Elevated Glucose Levels Preserve Glucose Uptake, Hyaluronan Production, and Low Glutamate Release Following Interleukin-1β Stimulation of Differentiated Chondrocytes

Abstract

Objective Chondrocytes are responsible for remodeling and maintaining the structural and functional integrity of the cartilage extracellular matrix. Because of the absence of a vascular supply, chondrocytes survive in a relatively hypoxic environment and thus have limited regenerative capacity during conditions of cellular stress associated with inflammation and matrix degradation, such as osteoarthritis (OA). Glucose is essential to sustain chondrocyte metabolism and is a precursor for key matrix components. In this study, we investigated the importance of glucose as a fuel source for matrix repair during inflammation as well as the effect of glucose on inflammatory mediators associated with osteoarthritis. Design To create an OA model, we used equine chondrocytes from 4 individual horses that were differentiated into cartilage pellets in vitro followed by interleukin-1β (IL-1β) stimulation for 72 hours. The cells were kept at either normoglycemic conditions (5 mM glucose) or supraphysiological glucose concentrations (25 mM glucose) during the stimulation with IL-1β. Results We found that elevated glucose levels preserve glucose uptake, hyaluronan synthesis, and matrix integrity, as well as induce anti-inflammatory actions by maintaining low expression of Toll-like receptor-4 and low secretion of glutamate. Conclusions Adequate supply of glucose to chondrocytes during conditions of inflammation and matrix degradation interrupts the detrimental inflammatory cycle and induces synthesis of hyaluronan, thereby promoting cartilage repair.

Anti-inflammatory effects induced by ultralow concentrations of bupivacaine in combination with ultralow concentrations of sildenafil (Viagra) and vitamin D3 on inflammatory reactive brain astrocytes

“…Restoration processes seem to have even better effects when cells are incubated in high-glucose conditions. High glucose has some anti-inflammatory effects [29,30]. In the present study, bupivacaine at extremely low concentrations in the presence of high glucose attenuated 5-HT-evoked intracellular Ca 2+ release in LPS-induced inflammatory astrocytes.…”

“…However, this triple combination showed effects on glutamate-evoked Ca 2+ signaling only. Sildenafil has anti-inflammatory effects at very low concentrations [27,29,30,40], and by testing the substance at different concentrations, we found that sildenafil attenuated ATP-evoked intracellular Ca 2+ release at low concentrations [28]. The combination of sildenafil and the above drugs particularly affects glutamate- and ATP-evoked Ca 2+ signaling [29].…”

“…We hypothesized that a combination of bupivacaine, sildenafil (both at ultralow concentrations), and vitamin D3 under high-glucose conditions exerts better anti-inflammatory properties than the individual substances. A high-glucose concentration might also have some anti-inflammatory properties [29,30].…”

The Importance and Control of Low-Grade Inflammation Due to Damage of Cellular Barrier Systems That May Lead to Systemic Inflammation

“…For this astrocytic metabolism, which consumes ATP, Na + /K + -ATPase activity is increased. Increased lactate release as a result of increased glucose uptake and glucose flux through the glycolytic pathway might contribute to anti-inflammatory cellular actions by inhibiting glutamate release (35). Glucose transport in low-grade inflammation and in autoimmune diseases is changed.…”

Role of Hyaluronan in Human Adipogenesis: Evidence from in-Vitro and in-Vivo Studies

“…HMW-HAs are further processed and broken down to low-molecular-weight (LMW)-HAs (<120 kDa). These smaller HA fragments have been proposed to play roles in many chronic diseases including diabetes, autoimmune diseases, inflammation and cancer [7,8,9,10]. Strategies to reduce LMW-HA production or action have therefore been undertaken in animal models and pre-clinical studies, including adoption of the Food and Drug Administration (FDA)-approved drug 4-MU, an inhibitor of HA biosynthesis [11,12,13,14].…”