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Protective effects of intra-articular formulated liraglutide in osteoarthritis : preclinical studies

      Purpose: Osteoarthritis (OA) is a degenerative joint disease affecting millions of individuals worldwide. Its development has been reported to be associated with cartilage degradation and inflammatory responses leading to pain, swelling and reduced function. Liraglutide, a Glucagon-Like-Peptide 1 Receptor (GLP-1R) agonist, is clinically used as a subcutaneous treatment for type 2 diabetes. Interestingly, immunomodulatory and anti-inflammatory properties of the GLP-1 pathway have been recently described in various diseases but its role in the pathogenesis of OA remains to be elucidated. The objective of this study was to evaluate the effects of intra-articular (IA) Liraglutide in in vitro and in vivo models of OA by evaluating surrogate markers of inflammation and cartilage matrix proteolysis, cartilage degradation and pain.
      Methods: IL-1β-stimulated mouse articular chondrocytes were treated with different concentrations of Liraglutide for 24h. Production of matrix metalloproteinases (MMP) and prostaglandin E2 (PGE2) was measured by ELISA. IA injections of Liraglutide or vehicle were performed in two chemically-induced inflammatory knee OA models: the mouse monosodium iodoacetate (MIA) model and the rat collagenase model. Paw withdrawal threshold and weight bearing distribution were performed for pain behavior assessment. Histopathological analyses (OARSI score) were conducted blindly by one observer in the rat collagenase OA model for evaluating cartilage degradation.
      Results: Liraglutide significantly reduced the IL-1β-induced production of PGE2 (1341±86 vs 1766±145 pg/ml for vehicle, p≤0.05, 50nM dose) and cartilage matrix catabolic enzymes MMP-3 (294±23 for vehicle vs 204±15 ng/ml, p≤0.01, 3nM dose; vs 197±23 ng/ml, p≤0.001, 50nM dose) and MMP-13 with a dose response (127±14 for vehicle vs 90±18 pg/ml, p≤0.01, 3nM dose; vs 70±10 ng/ml, p≤0.001, 10nM dose; vs 52±6 ng/ml, p≤0.001, 50nM dose) in murine chondrocytes. In both in vivo OA models, Liraglutide IA injections significantly attenuated pain symptoms. Indeed, in the mouse MIA model, single injection of IA Liraglutide increased paw withdrawal threshold (0.37±0.39 vs 0.13±0.11 g for vehicle, p≤0.05, day 7) and improved weight distribution to the affected limb (80±7% at day 7 and 83±4% at day 10, p≤0.001) compared to vehicle (71±6% at day 7 and 74±4% at day 10). The response was found similar to the one after an IA injection of dexamethasone (79±8% at day 7 and 81±4% at day 10). In the rat collagenase OA model, repeated IA injections of Liraglutide improved weight bearing deficit at multiple time-points (50±4 at week 1, 66±5 at week 3 and 66±4% at week 6, p≤0.001) compared to vehicle (42±4 at week 1, 57±4 at week 3 and 59±3% at week 6). Histological assessment of rat collagenase-injected knee joint revealed a significant (p≤0.05) decrease of the total joint score in the IA Liraglutide treated group (8±4) compared to vehicle (11±4).
      Conclusions: IA injection of Liraglutide has demonstrated anti-catabolic, anti-inflammatory and pain-relieving effects in preclinical OA models, opening the wave to considering now this molecule as a potential disease-modifying OA drug.