<p>Activation of GPR40 Suppresses AGE-Induced Reduction of Type II Collagen and Aggrecan in Human SW1353 Chondrocytes</p>

Abstract

Introduction: Osteoarthritis (OA) is an age-related chronic degenerative disease. Accumulation of advanced glycation end products (AGEs) induces degradation of the articular extracellular matrix (ECM) and is considered a critical step toward the development and progression of OA. GPR40 is a well-known free fatty acid receptor, which possesses pleiotropic effects in different types of diseases. However, the biological function of GPR40 in OA is indistinct. The purpose of the present study was to determine the impact of the GPR40 agonist GW9508 on AGEs-treated chondrocytes. Materials and Methods: Cultures of human SW1353 chondrocytes were stimulated with GW9508, followed by exposure to 100 µg/mL AGEs. Gene and protein expression of TNF-α, IL-6, MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5 were measured by real-time PCR and ELISA analysis. The levels of type II collagen, aggrecan, and nuclear NF-κB p65 were measured by Western blot analysis. A luciferase assay measured the transcriptional activity of NF-κB. Results: The results show that treatment with AGEs decreased the expression of GPR40 in human SW1353 chondrocytes. Treatment with GW9508 plays a beneficial role in protecting type II Collagen and aggrecan from degeneration by attenuating the expression of MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5. Additionally, GW9508 reduces the appearance of proinflammatory cytokines and suppresses NF-κB activation in AGEs-induced chondrocytes. Notably, co-treatment with GW1100, a specific antagonist of GPR40, abolishes the beneficial role of GW9508 against AGEs, implying that GPR40 mediates these effects of GW9508. Conclusion: Our results suggest that GPR40 is a novel therapeutic target for OA and that GPR40 agonists, including GW9508, may have therapeutic potential in preventing and slowing the progression of OA.

Blood–Brain Barrier Disruption Mediated by FFA1 Receptor—Evidence Using Miniscope

“…To further demonstrate that the reduction in resistance was FFA1 dependent, RBMVEC grown on ECIS arrays were pretreated with the FFA1 antagonist GW1100 before the addition of AMG837. Pretreatment with GW100 (10 µM), in a concentration similar to that used in other studies [28,45,46], reduced the effect of AMG837 on RBMVEC resistance. RBMVEC resistance returned to basal levels within 24 h after treatment with AMG837.…”

G Protein-Coupled Receptors in Osteoarthritis

“…OA progression in the knee joint instability-induced OA model was aggravated in GPR40 -/mice, and GPR40 -/chondrocytes secreted more inflammatory mediators and decreased anabolism upon IL-1b treatment (77). In contrast, GW9508, a GPR40 agonist, blocked degeneration of type II collagen and aggrecan by attenuating the expression of matrix-degrading enzymes and pro-inflammatory cytokines in vitro (78). GPR120 -/mice displayed an accelerated progression of ACLT surgery-induced OA (79).…”

G Protein-Coupled Receptors in Osteoarthritis: A Novel Perspective on Pathogenesis and Treatment

“…However, the characteristics of induced OA were much more serious in GPR40-deficient models, suggesting that GPR40 activation could alleviate or slow the progression of OA. GW9508, the selective agonist of GPR40, could significantly downregulate the expression of MMP-3 and MMP-13 to inhibit the degradation of type II collagen against the stimulation of AGEs and suppress the activation of the NF-κB signaling pathway, showing a protective effect on OA ( Gu et al, 2020 ).…”