Interleukin 1 beta-induced chloride currents are important in osteoarthritis onset: an in vitro study

Abstract

Persistent hypotonic and inflammatory conditions in the joint cavity can lead to the loss of cartilage matrix and cell death, which are the important mechanisms of osteoarthritis (OA) onset. Previous studies have confirmed that the existence of a hypotonic environment is a red flag for inflammation, as hypotonic environment induces the opening of the chloride channel of the cell and promotes chloride ion efflux, which prompts the cell volume to increase. Chloride channels play an important role in the regulation of mineralization and chondrocyte death. Here, we reported that OA chondrocytes showed a significant increase of cell death rate and the imbalance of cartilage matrix catabolism. We found that the distribution of skeleton protein F-actin was disordered. In addition, the volume-sensitive chloride current of OA chondrocytes decreased significantly with the increase of the expression levels of inflammation-related proteins caspase-1, caspase-3, and NLRP3. Moreover, interleukin-1β (IL-1β) showed a potential to activate the chloride current of normal chondrocytes. These results indicate that IL-1β-induced chloride channel opening in chondrocytes may be closely related to the occurrence of OA. This chloride channel opening process may therefore be a potential target for the treatment of OA.

The Homeostasis of Cartilage Matrix Remodeling and the Regulation of Volume-Sensitive Ion Channel

“…Many inflammatory factors such as interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α) upregulate the expression of MMP-13, which in turn triggers an increase in matrix catabolism, disrupts the balance between cartilage matrix synthesis and catabolism, and leads to cartilage degenerative diseases, such as OA. We recently confirmed that increased expression of COL I, decreased expression of COL II, a disordered cytoskeletal protein distribution, and loss of cell membrane integrity are important characteristics of OA, indicative of a decrease of anabolism of human OA chondrocytes [ 7 ]. We also confirmed that high expression of MAPK-14 may promote chondrocyte death [ 8 ].…”

Chloride Channel and Inflammation-Mediated Pathogenesis of Osteoarthritis

“… 32–35 Studies have shown that artificially reducing the osmotic pressure of the extracellular fluid induces cell swelling, which activates the release of caspase-1 and the inflammatory factor IL-1β through the NLRP3 inflammasome, and then triggers a series of cellular inflammatory reactions, and a large number of activated inflammatory factors will eventually lead to inflammatory cell death. 36 , 37 These pathophysiological processes are related to the abnormal increase in cell volume mediated by the abnormal activation of cell chloride ion channels. One previous study showed a functional deactivation and disordered distribution of LRRC8A chloride channels in OA chondrocytes, 37 which we believe may be a new and valuable research direction.…”

“… 36 , 37 These pathophysiological processes are related to the abnormal increase in cell volume mediated by the abnormal activation of cell chloride ion channels. One previous study showed a functional deactivation and disordered distribution of LRRC8A chloride channels in OA chondrocytes, 37 which we believe may be a new and valuable research direction.…”

“…Furthermore, IL-1β can induce the continuous opening of the chloride channel of healthy chondrocytes and damage the RVD mechanism of healthy chondrocytes, which participate in the pathogenesis of OA. 37 The above-mentioned inflammation-related proteins cause abnormal intracellular skeleton distribution and abnormal extracellular matrix metabolism in healthy chondrocytes, thus damaging healthy cells or even leading to cell death. 37 , 65 This further explains the mechanism of the aforementioned pathological processes in OA.…”

“… 37 The above-mentioned inflammation-related proteins cause abnormal intracellular skeleton distribution and abnormal extracellular matrix metabolism in healthy chondrocytes, thus damaging healthy cells or even leading to cell death. 37 , 65 This further explains the mechanism of the aforementioned pathological processes in OA. Chen et al studied epithelial cells and macrophages to show that vitamin A affects the expression of downstream Chloride Channel Accessory 1 (CLCA1) and other Ca 2+ -sensitive chloride channels by regulating the expression of IL-4, which may be related to subsequent inflammation.…”