Hyperglycemia-induced accumulation of advanced glycosylation end products in fibroblast-like synoviocytes promotes knee osteoarthritis

• Published in: Experimental & molecular medicine Vol. 53; no. 11; pp. 1735 - 1747
• Main Authors: Li, Qingxian, Wen, Yinxian, Wang, Linlong, Chen, Biao, Chen, Jun, Wang, Hui, Chen, Liaobin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2021; Springer Nature B.V; 생화학분자생물학회
• Subjects: 13/1; 13/51; 14/19; 38/77; 631/80/221; 631/80/304; Advanced glycosylation end products; Animals; Arthritis; Biomarkers; Biomedical and Life Sciences; Biomedicine; Blood glucose; Cartilage diseases; Cells, Cultured; Chondrocytes; Degeneration; Diabetes; Diabetes mellitus; Disease Models, Animal; Disease Susceptibility; Endoplasmic reticulum; Fibroblasts; Fibroblasts - metabolism; Gene Expression Regulation; Glucose; Glucose - metabolism; Glucose transporter; Glycation End Products, Advanced - metabolism; Glycosylation; Hyperglycemia; Hyperglycemia - complications; Hyperglycemia - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Immunohistochemistry; Immunophenotyping; Inflammation; Joint diseases; Knee; Medical Biochemistry; Molecular Medicine; Osteoarthritis; Osteoarthritis, Knee - etiology; Osteoarthritis, Knee - metabolism; Osteoarthritis, Knee - pathology; Protein transport; Rats; Severity of Illness Index; Stem Cells; Synovial Membrane - metabolism; Synovial Membrane - pathology; Synoviocytes; Synoviocytes - metabolism; Synoviocytes - pathology; Synovium; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-021-00697-6

Osteoarthritis (OA) is significantly associated with diabetes, but how hyperglycemia induces or aggravates OA has not been shown. The synovium plays a critical role in cartilage metabolism and substance exchange. Herein, we intended to investigate whether and how hyperglycemia affects the occurrence and progression of OA by influencing the synovium. In patients with knee OA and diabetes (DM OA), we found a more severe inflammatory response, higher endoplasmic reticulum stress (ERS) levels, and more advanced glycosylation end products (AGEs) accumulation in the synovium than in patients without diabetes. Subsequently, we found similar results in the DM OA group in a rat model. In the in vitro cocultivation system, high glucose-stimulated AGEs accumulation, ERS, and inflammation in rat fibroblast-like synoviocytes (FLSs), which resulted in chondrocyte degeneration due to inflammatory factors from FLSs. Furthermore, in the synovium of the DM OA group and FLSs treated with high glucose, the expression of glucose transporter 1 (GLUT1) and its regulatory factor hypoxia-inducible factor (HIF)-1α was increased significantly. Inhibitors of HIF-1α, GLUT1 or AGEs receptors attenuated the effect of high glucose on chondrocyte degradation in the FLS-chondrocyte coculture system. In summary, we demonstrated that hyperglycemia caused AGEs accumulation in FLSs via the HIF-1α-GLUT1 pathway, which increases the release of inflammatory factors from FLSs, subsequently inducing chondrocyte degradation and promoting OA progression. Osteoarthritis: clarifying the links to diabetes High blood sugar caused by diabetes can promote the progression of osteoarthritis (OA) by triggering joint-damaging inflammation. Although OA is known to be linked to diabetes, the mechanism was unclear. Liaobin Chen and Hui Wang at Wuhan University in China and coworkers investigated how high blood sugar affects OA progression in the synovium, the membrane surrounding the fluid-filled capsule inside the knee and other joints. The researchers found that the synovium was more inflamed in patients with diabetes and OA than in patients with OA alone. Investigation in a rat model showed that high blood sugar levels caused accumulation of sugar–protein complexes (AGEs) that trigger inflammation, and of a protein that transports sugar (GLUT1). Blocking GLUT1 in cultured cells decreased AGEs accumulation, flagging it as a potential target for developing treatments for knee OA.