Advanced glycation end-products induced VEGF production and inflammatory responses in human synoviocytes via RAGE-NF-κB pathway activation

Abstract

Aging and diabetes are known to be the major cause to affect the progression of osteoarthritis (OA). Advanced glycation end products (AGEs) have been observed to accumulate in various organs especially in joint tissue and do damage to the joint tissue during aging and diabetes. Synovial angiogenesis and inflammation are observed across the full range of OA severity. The signaling pathway of AGEs on vascular endothelial growth factor (VEGF) production and inflammatory responses in synoviocytes are still unclear. Here, we investigated the role of receptor for AGEs (RAGE) and the signaling pathway involved in AGEs-induced VEGF production and inflammatory responses in human synoviocytes. Human synoviocytes were cultured and treated with AGEs(25-100 mg/ml). AGEs significantly induced the protein expressions of cyclooxygenase-2 (COX-2) and VEGF and the productions of prostaglandin-E2 (PGE2), VEGF, interleukin-6 (IL-6), and metalloproteinase-13 (MMP-13) in human synoviocytes in a dose-dependent manner. Moreover, AGEs markedly activated the phosphorylations of IkB kinase (IKK)a/b, IkBa, and nuclear factor (NF)-kB-p65 proteins in human synoviocytes in a time-dependent manner. Treatment with neutralizing antibody for RAGE statistically significantly decreased the AGEs-induced increase in COX-2, VEGF, PGE2, IL-6, and MMP13 and AGEs-activated NF-kB pathway activation. Taken together, these findings indicate that AGEs are capable of inducing VEGF production and inflammatory responses via RAGE-NF-kB pathway activation in human synoviocytes. ß

Synergistic alveolar bone resorption by diabetic advanced glycation end products and mechanical forces

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“…The activation of the AGE‐RAGE axis seems to be involved in the VEGF‐mediated synovial neoangiogenesis as well, as the administration of AGEs in vitro induced a dose‐dependent expression of VEGF, IL‐6, COX‐2, PGE 2 , and MMP‐13 via the NF‐κB in human synoviocytes . Indeed, an animal study involving a mouse model of intraarticular fracture and subsequent post‐traumatic OA showed a marked grade of synovitis and cartilage degradation due to RAGE activation, while knockout animals for the RAGE gene demonstrated a faster recovery from synovial inflammation and bone fracture, thus not leading to a frank OA …”

“…Indeed, metylglyoxal (MG) and free metylglyoxal-derived hydroimidazolone (MG-H1) levels in the F I G U R E 1 Hypothetical model depicting the role of hyperglycaemia in the development of OA synovial fluid were reported to be significantly correlated with OA, while levels of phosphatidylcholine acyl-alkyl (PC) C34:3 and C36:3, which have protective properties against AGE-mediated oxidative stress, were lower 52. The activation of the AGE-RAGE axis seems to be involved in the VEGF-mediated synovial neoangiogenesis as well, as the administration of AGEs in vitro induced a dose-dependent expression of VEGF, IL-6, COX-2, PGE 2 , and MMP-13 via the NF-κB in human synoviocytes 66. Indeed, an animal study involving a mouse model of intraarticular fracture and subsequent post-traumatic OA showed a marked grade of synovitis and cartilage degradation due to RAGE activation, while knockout animals for the RAGE gene demonstrated a faster recovery from synovial inflammation and bone fracture, thus not leading to a frank OA 67.…”