9 are elevated in the synovium of OA patients and that high S100A8/A9 serum levels correlate with 2-year progression of the disease. Furthermore, in experimental OA these S100-proteins are involved in cartilage degradation and synovial activation. Paquinimod is a quinoline-3-carboxamide compound with immunomodulatory properties that is currently in clinical development for treatment of systemic sclerosis. It targets the S100A9 protein and disrupts the binding of S100A9 to RAGE and TLR-4.
In the current study we investigated the effect of the S100A9-blocking compound paquinimod on experimental osteoarthritis with different degrees of synovial activation.
Methods: 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 4 days before induction of OA in both CIOA and DMM and refreshed twice a week. 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.
Results:
First, we assessed the effect of paquinimod on DMM development at day 56. Synovial activation in this surgical model is low, as are S100A8/A9 levels in the synovium. No differences were observed on osteophyte size between paquinimod-treated and non-treated animals at both medial tibia and medial femur. Furthermore, OA-like cartilage pathology was only significantly reduced by paquinimod-treatment at the medial femur (-64%), not at other surfaces and not in the total joint score (-16%).
Then, we treated collagenase-induced OA (CIOA) with paquinimod and evaluated the effects at day 42. In CIOA, synovial activation is high and S100A8/A9 levels in the synovium are significantly higher than those in DMM. Synovial activation was significantly reduced by paquinimod-treatment at the medial side of the patella-femur region (-57%). Osteophyte size was significantly reduced at the medial femur (66%) and cruciate ligaments (-67%). Finally, OA-like cartilage pathology in CIOA was significantly reduced after paquinimod treatment on the medial side of both tibia and femur (-47% and -75% respectively) as well as in the total joint score (-46%).
Conclusion:
Paquinimod administered in the drinking water reduces synovial activation, osteophyte formation and OA-like cartilage pathology in CIOA. In contrast, in an experimental OA model where synovial activation is nearly absent (DMM), the effect of paquinimod is marginal.
Paquinimod could prove a very promising treatment for osteoarthritis patients with high synovial activation by blocking S100A9.
Disclosure:
R. Schelbergen,
None;
A. B. Blom,
None;
T. Leanderson,
Active Biotech,
1,
Part-time employee of Active Biotech,
3;
H. Eriksson,
Active Biotech,
1,
Active Biotech,
3;
W. B. van den Berg,
None;
P. L. E. M. van Lent,
Active Biotech,
2.
ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-s100a9-inhibitor-paquinimod-abr-215757-reduces-synovial-activation-osteophyte-formation-and-cartilage-damage-in-experimental-osteoarthritis/