Sorbonne University - Saint-Antoine hospital Paris, France
Francis Berenbaum1, Coralie Meurot2, Celine Martin2, Jerome Breton2, Claire Jacques3, Jacob favret4, Jed Pheneger4, Revital Rattenbach2, Alison Bendele4 and Keren Bismuth2, 1Sorbonne University - Saint-Antoine hospital, Paris, France, 24P Pharma, Lille, France, 3Sorbonne University, Paris, France, 4Inotivco Boulder, West Lafayette, IN
Background/Purpose: Osteoarthritis (OA) is a whole-joint disease characterized by synovial inflammation, cartilage degradation and bone changes leading to swelling, pain, and loss-of-function. To date, only symptomatic anti-inflammatory treatments are available, however there is an urgent unmet need for a disease-modifying OA drug. Glucagon-Like-Peptide 1 Receptor (GLP-1R) agonists are widely prescribed for the treatment of type 2 diabetes. Interestingly, they also have anti-inflammatory and anti-degradative properties independently of their antidiabetic effect1. Here, we used three animal models of inflammatory and post-traumatic OA to evaluate the impact of intra-articular (IA) liraglutide, one GLP1-R agonist, on the whole knee joint structure.
Methods: The impact of IA liraglutide on synovial membrane inflammation and catabolic markers was evaluated by histology and RT-qPCR, respectively, in a short-term inflammatory model of OA, namely the mono-iodo-acetate (MIA) mouse model. The structural effect of IA-delivered liraglutide on cartilage damage and knee joint structure were evaluated in the destabilization of the medial meniscus (DMM) model of OA in rats as well as in the type II collagenase rat model. Histopathological analyses and scoring were performed by independent investigators in a blinded manner.
Results: In the MIA model, a single IA liraglutide into the knee joint resulted in a significant dose-dependent decrease of catabolic markers, and in particular on ADAMTS-5 gene expression 8 days following treatment (2.32± 0.73 for vehicle vs 2.01±0.45, 1.57±0.27 and 0.76±0.26 for Liraglutide 10, 20 and 30 µg, respectively, p=0,023), as well as an improved synovitis score inflammation (liraglutide 20 µg p = 0.0099, compared to vehicle-treated group). Histological analyses following 6 weeks of IA liraglutide into the knee joint in the rat DMM-induced OA model resulted in a significant reduction (-13%, p=0.028 in liraglutide-treated vs vehicle) in total cartilage degeneration width. Interestingly, zonal analysis of damaged tibial cartilage revealed that liraglutide preferentially numerically reduces lesions in the most inner zone of the tibial cartilage (zone 3) which accounts for proteoglycan loss (0.53±0.03 vs 0.40±0.07 for vehicle and liraglutide-treated, respectively). This tendency for a targeted action on zone 3 was also confirmed in the type II collagenase model (0.88+/-0.64 vs 0.38+/-0.52). Furthermore, along with reducing cartilage degeneration, liraglutide-treated DMM rats presented a numerically decreased osteophyte score (3.14±0.35 vs 2.47±0.32 for vehicle and liraglutide, respectively).
Conclusion: Using 3 experimental models of OA, we have demonstrated a potential effect of liraglutide on the whole structure of the joint (cartilage, synovial tissue and bone) and not only on the cartilage, allowing us to consider this drug as a disease-modifier rather than a cartilage-modifier OA drug only.
1 Meurot C et al. Liraglutide, a glucagon-like peptide 1 receptor agonist, exerts analgesic, anti-inflammatory and anti-degradative actions in osteoarthritis. Sci Rep. 2022 Jan 28;12(1):1567
Disclosures: F. Berenbaum, 4Moving Biotech; C. Meurot, None; C. Martin, None; J. Breton, None; C. Jacques, None; J. favret, Inotiv; J. Pheneger, Inotiv; R. Rattenbach, 4moving Biotech, 4P-Pharma; A. Bendele, Inotiv; K. Bismuth, 4P Pharma.
