Calcium chelator BAPTA‑AM protects against iron overload‑induced chondrocyte mitochondrial dysfunction and cartilage degeneration

Abstract

Osteoarthritis (OA) is a common joint disease that is characterized by cartilage degradation. Iron deposition in the joints is common during the pathogenic progression of OA and recent studies have indicated that iron overload is an important contributor to OA progression. calcium chelators have been reported to inhibit iron influx via modulating transferrin receptor protein 1 internalization, and they have been identified as a potential approach to the treatment of iron overload-induced diseases. The aim of the present study was to investigate the effect of calcium chelators on the progression of iron overload-induced OA. Primary chondrocytes were treated with various concentrations of ferric ammonium citrate (FAc) to mimic iron overload in vitro, followed by co-treatment with the calcium chelator BAPTA acetoxymethyl ester (BAPTA-AM). Subsequently, intracellular iron levels, cell viability, reactive oxygen species (ROS) levels, mitochondrial function and morphological changes, as well as MMP levels, were detected using commercial kits. It was demonstrated that FAC treatment significantly promoted chondrocyte apoptosis and the expression of MMPs, and these effects were reversed by co-treatment with BAPTA-AM. Moreover, BAPTA-AM suppressed iron influx into chondrocytes and inhibited iron overload-induced ROS production and mitochondrial dysfunction. These results indicated that calcium chelators may be of value in the treatment of iron metabolism-related diseases and iron overload-induced OA progression.

The Role Played by Ferroptosis in Osteoarthritis: Evidence Based on Iron Dyshomeostasis and Lipid Peroxidation

“…The iron chelator DFO [ 9 , 57 , 60 , 83 , 88 , 116 ] and the antioxidants Fer-1 [ 8 , 9 , 71 , 82 , 83 , 117 ] and CoQ10 [ 119 , 120 ] have shown significant anti-OA effects both in vitro and in vivo. This anti-OA effect has also been demonstrated in vitro by the calcium chelator BAPTA acetoxymethyl ester [ 86 ], the natural iron chelator lactoferrin [ 89 ], and the antioxidants NAC [ 101 , 116 ] and vitamin E [ 109 ]. An increasing number of agents, such as platelet-rich plasma [ 78 ], nifedipine [ 94 ], and icariin [ 97 ], have also been studied.…”

“…Furthermore, high doses of FAC increased labile iron and ROS levels, decreased COL2 production, disrupted the cell cycle, and increased the cell death rate compared with untreated controls. Jing et al [ 86 ] found increased intracellular iron and ROS levels and higher expression of MMP-3, MMP-13, and ADAMTS-5 in FAC-treated chondrocytes. Moreover, they detected mitochondrial dysfunction.…”

Interplay Between Iron Overload and Osteoarthritis: Clinical Significance and Cellular Mechanisms

“…Jing et al reported that the calcium chelator BAPTA-AM could decrease the extent of iron influx realized into chondrocytes. This helped inhibit iron overload-stimulated ROS accumulation and mitochondrial dysfunction (Jing et al, 2021b). In addition, D-mannose exerted a chondroprotective effect by attenuating the sensitivity of chondrocytes toward ferroptosis and alleviating OA progression.…”

“…Based on the theory that iron overload promotes OA by inducing ROS production and mitochondrial dysfunction, Han et al further revealed that the calcium chelator, BAPTA-AM, suppressed the influx of iron into chondrocytes and effectively restrained iron overload-mediated ROS accumulation and mitochondrial dysfunction. This suggested that calcium chelators played important roles during the treatment of iron metabolism-related OA (Jing et al, 2021b).…”

Enhanced sciatic nerve regeneration by relieving iron-overloading and organelle stress with the nanofibrous P(MMD-co-LA)/DFO conduits

“…Excess iron causes an increased production of reactive oxygen species leading to cell dysfunction or death, tissue damage and organ disease [ 9 ]. Iron overload has been shown to promote apoptosis of osteoblasts, chondrocytes, cardiomyocytes and liver cells by inducing endoplasmic reticulum (ER) stress or mitochondrial dysfunction [ [10] , [11] , [12] ]. However, the effect of iron overload on peripheral nerves is rarely studied.…”