Intracellular accumulation of advanced glycation end products induces apoptosis via endoplasmic reticulum stress in chondrocytes

Abstract

Mammalian cells attempt to maintain their homeostasis under endoplasmic reticulum (ER) stress. If the stress cannot be alleviated, cells are led to apoptosis through induction of C/EBP homologous protein (CHOP). ER stress is provoked in osteoarthritis chondrocytes, and intracellular accumulation of advanced glycation end products (AGEs) in chondrocytes is a possible cause. To clarify the role of intracellular AGE accumulation in chondrocytes, the present study investigated the effect of intracellular AGE accumulation on ER stress and apoptosis by in vitro and in vivo analysis. Intracellular AGE accumulation induced by AGE precursors caused apoptosis, induced expression of ER stress markers, and led to co-localization of AGEs with glucose-regulated protein 78, leading to formation of highmolecular-weight complexes in cultured chondrocytes. These reactions were inhibited by an AGE formation inhibitor. CHOP deletion inhibited apoptosis induced by intracellular AGE accumulation. In vivo intracellular AGE accumulation induced by intra-articular injection of AGE precursors caused ER stress and apoptosis in chondrocytes and led to degradation of articular cartilage. Additionally, intracellular AGE accumulation increased the degree of cartilage degradation in an osteoarthritis model. These data indicate that intracellular accumulation of AGEs induces modification of unfolded protein response-related protein by AGEs and apoptosis via ER stress in chondrocytes. Moreover, the in vivo study showed that intracellular AGE accumulation in chondrocytes is involved in the occurrence and progression of osteoarthritis through ER stress. Thus, research on mechanisms of apoptosis via ER stress induced by intracellular AGE accumulation in chondrocytes will lead to a new understanding of osteoarthritis pathology.

ER stress-induced cell death mechanisms

“…Glycated proteins function abnormally and have been reported to induce ER stress as evidenced by increasing levels of Grp78 and apoptosis in adipocytes treated with glycated serum albumin. In addition, the ER stress inhibitor taurine conjugated ursodeoxycholic acid (TUDCA), which acts as a chaperone that promotes the folding and trafficking of unfolded or malfolded proteins, prevents AGE-induced apoptosis [106]. Like glycated albumin, extracellular matrix is frequently modified by advanced glycation in the skin of diabetic patients.…”

Apoptosis signaling pathways in osteoarthritis and possible protective role of melatonin

“…In human chondrocytes, AGEs induce ER stress and stimulate the expression of COX‐2 and PGE2 through eIF2α, p38‐MAPK, and NFκB pathways . The intra‐articular injection of AGE precursor (glycolaldehyde) in the mouse knee joint induced intracellular AGE accumulation and expression of CHOP in chondrocytes and caused apoptosis, which led to degradation of articular cartilage …”

Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis

“…AGEs contribute to the degradation of type II collagen via the upregulation of matrix metalloproteinase-13 (MMP-13) [18], the induction of ER stress signaling [19,20,21], and initiation of inflammatory NF-κB and MAPK signaling [19,22]. Although AGE/RAGE activity in articular cartilage has been shown to increase with age, Larkin et al (2013) demonstrated that, following knee destabilization surgery, young RAGE-knockout mice were protected from developing OA [23].…”