Targeting the GLP-1/GLP-1R axis to treat osteoarthritis: A new opportunity?

Osteoarthritis (OA) is a degenerative joint disease affecting millions of people worldwide. In OA, chondrocytes, synovial cells and other joint cells become activated when exposed to an abnormal environment, including mechanical stress, inflammatory cytokines or disorganization of matrix proteins. Several analogues of the hormones called incretins have been developed and are used notably for treating type 2 diabetes mellitus. Data has accumulated to suggest that incretinomimetics, which bind to the glucagon-like peptide-1 receptor (GLP-1R), have beneficial pleiotropic effects such as immunomodulation, anti-inflammation and neuronal protection. Thus, because of their anti-inflammatory properties, GLP-1-based therapies could benefit OA patients. This review focuses on the GLP-1R pathway, molecular mechanisms and phenotypes related to OA pathogenesis. The translational potential of this article: The search for new therapeutic targets to treat people suffering from OA remains urgent as there is currently no disease-modifyingtherapy available for this disease. This review discusses how GLP-1 analogues could be potential DMOADs for treating OA thanks to their anti-inflammatory, immunoregulatory and differentiation properties.

Liraglutide, a glucagon-like peptide 1 receptor agonist, exerts analgesic, anti-inflammatory and anti-degradative actions in osteoarthritis.

Osteoarthritis (OA) is a common disabling disease worldwide, with no effective and safe disease-modifying drugs (DMOAD) in the market. However, studies suggest that drugs, such as liraglutide, which possess strong potential in decreasing low-grade systemic inflammation may be effective in treating OA. Therefore, the aim of this study was to examine the anti-inflammatory, analgesic, and anti-degradative effects in OA using in vitro and in vivo experiments. The results showed that intra-articular injection of liraglutide alleviated pain-related behavior in in vivo sodium monoiodoacetate OA mouse model, which was probably driven by the GLP-1R-mediated anti-inflammatory activity of liraglutide. Moreover, liraglutide treatment significantly decreased IL-6, PGE2 and nitric oxide secretion, and the expression of inflammatory genes in vitro in chondrocytes and macrophages in a dose-dependent manner. Additionally, liraglutide shifted polarized macrophage phenotype in vitro from the pro-inflammatory M1 phenotype to the M2 anti-inflammatory phenotype. Furthermore, liraglutide exerted anti-catabolic activity by significantly decreasing the activities of metalloproteinases and aggrecanases, a family of catabolic enzymes involved in cartilage breakdown in vitro. Overall, the findings of this study showed that liraglutide ameliorated OA-associated pain, possess anti-inflammatory and analgesic properties, and could constitute a novel therapeutic candidate for OA treatment.

Neuregulin signaling regulates neural precursor growth and the generation of oligodendrocytes in vitro.

Neuregulin 1 (Nrg-1) isoforms have been shown to influence the emergence and growth of oligodendrocytes, the CNS myelin-forming cells. We have investigated how Nrg-1 signaling of ErbB receptors specifically controls the early stages of oligodendrocyte generation from multipotential neural precursors (NPs). We show here that embryonic striatal NPs express multiple Nrg-1 transcripts and proteins as well as their specific receptors, ErbB2 and ErbB4, but not ErbB3. The major isoform synthesized by striatal NPs is a transmembrane type III isoform called cysteine-rich domain Nrg-1. To examine the biological effect of Nrg-1, we added soluble ErbB3 (sErbB3) to growing neurospheres. This inhibitor of Nrg-1 bioactivity decreased mitosis of NPs and increased their apoptosis, resulting in a significant reduction in neurosphere size and number. When NPs were induced to migrate and differentiate by adhesion of neurospheres to the substratum, the level of type III isoforms detected by RT-PCR and Western blot decreased in parallel with a reduction in Nrg-1 fluorescence intensity in differentiating astrocytes, neurons, and oligodendrocytes. Pretreatment of growing neurospheres with sErbB3 induced a threefold increase in the proportion of oligodendrocytes generated from NPs migrating out of the neurosphere. This effect was not observed with an unrelated soluble receptor. Addition of sErbB3 during NP growth and differentiation enhanced oligodendrocyte maturation as shown by expression of galactocerebroside and myelin basic protein. We propose that both type III Nrg-1 signaling and soluble ErbB receptors modulate oligodendrocyte development from NPs.