Fig. 2.

GLP-1R signalling pathways in different cell types of the joint. Proposed models of intracellular network associated with activation of GLP-1R regulating chondrocytes (A), macrophages (B), osteoblast/osteoclasts (C) and adipocytes (D). GLP-1 or GLP-1 analogues bind to GLP-1R and activate adenylyl cyclase inducing cyclic AMP (cAMP) release, which principally activates (PKA/CREB) and ERK1/2 pathways. These pathways are available to stimulate the expression of several genes involved in protective or repair effects such as SOX9 or CREB. Other physiological effects mediated by GLP-1 include lipolysis, bone metabolism, or mitochondrial biogenesis. Moreover, in chondrocytes, cAMP can indirectly activate the PI3K/Akt signalling pathway. This pathway inhibits autophagy, apoptosis as well as inflammation, endoplasmic reticulum (ER) stress and catabolism via inhibition of NF-κB pathway. GLP-1 can also indirectly inhibit the NF-κB pathway by inhibiting levels of cytokines present in synovial fluid owing to the GLP-1 anti-inflammatory effect. This strong anti-inflammatory activity allows GLP-1 to promote a switch of macrophage phenotype from M1 pro-inflammatory to M2 anti-inflammatory. In adipocytes, the secretion of leptin is captured by the hypothalamus and the pituitary gland, which will induce the secretion of cortisol by the kidneys and allow for better management of adipogenesis. In bone cells, GLP-1 promotes the osteoblastogenesis process.