Session Title: Osteoarthritis & Joint Biology – Basic Science Poster
Session Type: Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Osteoarthritis (OA) is an age-related joint disease affecting millions of individuals worldwide and associated with an extremely high burden largely attributable to disability. To date, there are only symptomatic treatments and no disease-modifying OA drugs (DMOADs) acting on both symptoms and structure are yet approved. Although OA is a disorder of the whole joint, progressive cartilage degeneration is considered as its hallmark. Indeed, differentiation and function of chondrocytes are impaired in OA, resulting in the breakdown of the cartilage matrix. Liraglutide is a Glucagon-Like-Peptide 1 Receptor (GLP-1R) agonist widely prescribed for the treatment of type 2 diabetes. We have previously shown that intra-articular (IA) liraglutide exerts anti-inflammatory and anti-degradative effects1. In this study, liraglutide was assessed for its pro-chondrogenic properties.
Methods: IA injection of liraglutide or vehicle was performed 2 days after injection of monoiodoacetate (MIA) or saline in mice. RTqPCR analyses of knee joint was performed 10 days following saline or MIA injection. The capacity of liraglutide (10-500nM) to induce chondrogenesis was evaluated using human mesenchymal stem cells (hMSCs) and mouse embryonic fibroblasts (MEFs) high-density micromass in-well culture systems. Safranin O and/or alcian blue staining was used to assess differentiation into chondrocytes. Exendin 9-39, a GLP-1R antagonist, was used to confirm target specificity. A commercial differentiation medium and bone morphogenetic protein 2 (BMP-2) were used as positive controls for hMSC and MEFs models, respectively.
Results: Col2a1 gene expression was significantly increased in total knee joints from MIA-induced mice treated with 30µg of liraglutide compared to vehicle (At Day 11, Liraglutide= 1.96±1.34, vs vehicle= 0.64±0.46, p< 0.05, fold change related to saline treatment). Moreover, there was a significant induction of Sox9 gene expression in MIA mice treated with 30µg and 20µg of liraglutide (Fold 2.46±1.84; 2.08±1.36, respectively, p≤0.05) compared to vehicle (0.92±0.67). Using hMSC, after 21 days of treatment, liraglutide but not vehicle induced their differentiation into chondrogenic 3D spheroids (Liraglutide 10nM= 5 alcian-blue positive spheroids out of 6 counted wells, p< 0.05; Liraglutide 100nM= 4/6, p=0.06, vs vehicle= 0/6). 5/6 alcian-blue positive spheroids were also observed for the positive control. Both Liraglutide or BMP-2 induced MEFs to differentiate into chondrocytes as revealed by cytologic analysis using alcian blue and safranin O staining. Spectroscopic quantification (in arbitrary unit, AU) of the Safranin O stain in MEFs after 21 days of chondrogenic differentiation indicated a significant increase of absorbance for liraglutide 500nM (2.90±0.03 AU, p< 0.001) and BMP-2 (3.17±0.06, p< 0.001) vs vehicle (1.99±0.34). The use of exendin 9-39 confirmed that the effect of liraglutide on chondrogenesis was GLP-1R dependent in both in vitro models.
Conclusion: Liraglutide promotes chondrocyte differentiation, which could facilitate cartilage regeneration in OA, and thus represents a potential DMOAD treatment for knee OA.
- Berenbaum et al, Arthritis Rheumatol. 2019; 71 (s10).
To cite this abstract in AMA style:Berenbaum F, Meurot C, Sudre L, Bismuth K, Rattenbach R, Denefle P, Martin C, Jacques C. Liraglutide as a Potential Intra-Articular Treatment for Cartilage Regeneration in Osteoarthritis: In Vitro and In Vivo Studies Supporting a Pro-Chondrogenic Effect [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/liraglutide-as-a-potential-intra-articular-treatment-for-cartilage-regeneration-in-osteoarthritis-in-vitro-and-in-vivo-studies-supporting-a-pro-chondrogenic-effect/. Accessed November 28, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/liraglutide-as-a-potential-intra-articular-treatment-for-cartilage-regeneration-in-osteoarthritis-in-vitro-and-in-vivo-studies-supporting-a-pro-chondrogenic-effect/